Original Win Zaw Maung Thesis

MATERNAL CAFFEINE CONSUMPTION AND
ADVERSE PREGNANCY OUTCOMES:

A SYSTEMATIC REVIEW AND META-ANALYSIS
A thesis submitted in partial fulfillment of the requirement for the

Degree of Master of Medical Science
(Disease Prevention and Control)
Defence Services Medical Academy, Yangon
WIN ZAW MAUNG

M.B., B.S.
Dip.Med.Sc. (Hospital Administration)
2022
CONTENTS
Pages
ACKNOWLEDGEMENTS i
ABSTRACT ii
LIST OF TABLES iv
LIST OF FIGURES vi
LIST OF ABBREVIATIONS viii
1. INTRODUCTION 1
1.1 Background Information 1

1.2 Problem Statement 3
1.3 Justification 4
1.4 Analytical Framework 5
2. LITERATURE REVIEW 6
2.1 Overview of Caffeine 6

2.2 Caffeine Contents in Different Types of Beverages 6
2.4 Pregnancy Outcomes 8
2.5 Previous findings of caffeine effect on pregnancy outcomes 10
3. RESEARCH QUESTION 11
4. AIM AND OBJECTIVES 12
4.1 Aim 12
4.2 Objectives 12
5. RESEARCH METHODOLOGY 13
5.1 Research Design 13

5.2 Process of Registration 13
5.3 Study Period 13
5.4 Eligibility Criteria 13
5.5 Information Sources and Search Strategy 16
5.6 Identification and Selection of Studies 18
5.7 Data Collection Process 19
5.8 Risk of Bias Assessment 19
5.9 Data Extraction 20
5.10 Data Synthesis and Analysis 20
5.11 Confidence in Cumulative Evidence 23
5.12 Reporting of the protocol and full review 23
5.13 Ethical Consideration 24
6. RESULTS 25
6.1 Summary of Selection Process 25

6.2 Characteristics of Included Studies 28
6.3 Risk of Bias Assessment 34
6.4 Qualitative Synthesis or Systematic Review 40
6.5 Meta-analysis or Quantitative Synthesis of Included Studies 52
6.6 Assessment of The Certainty of A Body of Evidence 72
7. DISCUSSION 77
7.1 Summary of Main Results 77

7.2 Potential Bias in Review Process 80
7.3 Overall Completeness and Applicability of Evidence 81
7.4 Certainty of The Evidence 81
7.5 Agreements and Disagreements with Other Reviews 82
7.6 Strengths and Limitations 83
8. CONCLUSION 86
9. RECOMMENDATIONS 87
10. REFERENCES 88
11. APPENDICES 99
Appendix 1: Administrative information 99

Appendix 2: Search Strategies 100
Appendix 3: JBI Critical Appraisal Checklists 104
Appendix 4: PRISMA (2020) Checklist 107
Appendix 5: PRISMA (2020) for Abstract Checklist 110
Appendix 6: Gantt Chart 112
ACKNOWLEDGEMENTS
My thesis could not be finished and would not take shape without the help and
encouragement of many nice people. Let me first of all express my gratitude for the
permission granted to me to undertake this research by Brigadier General Khin Aung
Htun, the Rector, and the board of studies of the Defence Services Medical Academy.
And then, I want to express my sincere gratitude to Colonel Kyaw Myo Tun, the
former head of the Department of Preventive and Social Medicine, for motivating us
to conduct such a thorough systematic review.
I owe a debt of gratitude to Major Tun Tun Win, the current head of the
Department of Preventive and Social Medicine, and who has given me permission to
carry out this study, for his critical guidance and meticulous oversight during the
study. I also want to express my gratitude to my supervisor, Major Linn Pyae who
performed as a third reviewer and the assistant lecturers from the department of
preventive and social medicine for their assistance, counsel, and technical assistance.
I want to express my gratitude to Captain Hpone Pji Kyaw, a colleague who
assisted me in finishing my job and acted as a second reviewer. Moreover, I would
want to thank my classmates for their support and encouragement in helping me finish
my study. Last but not least, I want to express my deep gratitude to my stunning wife,
who contributed to my professional success and gave me the ongoing encouragement
and drive to complete this thesis.
i
ABSTRACT
Coffee, tea, cola, and soft drinks are the main natural sources of caffeine,
which is also widely used as a psychoactive substance. Caffeine is quickly absorbed
after consumption, can easily cross the placental barrier, and can affect fetal growth
and development, but numerous studies on birth outcomes have produced conflicting
results. This systematic review and meta-analysis aimed to explore the risk of adverse
pregnancy outcomes and maternal caffeine consumption during pregnancy.
This review's protocol was documented in PROSPERO (ID was
CRD42022343813). Between August 2021 and January 2023, systematic searches in
only the English language were conducted in PubMed, Google Scholar, HINARI, and
Hand search. Studies had to provide information on links between caffeine
consumption and spontaneous abortion, small for gestational age, preterm delivery,
low birth weight, and stillbirth among low-risk pregnant women in order to be
included.
The original selection of 1225 articles resulted in the selection of 70 for
thorough review. The criteria for 25 of these research' inclusion were met. The JBI
Critical Appraisal tools were used to critically evaluate the included studies. A meta-
analysis was performed utilizing 21 included studies in Rev-Man software for adverse
pregnancy outcomes, such as miscarriage, small for gestational age, preterm delivery,
low birth weight, and stillbirth.
This review comprised 13 cohort studies, 6 case-control studies, and 6 cross-
sectional studies. Among them, 6 studies reported miscarriage, 12 studies for SGA, 10
articles for preterm delivery, 10 articles for low birth weight, and 3 publications for
stillbirth in a qualitative synthesis. The overall pooled effect size of maternal caffeine
consumption equal or more than 200 mg was associated with OR 1.54 [(95% CI 1.30,
1.81), I2 = 45%, p value = 0.16] for miscarriage, 1.43 [(95% CI 1.24, 1.65), I2 = 64%,
p value = 0.003] for small for gestational age, 1.19 [(95% CI 1.09, 1.29), I2 = 0%, p
value = 0.81] for preterm delivery, 1.58 [(95% CI 1.21, 2.06), I2 = 76%, p value =
0.0001] for low birth weight and 1.66 [(95% CI 0.90, 3.06), I2 = 60%, p value = 0.11]
for stillbirth. However, in stratified analysis compared to reference category or very
low caffeine level, the summary risk (OR) of miscarriage was 1.46 (95% CI 1.13,
1.88) for low caffeine level (100-299 mg) and 1.63 (95% CI 1.21, 2.20) for moderate
caffeine level (300-499 mg); the pooled effect (OR) of small for gestational age was
ii
1.21 (95% CI 1.09, 1.33) for low caffeine level (100-299 mg), 1.63 (95% CI 1.28,
2.06) for moderate caffeine level (300-499 mg) and 1.95 (95% CI 1.73, 2.21) for high
caffeine level (≥500 mg) but not significantly associated with level of exposure in
preterm delivery, low birth weight and stillbirth.
It can be conclude that maternal caffeine intake of equal or more than 200 mg
per day during pregnancy was significantly associated with risks for all adverse
pregnancy outcomes, with the exception of stillbirth in which there was no
statistically significant. Increasing levels of caffeine exposure increased the risks for
miscarriage and small for gestational age, but the risks for preterm delivery, low birth
weight, and stillbirth were unclear.
iii
LIST OF TABLES
Pages
Table 2.1 Caffeine contents in coffee 6
Table 2.2 Caffeine contents in tea 7
Table 2.3 Caffeine contents in sodas 7
Table 2.4 Caffeine contents in energy drinks 7
Table 5.1 Inclusion and exclusion criteria 16
Table 5.2 Preliminary keywords and converted terms 17
Table 6.1 Excluded studies 26
Table 6.2 Characteristics of Included Studies (Cross-sectional studies) (n=6) 29
Table 6.3 Characteristics of Included Studies (Case-control studies) (n=6) 30
Table 6.4 Characteristics of Included Studies (Cohort studies) (n=13) 31
Table 6.4 Characteristics of Included Studies (Cohort studies) (n=13) (Continued) 32
Table 6.4 Characteristics of Included Studies (Cohort studies) (n=13) (Continued) 33
Table 6.5 Overview risk of bias assessment in cohort studies 34
Table 6.6 Detail description of risk of bias in cohort studies 35
Table 6.7 Overview risk of bias assessment in case-control studies 36
Table 6.8 Detail description of risk of bias in case-control studies 37
Table 6.9 Overview risk of bias assessment in cross-sectional studies 38
Table 6.10 Detail description of risk of bias in cross-sectional studies 39
Table 6.11 Description of main outcomes on maternal caffeine in relation to
miscarriage 43
Table 6.12 Description of main outcomes on maternal caffeine in relation to small for
gestational age 44
gestational age (Continued) 45
gestational age (Continued) 46
Table 6.13 Description of main outcomes on maternal caffeine in relation to preterm
delivery 46
Table 6.13 Description of main outcomes on maternal caffeine in relation to preterm
delivery (Continued) 47
Table 6.14 Description of main outcomes on maternal caffeine in relation to low birth
iv
weight 48
Table 6.14 Description of main outcomes on maternal caffeine in relation to low birth
weight (Continued) 49
Table 6.15 Description of main outcomes on maternal caffeine in relation to
stillbirth 50
Table 6.16 Statistical models for miscarriage 54
Table 6.17 leave-one-out analysis for miscarriage 54
Table 6.18 Statistical models for small for gestational age 59
Table 6.19 Statistical models for preterm delivery 64
Table 6.20 Statistical models for low birth weight 69
Table 6.21 Statistical models for stillbirth 72
Table 6.22 Leave-one-out analysis for stillbirth 72
Table 6.23 Summary findings of certainty of evidence 74
Table 6.23 Summary findings of certainty of evidence (Continued) 75
Table 6.23 Summary findings of certainty of evidence (Continued) 76
v
LIST OF FIGURES
Pages
Figure 1.1 Analytical framework 5
Figure 6.1 Included Studies in Review 25
Figure 6.2 PRISMA Flow Diagram 27
Figure 6.3 Overall pooled effect of Miscarriage by caffeine exposure more than 200
mg 52
Figure 6.4 Estimated risk of miscarriage by level of caffeine exposure 53
Figure 6.5 Overall pooled effect of Small for gestational age of caffeine consumption
more than 200 mg 55
Figure 6.6 Subgroup analysis of estimated risk of Small for gestational age by study
designs 56
Figure 6.7 Estimated risk of Small for gestational age by level of caffeine exposure 57
Figure 6.8 Begg’s funnel plot for small for gestational age 58
Figure 6.9 Egger’s test for small for gestational age 58
Figure 6.10 Leave-one-out analysis for small for gestational age 59
Figure 6.11 Overall pooled effect of Preterm delivery of caffeine consumption more
than 200 mg 60
Figure 6.12 Subgroup analysis of estimated risk of Preterm delivery by study designs
61
Figure 6.13 Estimated risk of Preterm delivery by level of caffeine exposure 62
Figure 6.14 Begg’s funnel plot for preterm delivery 63
Figure 6.15 Egger’s test for preterm delivery 63
Figure 6.16 Leave-one-out analysis for preterm delivery 64
Figure 6.17 Overall pooled effect of Low birth weight of caffeine consumption more
than 200 mg 65
Figure 6.18 Subgroup analysis of estimated risk of Low birth weight by study designs
66
Figure 6.19 Estimated risk of Low birth weight by level of caffeine exposure 67
Figure 6.20 Begg’s funnel plot for low birth weight 68
Figure 6.21 Egger’s test for low birth weight 68
Figure 6.22 Leave-one-out analysis for low birth weight 69
Figure 6.23 Overall pooled effects of Stillbirth of caffeine consumption more than
vi
200 mg 70
Figure 6.24 Estimated risk of stillbirth by level of caffeine exposure 71
vii
LIST OF ABBREVIATIONS
ACOG - American College of Obstetricians and Gynecologists

CAT - Critically Appraised Topics
CBI - Coffee Business Intelligence
CI - Confident Interval
CRD - Central Registration Depository
CYP1A2 - Cytochrome P450 1A2 Enzyme
DEF - Data Extraction form
DHQ - Diet History Questionnaire
DSMA - Defence Services Medical Academy
EFSA - European Food Safety Authority
ET - Excess Tea
FFQ - Food Frequency Questionnaire
FGR - Fetal Growth Retardation
GRADE - Grading of Recommendations, Assessment, Development and
Evaluation
IBS - Irritable Bowel Syndrome
IUGR - Intrauterine Growth Restriction
JBI - Joanna Briggs Institute
LBW - Low Birth Weight
MCS - Mayo Clinic Staff
NA - Not Applicable
NCA - National Coffee Association
NCDT - National Coffee Data Trend
NHS - National Health Service
OR - Odds Ratio
PB - Preterm Birth
PRISMA - Preferred Reporting Items for Systematic reviews and
Meta-Analyses
PROSPERO - International prospective register of systematic reviews
Rev-Man - Review Manager Version 5.4
RR - Relative Risk
SB - Stillbirth
viii
SGA - Small for Gestational Age
STATA - Statistics and Data Science Version 17
UI - Uncertainty Interval
UK - United Kingdom
USA - United States of America
UT - Usual Tea
WHO - World Health Organization
ix
1. INTRODUCTION
1.1 Background Information

The main naturally occurring sources of caffeine are coffee, tea, cola, soft
drinks, and chocolate. Synthetic caffeine is also added to items to enhance their
stimulant effects. Health regulatory and authorities bodies of the caffeine
consumption association have been watching the overall potential effects of caffeine
on behavioral and physiological sciences more critically than they have been
watching the increased amounts of caffeine in food products or changes in caffeine
consumption patterns of the more traditional sources of products in recent years
(Maslova et al., 2010). According to data from Coffee Business Intelligence, around
$40 billion is spent by consumers on coffee each year. Overall, 54% of people drank
coffee every day, with people over 60 drinking the most coffee nearly 68% of them
did so every day. 37% of children between the ages of 13 and 18 drank coffee (CBI,
2018).
The risk of caffeine consumption among susceptible populations, including
children, adolescents, young adults, pregnant and breastfeeding women, and those
with underlying cardiac and other medical disorders, has recently come to the
attention of health and regulatory authorities (Temple et al., 2017). Moreover,
caffeine is easily absorbed after consumption and can impair fetal growth and
development by easily crossing the placental barrier (Arnaud et al., 1983).
Since caffeine effortlessly crosses the placental barrier from the mother to the
fetus, maternal caffeine intake during pregnancy directly affects fetal caffeine
exposure levels. The placenta and fetus lack cytochrome CYP1A2, the main enzyme
involved in the metabolism of caffeine. Caffeine intake during pregnancy raises
catecholamine levels in the blood, which may ultimately result in placental
vasoconstriction and hypoxia that impact fetal development and growth (Bakker et al.,
2010).
Studies conducted on animals hint at potential negative impacts on
reproductive results, including fetal growth (Wilcox et al., 1988). Several studies have
revealed that caffeine consumption during pregnancy may contribute to human
embryonic development retardation (Clausson et al., 2002) Consuming caffeine has
been linked to fetal development limitation, preterm birth, and abortion (Hoeven et
al., 2017). Higher maternal caffeine intakes were linked to unfavorable birth
outcomes, such as LBW, in three meta-analyses that focused on birth outcomes.
Several studies, including a recent overarching meta-analysis, suggest that maternal
caffeine use may have a deleterious effect on birth and, consequently, child health
outcomes (Vitti et al., 2018)..
2
1.2 Problem Statement
A major health issue, adverse birth outcomes include a number of pregnancy-
related and newborn-related health impacts. Age, antepartum hemorrhage, previous
abortion history, gestational age, anemia, and malnutrition in the mother have all been
associated with poor birth outcomes (Abadiga et al., 2022). Many beverages and
foods eaten while pregnant contain caffeine. The pharmacological effects of caffeine
point to potential risks to fetal development from maternal caffeine use (Bakker et al.,
2010).
Several observational studies on pregnant women who drink caffeine have
suggested an elevated risk for a variety of unfavorable pregnancy outcomes in recent
years. The strength of any relationship, as well as the potential for a threshold effects
have not been adequately defined. The effect of coffee, caffeine connected with the
pregnancy outcomes are diverse conclusions by numerous studies.
The current policy recommendation makes the assumption that "moderate"
caffeine consumption is safe during pregnancy (James, 2021). But it is still unclear
how caffeine and coffee affect the course of a pregnancy. Hence, the contradictory
findings in the literature may make it challenging for medical professionals to advise
expectant women on their coffee consumption habits.
3
1.3 Justification
Adverse birth outcomes are a significant health issue because they have a
number of negative pregnancy and baby health implications. The newborn baby who
has one or more birth abnormalities is more likely to die and experience various
health and infant development issues. So, a pregnant woman who experiences one of
the unfavorable pregnancy outcomes may have a greater emotional and financial
burden on the family. Due to caffeine's ability to quickly digest, absorb, and pass
through the placenta barrier to the fetus, causing feto-placental vasoconstriction and
delaying fetal growth, coffee use is one of the reasons of these unfavorable
consequences. Yet, it is unclear how much coffee is safe to consume while pregnant.
In Myanmar, many pregnant mothers drink coffee and tea while they are
pregnant, and as a developing nation, the rate of adverse pregnancy outcomes is still
high. Also, there are not many studies on the relationship between caffeine use during
pregnancy and the likelihood of difficulties in the Myanmar region, although there are
plenty of observational studies on the topic published in international publications.
Yet, different research revealed varying impacts of caffeine intake on birth outcomes,
making it difficult for medical professionals to provide reliable guidance on the
subject. Consequently, in order to provide more insightful knowledge regarding
caffeine consumption and risk of adverse pregnancy outcomes, more studies are
necessary to investigate the risks of adverse pregnancy outcomes owing to caffeine
exposure during pregnancy based on international evidence-based studies.
Meta-analyses and comprehensive literature evaluations are crucial
components of science. Systematic reviews determine whether scientific findings are
reliable and generalizable across populations, situations, and different types of
treatments, or whether they differ considerably by specific subgroups. In particular,
meta-analyses can improve the accuracy and power of estimates of treatment effects
and exposure hazards. In systematic reviews, clear approaches are employed to limit
bias and, idea, to increase the dependability and accuracy of results.
This review focused on as many linked factors to each outcome variable and
different caffeine exposure levels. Therefore, this review explored substantial proof of
a link between coffee consumption, caffeine intake, and birth outcomes. The finest
information of knowledge gaps (unclear facts) regarding caffeine consumption during
pregnancy was provided.
4
1.4 Analytical Framework
Pregnant women Pregnancy

Caffeine Outcomes
1. Coffee drinking (Low risk and
2. Tea apparently Healthy)
1. Miscarriage
2. Small for Gestational Age
Level of caffeine 3. Low birth weight
1. mg/day 4. Preterm delivery
2. cups/day 5. Stillbirth
Figure 1.1 Analytical framework
5
2. LITERATURE REVIEW
2.1 Overview of Caffeine

Caffeine is the most commonly consumed psychoactive stimulant in history
since intake is virtually unrestricted by age, gender, geography, or culture. Pregnant
women are consumers as well, with 82% of them reportedly consuming caffeine
every day in the United States (USA) and 91% in France (Hoyt et al., 2014). The
reports of pharmacologically active caffeine concentrations in the blood of the
majority of newborn infants in France and the United Kingdom (UK) support the
notion that caffeine is often ingested during pregnancy (James, 2021).
Pregnant women are advised by the American College of Obstetricians and
Gynecologists (ACOG) to safely consume up to 200mg of caffeine per day, which is
roughly equivalent to two cups of moderate-strength coffee. Similar to this, the UK
National Health Service (NHS) advises pregnant women to "limit" daily intake to
200mg, and the European Food Safety Authority (EFSA) states that maternal
consumption of caffeine up to 200mg per day "does not give rise to safety concerns
for the fetus" (James, 2021).
2.2 Caffeine Contents in Different Types of Beverages

A cup of coffee or tea may or may not contain any caffeine at all. The amount
of caffeine is influenced by things like preparation and brewing time. As a result, the
accompanying tables serve as a guide (MCS, 2022);
Table 2.1 Caffeine contents in coffee
Coffee drinks Size in oz. (mL) Caffeine (mg)
Brewed 8 (237) 96
Brewed, decaf 8 (237) 2
Espresso 1 (30) 64
Espresso, decaf 1 (30) 0
Instant 8 (237) 62
Instant, decaf 8 (237) 2
6
Table 2.2 Caffeine contents in tea
Teas Size in oz. (mL) Caffeine (mg)
Brewed black 8 (237) 47
Brewed black, decaf 8 (237) 2
Brewed green 8 (237) 28
Ready-to-drink, bottled 8 (237) 19
Table 2.3 Caffeine contents in sodas
Sodas Size in oz. (mL) Caffeine (mg)
Citrus (most brands) 8 (237) 0
Cola 8 (237) 22
Root beer (most brands) 8 (237) 0
Table 2.4 Caffeine contents in energy drinks
Energy drinks Size in oz. (mL) Caffeine (mg)
Energy drink 8 (237) 71.9
Energy shot 2 (60) 215
2.3 Coffee
Coffee is one of the most widely consumed beverages in the globe. Caffeine,
phenolic compounds, diterpenes, magnesium, trigonelline, quinides, lignans, and
other chemicals make up coffee's intricate chemical makeup (Farah, 2012). There are
many myths surrounding the discovery of coffee, but nobody is certain of the facts.
Coffea, the genus of plants that includes coffee, contains more than 500 genera and
6,000 species of tropical trees and shrubs. There are around 25 to 100 different
species of coffee plants worldwide (NCA, 2022b).
There are two significant species of coffee, among others. The primary variety,
Coffea Arabica, is grown in Ethiopia and accounts for roughly 70% of global coffee
7
production. The secondary variety, Coffea canephora, or Robusta, is grown in Brazil,
parts of Southeast Asia, including Indonesia and Vietnam, and Central and Western
Africa, and accounts for roughly 30% of global coffee sales. Moreover, Excelsa and
Liberica account for around 7% of global coffee consumption, with Liberica being
more frequent in the Philippines and Excelsa being a subtype of Liberica that can be
found across Southeast Asia (NCA, 2022b).
2.3.1 Health Benefits of Coffee
The highlights of scientific research and evidence of coffee’s unique health
benefits related to -
1. Longevity,
2. Cancer,
3. Diabetes,
4. Cardiovascular disease,
5. Stroke,
6. Liver and kidney health, and
7. Mental health (NCA, 2022a).
2.3.2 Drawbacks and Side Effects of Coffee
Coffee has certain drawbacks and side effects -
1. Caffeine, which is present in coffee, may increase blood pressure
2. Coffee may cause insomnia
3. Caffeine withdrawal causes unpleasant adverse effects like headaches
4. Coffee may worsen acid reflux and heartburn symptoms
5. Caffeine can cause anxiety and panic attacks
6. Coffee increases the risk of miscarriage in pregnancy
7. Coffee may contribute to IBS and other digestive problems
8. Some coffee drinks contain large amounts of sugar and hydrogenated oils
9. Some people are seriously allergic/ intolerant to coffee (NCA, 2022a).
2.4 Pregnancy Outcomes

The consequence of a fertilization event is a pregnancy. Adverse birth
outcomes include;
1. Miscarriage
2. Small for gestational age (SGA)
3. Preterm delivery, preterm birth (PB)
8
4. Low birth weight (LBW)
5. Stillbirth (SB) (Boylan et al., 2008).
2.4.1 Miscarriage
The term "miscarriage" refers to the loss of a pregnancy before viability.
Worldwide, there are thought to be 23 million miscarriages annually or 44 pregnancy
losses every minute. For all confirmed pregnancies, the combined risk of miscarriage
was 15.3% (95% CI 12.5–18.7%). One miscarriage occurred in 10.8% of the
population (95% CI = 10.3 to 11.4%), two occurred in 1.9% (95% CI = 1.8 to 2.1%),
and three or more occurred in 0.7% (95% CI = 0.5 to 0.8%) of the population
(Quenby et al., 2021).
2.4.2 Small for gestational age (SGA)
For determining the projected weight for the child's gestational age, the
threshold for being considered tiny for gestational age is set at less than the 10th
centile of a reference population for fetal growth (SGA). According to an estimate of
SGA in 2010, 27% of all live births or 32.4 million babies were born SGA in low- and
middle-income nations (Embleton et al., 2015).
2.4.3 Preterm birth (PB)
A live birth before the 37th week of pregnancy is considered a preterm birth.
A global PB rate of about 11% is indicated by the estimated 15 million preterm births
each year (Walani, 2020).
2.4.4 Low birth weight (LBW)
The World Health Organization (WHO) defines low birth weight as weighing
less than 2500 g at birth (5.5lb). LBW is still a major global public health issue, and it
has a variety of short- and long-term repercussions. In all, 15% to 20% of births
worldwide, or more than 20 million birth years, are thought to be LBW (WHO, 2015).
2.4.5 Stillbirth (SB)
The term "stillbirth" refers to the loss or death of a child before or during
delivery after 20 weeks of pregnancy. Worldwide in 2019, there were an estimated 2.0
million stillbirths at 28 weeks or more gestation (90% uncertainty interval [UI] = 1.9
to 2.2), resulting in a SB rate of 13.9 stillbirths (90% UI = 13.5 to 15.4) per 1,000 live
births (Hug et al., 2021).
9
2.5 Previous findings of caffeine effect on pregnancy outcomes
Smaller femur lengths in the second and third trimesters as well as shorter
first-trimester and birth lengths were linked to higher coffee use (p value < 0.05).
Small-for-gestational-age newborns are more likely to be born to offspring of moms
who ingested more than or equal six caffeine units per day (Bakker et al., 2010).
Adding 100 g of caffeine increased the incidence of spontaneous abortion by 14%
(95% CI = 10 to 19%), SB by 19% (95% CI = 5 to 35%), PB by 2% (95% CI = 2 to
6%), LBW by 7% (95% CI = 1 to 12%), and spontaneous abortion by 10% (95% CI =
6 to 14%) (Thatcher et al., 2014).
The overall risk ratio (RR) for fetal outcomes per 100 mg/day was 1.07 (95%
CI = 1.03 to 1.12). This can also be written as 1.23 (95% CI = 1.09 to 1.39) per 300
mg/day increment or 1.42 (95% CI = 1.6 to 1.74) per 500 mg/day increment of
maternal caffeine intake to enable comparability with the categorical analysis (Chen
et al., 2015). A higher gestational age was significantly linked with daily caffeine
intake of more than 300 mg compared to less than 100 mg (linear regression
coefficient = 2.00 days (95% CI = 0.12 to 4.21, p value = 0.03) (Hoeven et al., 2017).
The highest caffeine intake categories from coffee consumption during
pregnancy were [ORLBW: 3.10 (95% CI = 1.08 to 8.89), ORPB: 2.74 (95% CI = 1.05 to
7.16)] and were associated with greater odds of adverse pregnancy outcomes. As
compared to the lowest intake groups with all p values < 0.05, the ORLBW was 2.47
(95% CI = 1.02 to 6.01), and the ORPB was 2.56 (95% CI = 1.14 to 5.75) for tea
consumption (Vitti et al., 2018).
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3. RESEARCH QUESTION
What are the risks of adverse pregnancy outcomes due to maternal caffeine
consumption?
11
4. AIM AND OBJECTIVES
4.1 Aim
To study the risks of adverse pregnancy outcomes due to maternal caffeine
consumption
4.2 Objectives
1. To calculate the pooled estimated risks of adverse pregnancy outcomes
related to maternal caffeine consumption
2. To find out the pooled estimated risks of adverse pregnancy outcomes
according to study design
3. To find out the pooled estimated risks of adverse pregnancy outcomes
according to level of caffeine
12
5. RESEARCH METHODOLOGY
5.1 Research Design

The research design was a systematic review and meta-analysis especially
focused on the risk or etiological or review, (PEO) frame – Population (P), Exposure
(E) and Outcome (O). This review answered the formulated research question, “What
are the risks of adverse pregnancy outcomes due to maternal caffeine consumption.”
5.2 Process of Registration

The registrations of only systematic reviews with the outcome connected to
health were discovered in the international database of prospectively registered
systematic reviews in health and social care (PROSPERO). As a result of registering
our methodology for systematic reviews, bias in the execution and reporting of the
review as well as unintentional repetition will be avoided, and transparency will also
be improved. By doing so, prospective registration made it possible for researchers to
adhere to PRISMA's preferred reporting items for systematic reviews and meta-
analyses while also creating a permanent record of the intended method.
The researchers' decision to publicize the findings was also motivated in part
by the registration process. It took less than an hour to complete the registration
procedure in PROSPERO, which was quite simple and only required the filling out of
22 data items and the details of 18 more fields (Booth et al., 2012). The registration
process was performed on 3rd July 2022, and then the protocol of the review was
submitted for publication and assessed by the PROSPERO editorial team and the ID
for registration, CRD42022343813, was provided on 13rd July 2022 after approval.
5.3 Study Period

This study was started in August 2022 and completed in March 2023.
5.4 Eligibility Criteria

The studies that were selected for a systematic review to answer the research
question were included and excluded based on the eligibility criteria definition. The
PEO framework's research title was taken into consideration when creating the
inclusion and exclusion criteria.
In this review, eligibility criteria were planned by –
13
1. Eligible study types/designs
2. Eligible population
3. Eligible exposure
4. Eligible outcomes
5. Eligible language and publication to be included in the review.
All studies that met the eligibility criteria in a satisfactory manner were
reviewed during both the searching and screening phases. Study design and language,
however, were not used as domains in the search algorithms; instead, they were used
as screening criteria to omit research. Bias in the selection process was prevented by
adherence to the proper eligibility criteria for the systematic review's search
mechanism. Moreover, predetermined eligibility standards set the systematic review
apart from a narrative review (Higgins et al., 2019).
5.4.1 Eligible Study Types/Designs
It was occasionally difficult to decide which studies to include in a systematic
review because the study design in particular had a significant impact on getting
accurate responses to a quantitative research issue. Also, establishing the labels of the
study designs was occasionally ambiguous and raises questions about potential bias.
More heterogeneity is anticipated. The variety of study designs included in the
evaluation were intended to provide thorough and synergistic conclusions for the
specified research question (Higgins et al., 2019).
All primary studies, such as published quantitative studies that examine
maternal caffeine consumption and pregnancy outcome risks, were considered to be
eligible studies for this study. This review also included peer-reviewed journals. This
study did not include systematic reviews, editorial reviews, narrative reviews,
government and organization recommendations, patents, or books. Observational
studies such as cohort, case-control, and cross-sectional studies, were included in the
review.
5.4.2 Eligible Population
It was crucial to make sure the systematic reviews could be replicated in order
to use them in practice. Transparency of the reviewing methods and process was
essential for achieving the review's replicable goal (Shokraneh & Adams, 2019). The
research conducted on the risk groups of pregnant women were determined to be the
exclusion criteria since these groups may be a confounding variable. In this study, low
14
risk and seemingly healthy pregnant women who used caffeine everyday were
identified as the inclusion criterion for eligibility.
5.4.3 Eligible Exposure
Coffee use is widespread among individuals of all ages, but due to the high
levels of caffeine consumed by pregnant women, it is a major contributor to
unfavorable pregnancy outcomes. Coffee drinking during pregnancy has been linked
to pregnancy problems, according to earlier study. The study's eligible exposure was
consuming caffeine-containing beverages, particularly coffee, with the measurement
of exposure being the amount of caffeine consumed in mg or cups daily.
5.4.4 Eligible Outcomes
Using synonyms described in the search method, the findings of this review
covered the adverse pregnancy outcomes, particularly miscarriage, small for
gestational age, preterm delivery, low birth weight, and stillbirth. Several types of
pregnancy outcomes were also excluded from this review along with any potential
risk variables that might have an impact on these outcomes.
5.4.5 Eligible Language and Publication
All primary studies published in English were classified under inclusion
criteria for this review despite the Cochrane handbook for systematic reviews'
warning about the risk of selection bias due to the review team's members' lack of
experience or training in conducting systematic reviews of the studies written in
languages other than English. In order to prevent translation bias and ensure that the
review team performed each step of the systematic review procedure on every eligible
article accurately, only papers that had been published in English were considered for
this study.
Also, fully available published articles were included in the review because
there are some expectations for quality assurance in published studies compared to
unpublished ones. Since one of the inclusive criteria was full access to published
studies, there may be some studies for which full access to articles was not possible.
In such a case, corresponding authors of potentially eligible studies were asked to
provide full access to articles via email and the request was recorded under "Studies
awaiting classification" if necessary. In order to achieve the primary goal of the
research question, this review was conducted using inclusion and exclusion criteria.
15
5.4.6 Summary of Inclusion and Exclusion Criteria
Eligible criteria for this review, consisting of inclusion and exclusion criteria,
were summarized in Table (5.1).
Table 5.5 Inclusion and exclusion criteria
Inclusion Criteria Exclusion Criteria
1. Systematic reviews, editorial reviews,
1. All primary research studies
narrative reviews, Government and
conducted by analytical observational
organization guidelines, patents and
study designs
books
2. Full text published, peer reviewed 2. Duplicated publications and the
studies and thesis and dissertations in insufficient data for pooling after contact
grey literatures with the author
3. High quality papers determined by
3. Other languages except English
review team
4. Assessment on caffeine exposure 4. Studies done on caffeine containing
especially from coffee and tea drugs and other than coffee or tea
5. All studies done on adverse 5. Papers that focused on neonatal or birth
pregnancy outcomes and included at outcomes such as neonatal morbidity and
least one of these outcomes infant death
6. Population of the studies was low risk
6. Studies done on high risk groups of
pregnant women and apparently healthy
pregnant women and comorbidity mother
gestational mother
5.5 Information Sources and Search Strategy

The databases MEDLINE via PubMed, Google Scholar, HINARI via
Research4life, and Hand search were investigated as the main information sources for
searching appropriate articles. Manual searches were conducted on the reference lists
of the included studies. The review would only include English-language articles that
were full-text accessible. Before doing final analyses, the search technique was
redone, and any additional studies found were added to this review.
16
5.5.1 Information Sources
The primary information sources of database for searching eligible articles
were MEDLINE via PubMed, Google Scholar, HINARI via Research4life and Hand
search. The web links of these databases were as followed –
1. MEDLINE via PUBMED – https://pubmed.ncbi.nlm.nih.gov/
2. Google Scholar – https://scholar.google.com.tw/
3. HINARI via Research4life – https://portal.research4life.org/
4. Hand search via local libraries and citation or reference
5.5.2 Search Strategy
To make sure the search was thorough enough to turn up all possibly
acceptable studies, keywords and search items were used in this review. The PEO
framework's domains, which were specified in the research question, were where the
key search terms were taken from. Together with the primary keywords, additional
search terms such as synonyms, related ideas, different spellings, and specialized
terms were also found. The list of preliminary keywords and converted terms that
were discovered for the search process is shown in Table (5.2).
Table 5.6 Preliminary keywords and converted terms
Search terms
Domains Preliminar
Converted terms/keywords
y
Populatio “Pregnant
“pregnancy” OR “gestation” OR “pregnant mother”
n (P) women”
Exposure
“Caffeine” “coffee” OR “caffeine” OR “tea”
(E)
“pregnancy complications” OR “birth outcomes” OR
“miscarriage” OR “abortion” OR “small for
Outcome “Pregnancy
gestational age” OR “preterm birth” OR “preterm
(O) outcomes”
delivery” OR “stillbirths” OR “fetal death” OR “low
birth weight” OR “birth weight”
In this evaluation, two independent reviewers, (WZM and HPK) developed a

search strategy for each database and chose the identified studies. The two reviewers
first attempted to generate the pertinent search terms/keywords and converted
17
synonyms and interchangeable meanings based on the PEO framework in order to
develop a search strategy. After gathering the search phrases, reviewers properly
constructed the search strategy by integrating these search terms for each database.
In order to find the appropriate articles for the review process and provide a
solution to the predetermined research topic, Boolean operators (OR, AND, NOT)
were used. Throughout the search process, the Boolean operators (OR) and (AND)
were employed, and (NOT) was not advised because it might result in the unintended
exclusion of relevant papers (Muka et al., 2020).
Reviewers independently examined the articles with finalized search
techniques and search terms in various databases after modifying the search keywords
and conducting pilot testing. Prior to doing final analysis, searches were again
conducted, and newly discovered papers were evaluated for eligibility. Each
database's specific search tactics were detailed in the appendix section (Appendix 2).
5.6 Identification and Selection of Studies

The two reviewers independently chose the suitable articles for consideration.
In the event that the selection of this review showed any instances of eligibility
debate, these issues were resolved by consensus or by consultation with a third
reviewer, supervisor, (LP).
Zotero referencing software Version 6.0 was used in this review, and data was
recorded in Microsoft Office Excel spreadsheets. First, all studies gathered from
various databases were added to referencing using Zotero software for the selection of
the articles. Duplicate articles were removed, and once the final selection of articles
was made, they were converted in Zotero into RIS format and imported into the JBI
SUMARI for reading of the title and abstract with the predefined eligibility criteria. In
Excel, duplicate and irrelevant articles were manually screened, and the results were
documented in an exclusion log along with the reasons for exclusion.
In the second phase, two independent reviewers evaluated the entire texts of
publications that had passed the title and abstract screening but were still pertinent. In
order to determine which publications were included for data extraction and synthesis,
two reviewers attempted to retrieve full-text versions of those that were available
from databases and read independently based on established criteria. If there was a
chance that one of the two reviewers might miss a study or classify it incorrectly,
18
reducing the amount of internal or external validation, the differences were settled by
consensus-building or by consulting the third reviewer.
5.7 Data Collection Process

Under the guidance of a third reviewer, two independent reviewers chose and
revised the papers that were submitted. Any differences between the opinions of the
two viewers were compared, and the reviewers promptly discussed them with the
supervisor to reach an agreement. Independent analysis was used to review the full-
text papers. The Zotero software was used to carry out the data collection technique.
The reporting of the identification and screening process followed the PRISMA flow
diagram.
5.8 Risk of Bias Assessment

All studies that would have satisfied the given inclusion criteria and been
chosen for inclusion in the systematic review went on to undergo a thorough
evaluation by two critical appraisers. The synthesis and interpretation of the study's
findings were influenced by the appraisal's findings. JBI Critical Appraisal Tools
were created by the JBI and collaborators, and after thorough peer review, were
authorized by the JBI Scientific Committee. JBI critical appraisal tools were utilized
while developing Critically Appraised Topics (CAT), in journal clubs, and as teaching
resources even though they were created for systematic review (Moola et al., 2017).
The risk of bias in the included studies was independently evaluated by two
reviewers using JBI critical appraisal techniques. A basic understanding was reached
to settle disagreements between the two reviewers. Each component of the appraisal
tool for each study they reviewed both the primary and secondary reviews was
covered. What is deemed acceptable to the review's objectives in terms of the
particular study features was discussed and modified.
To assign a positive evaluation as compared to a negative or a response of
"unclear," the reviewers must be certain of the acceptable amounts of information. To
help in the evaluation of systematic reviews or meta-analyses, there are 11 questions
for cohort studies, 10 questions for case-control studies, and 8 questions for cross-
sectional analytical research. Each question received a "Yes," "No," or "Unclear"
response. There was also a "NA" for not applicable.
19
The answer rates were scored 0 for "Not reported" or "Unclear" and 1 for
"YES," therefore the ranges for cohort studies, case-control studies, and cross-
sectional analytical studies were 0 to 11, 0 to 10, and 0 to 8, respectively. The quality
scores were then converted into percentages in accordance with JBI criteria and
classified as having a "High risk of bias" if they were less than 50%, a "Medium risk
of bias" if they were between 50% and 75%, and a "Low risk of bias" if they were
more than 75%. Only high qualified studies and those with medium qualifications
(satisfying 50% of the quality assessment parameter) were included in the qualitative
and quantitative analysis. The appendix section contained attachments for each
appraisal tool (Appendix 3).
5.9 Data Extraction

To eliminate data entry errors, data from each study was collected by two
independent reviewers, who then entered the data independently into each excel
spreadsheet. Any discrepancies between two reviewers were resolved by consensus
and the advice of a third expert. The data extraction process was carried out by these
two reviewers in parallel with separate validity checks. The designed data extraction
form was used to extract and document the general characteristics of the studies and
data for analysis (DEF). The Data extraction form in Excel spreadsheet included the
following information –
1. Study (Author/year)
2. Country
3. Age group
4. Setting/Context
5. Study period
6. Exposure (Types/Dosages)
7. Outcomes measured
8. Description of main results (+follow-up duration in cohort studies).
According to data availability, re-modifying or justifying of DEF was also
performed. The predesigned data extraction form was described in the dummy tables
section.
5.10 Data Synthesis and Analysis
20
The use of Excel spreadsheets, STATA version 17, and Review Manager
Version 5.4 was used for analysis and data display. Data preparation and synthesis
were done in MS Excel Version 2019, forest plot and sensitivity analysis were done in
Review Manager, publication bias, Begg's funnel plot, and Egger's test were done in
STATA.
5.10.1 Preparation for Data Synthesis
Two reviewers independently tabulated and collected the study parameters,
such as design, sample size, population, exposure, and outcome, using a standardized
data extraction form to evaluate the consistency between studies. Based on the study
design and exposure level, data extraction for each outcome was carried out in an
Excel sheet.
5.10.2 Statistical Analysis
A fixed or random effect model was used after heterogeneity was evaluated in
order to get the pooled effect size. Several publications in this review used varied
effect sizes, including multivariable-adjusted OR, relative risks (RR), and hazard
ratios. The odds ratio (OR) was used as a measure of risk estimates in the meta-
analysis because many studies described the adjusted odds ratio (OR), and since the
outcome only occurred in less than 10% of the population who were not exposed, it
was reasonable to assume that the odds ratio (OR) was roughly similar to the risk ratio
(RR) (Viera, 2008).
The cut-off points for the various categories of caffeine intake differed
between studies. The median value for each category of caffeine intake was assigned
in order to aggregate the risk estimations from several categories in various research.
The middle point represented an estimate of the category's median caffeine intake
when the category's lower and upper boundaries were given. It was assumed that the
border had the same amplitude as the second-highest category if the upper boundary
of the highest category wasn't given. The lower border was to be zero if the lowest
category's lower boundary was not specified (Chen et al., 2015). A total of 100 mg of
caffeine was predicted to be consumed in one cup of coffee based on primary research
that reported coffee consumption in cups per day (Bech et al., 2015; Wisborg, 2003).
First, the cutoff point level of exposure status was considered to be less than
200 mg of caffeine intake as the reference value (safe caffeine level in pregnancy),
and equal to or higher than 200 mg as the exposure group, in order to determine the
pooled analysis and subgroup analysis for each outcome (Thatcher et al., 2014).
21
Second, four levels of caffeine consumption were classified for the stratified analysis
of exposure level based on the assigned median level: (i) reference category (< 100
mg/d); (ii) low caffeine consumption (100-299 mg/d); (iii) moderate caffeine
consumption (300-499 mg/d); and (iv) high caffeine consumption (500 mg/d). The
random-effects model or fixed effect model was used to integrate the effect estimates
from the various studies, depending on the statistical heterogeneity among the studies,
which was assessed using the Cochran Q test and I2 statistics.
5.10.3 Assessment for Heterogeneity
The assessment of impact estimates in the forest plot, Cochran Chi-square test,
and I2 statistics were used in this review to examine the hypothesis of homogeneity or
heterogeneity amongst included studies. The Chi-Square test's significant threshold
for determining the degree of inter-study consistency was established at a p value of
0.10 (Higgins et al., 2019).
Following thresholds for interpreting the 𝐼² statistics were considered as:
a. 0% to 40%: not important
b. 30% to 60%: moderate heterogeneity
c. 50% to 90%: substantial heterogeneity
d. 75% to 100%: considerable heterogeneity.
Heterogeneity in this review was considered as significant if p value < 0.10
and 𝐼² > 50%. Source of heterogeneity (if present) was presented by subgroup
analysis.
5.10.4 Analysis of Subgroups
To determine where the heterogeneity originated, subgroup analysis was used.
Study design, population, and exposure were three potential sources of heterogeneity
that were investigated through subgroup analysis in order to pinpoint the source of
heterogeneity across the studies. Each subgroup was then analyzed with the same
significance level and reference degree of heterogeneity established above. Subgroup
analysis was done in this review using study design and various level of caffeine
consumption.
5.10.5 Assessment for Publication Bias
To minimize the effect modification of the pool estimate by publication bias in
this review and to discover potential small study effects, the evaluation was conducted
using a funnel plot and Egger's test. Secondly, in order to gather as many eligible
studies as possible, the included papers were carefully chosen throughout the search
22
process. Also, a Begg's funnel plot was created and graphically displayed, comparing
the effect estimated on the X-axis to its standard error on the Y-axis. Potential
publication bias was indicated by the funnel plot's asymmetry and the exclusion of
95% of the studies from the pseudo-confidence interval lines. The confirmation of
publication bias was next tested using Egger's regression test at a substantial level (p
value = 0.1). Moreover, the Egger's regression intercept and associated p value were
described together in the funnel plot.
5.10.6 Sensitivity Analysis
The strength of the review was assessed using sensitivity analysis utilizing the
leave-one-out approach, which looked at how any particular study and statistical
model using the random or fixed effect method influenced the pool effect estimate.
Tabular and graphical presentations were used to describe the results.
5.11 Confidence in Cumulative Evidence

Grading of Recommendations, Assessment, Development, and Evaluation
(GRADE) was used to determine the overall strength of the body of evidence. The
study design constraints (risk of bias), inconsistent results, indirectness of the
evidence, imprecision, and publication bias were among the issues that affected the
review's quality of the evidence (Guyatt et al., 2008). These are the four levels of
evidence quality:
High Grade - There have a high level of certainty that the real effect is about
in line with the effect estimate.
Moderate Grade - There have a moderate level of confidence in the effect
estimate; the actual effect is probably going to be somewhat similar to the estimate,
but it's also possible that it will be much different.
Low Grade - There have little faith in the effect estimate since the actual
effect can differ significantly from the estimate.
Very Low Grade - The confidence in the effect estimate is quite low because
the genuine effect is probably going to differ greatly from the effect estimate.
Grading of Recommendations, Assessment, Development, and Evaluation
(GRADE) was used to gauge the overall strength of the body of evidence.
5.12 Reporting of the protocol and full review
All systematic reviews and meta-analyses conducted in the context of
secondary literature analysis should be published in accordance with PRISMA
23
standards. As a result, the PRISMA 2020 checklist for reporting systematic reviews
was also followed while reporting this review as shown in Appendix (4).
5.13 Ethical Consideration

A full ethical form for a systematic review proposal was submitted, and the
Academic Postgraduate Board of Studies, DSMA, granted ethical clearance and
permission after taking into account any potential ethical issues from each of the
primary research that was part of the review. The reviewers did not purposefully
misinterpret the results of the publications they looked at, and they were given a
summary of the information they had found in order to reach a valid, truthful, and
open conclusion.
24
6. RESULTS
6.1 Summary of Selection Process

The two reviewers independently searched the articles (n=1225) from different
databases using search terms and removed the duplicated papers (n=27) in referencing
software, Zotero. After that, the searched articles (n=1198) were changed RIS format
to enroll in JBI summari for screening process. The two reviewers also independently
performed the title and abstract screening for retrieval of full text screening. The
included studies (n=70) in full text screening were checked for availability of full text
(unavailable full text (n=10), which were contacted to corresponding authors via
emails and waited before final analysis) and then all the full text articles (n=42) were
reviewed independently by two reviewers based on eligibility criteria. Finally, the two
reviewers selected the eligible papers for review (n=25) and analysis (n=21). The
detail of selection process was showed in following as PRISMA flow diagram in
Figure (6.2).
6.1.1 Included studies
There were 25 included studies in this review -
Cohort studies (n=13)
Case-control studies
Included studies (n=25)
(n=6)
Cross-sectional studies
(n=6)
Figure 6.2 Included Studies in Review
25
6.1.2 Excluded studies
Table 6.7 Excluded studies
Numbers
No. Reasons Studies
(n=49)
1 Same studies/ (Armstrong et al., 2008; S. Boylan et al., 2009; 18
duplications CARE Study Group, 2009, 2010; Fenster et al.,
1990; Guth, 2008; Infante-Rivard, 1993;
Nisenblat & Norman, 2009; Parazzini et al.,
2005a; Sindiani et al., 2020a; Srisuphan, 1983,
1984; Taslimi & Herrick, 1986; Weng et al.,
2008a; Wierzejska et al., 2011; Wisborg et al.,
2003, 2003; Yosuf, 2017)
2 Unavailable (Desrosiers & Beaulac-Baillargeon, 1986; 10
full text Fortier et al., 1991; Gamaoun et al., 2011, 2012;
Martin, 2014; Messina & Martino, 2022;
Nisenblat & Norman, 2009; Oliveira, 2016;
Preimesberger & Lozeau, 2008; Stapleton,
1995)
3 Ineligible (Grosso et al., 2005; Lu et al., 2017) 2
exposure
4 Ineligible (Chen et al., 2018; Choi et al., 2020; Clausson 6
outcomes et al., 2002; Larroque et al., 1993; Martin et al.,
1980; Vlajinac et al., 1997)
5 Ineligible (Hinds et al., 1996; Jahanfar & Jaafar, 2009, 5
study design 2015; Purcell, 2005; Rashed et al., 2019)
6 Ineligible (Partosch et al., 2015; Yusof, 2021) 2
participants
7 Ineligible (Qin & Fang, 2017; Yang et al., 2018) 2
language
8 Insufficient (Mannucci et al., 2020; Sengpiel et al., 2013; 3
data Srisuphan & Bracken, 1986)
9 Invalid (Jasim et al., 2021) 1
exposure level
26
PRISMA Flow Diagram
Identification of studies via databases and registers
Studies identified from:

Identification
Databases (n=1225) Studies removed before

1. PubMed (n=795 ) screening:
2. Google Scholar (n=87 ) Duplicate records removed
3. HINARI (n=338 ) (n=27)
4. Hand search (n=5)
Studies excluded
Studies screened (n=1198) (n=1128)
Screening
Studies not retrieved (n =28):

Studies sought for retrieval Same studies (n=18)
(n=70) Unavailable full text (n=10)
Studies excluded (n=17):

Ineligible exposure: (n=2)
Eligibility
Studies assessed for eligibility

Ineligible outcomes: (n=6)
(n=42)
Ineligible study design: (n=5)
Ineligible participant
Studies included in review characteristics: (n=2)
(n=25) Ineligible language: (n=2)
Included
Studies excluded (n=4):

Studies included in meta- Insufficient data (n=3)
analysis (n=21) Invalid exposure level (n=1)
Figure 6.3 PRISMA Flow Diagram
27
6.2 Characteristics of Included Studies
In this review, there were a total of 25 studies. Regarding the study design,
there were 6 case-control papers, 6 cross-sectional analytical studies, and 13 cohort
studies. The majority of these articles (n = 6) were conducted in the United States of
America (USA), followed by the United Kingdom (UK) (n = 3) and Italy (n = 3),
Canada (n = 2), Denmark (n = 2), and the Netherlands (n = 2), and the remaining
countries (n = 1) were Brazil, Iraq, Japan, Jordan, Norway, Poland, Southern Ethiopia,
and Iraq, respectively. The research periods for two studies were not specified, and
five studies were completed before the year 2000, seven studies were completed
between 2000 and 2010, another seven studies were completed after 2010 but before
2020, and the other studies were completed in 2020 or beyond.
In addition, many studies were set in hospital setting (n=18), few articles were
taken in community (n=5) and clinic (n=2). The exposure assessment was applied
using different methods such as telephone interview, personal interview,
questionnaires and pretested structured questionnaires. The exposure amount was
calculated in cups per day and milligrams per day. The cumulative sample sizes of the
studies ranged from 135 to 89,539 individuals. The listed studies' specific
characteristics were explained in the Table (6.2), Table (6.3) and Table (6.4).
28
Table 6.8 Characteristics of Included Studies (Cross-sectional studies) (n=6)
Author/ Age group Context Sampl Study Setting Exposure Exposure Exposure Outcomes
Year e size period type assessment measuremen
method t method
Linn et <35: 37.5%, USA 14458 Aug 8, Hospital Coffee, Interview Cups/day LBW
al., ≥35: 62.5% 1997 - Tea
(1982) Mar 31,
1980
Fenster et ≤34: 1072, USA 1230 1986 - Community Caffeine Telephone mg/day LBW, IUGR
al., >34: 158 1987 interview
(1991a)
Fortier et <20 – 165 Canada 7025 Jan 1 - Community Caffeine Telephone mg/day IUGR
al., 20-24: 1387 Oct 15, Health interview
(1993) 25-29: 3147 1989 Department
30-34: 1847
≥35: 452
Jarosz et Range 16- Poland 509 2005 - Clinics of Caffeine Face to face mg/day Preterm & Birth
al., 44 2007 O&G questionnaire weight
(2012)
Hoeven Mean age Netherlands 936 initiated Community Coffee, Questionnaire Cups/day & SGA & Birth
et al., 32.4±4 in 2001 Tea, mg/day weight
(2017) Caffeine
Mannucc ET group - Italy 5405 2014- Hospital Coffee Questionnaire mg/day Abortion,
i et al., 35.9±15.1, 2017 with patient Premature labor,
(2020) UT group - clinical LBW
35.3±12.1 record
Table 6.9 Characteristics of Included Studies (Case-control studies) (n=6)

29
Author/ Age group Context Sample Study Setting Exposure Exposure Exposure Outcomes
Year size period type assessment measurement
method method
Fenster et Cases,Control USA Cases - June, Community Coffee, Telephone mg/day Miscarriage
al., ≤34: 472, 1132 616, 1986 - Tea, interview
>34: 144, 160
(1991b) Control Feb, Caffeine
-1292 1987
Infante- Case,Control Canada Cases - May, Hospital Caffeine Face to face mg/day Abortion
Rivard et <20: 17, 59 331, 1987 - interview
20-34: 262, 866
al., >34: 52, 68
Control Nov,
(1993) - 993 1989
Parazzini Cases; mean Italy Cases - Since Hospital Coffee Questionnaire Cups/day SGA
et al., age: 31 (16-43) 555, June
Control; mean
(2005) age: 31 (14-43)
Control 1993
- 1966
Hoyt et Case,Control USA Cases - Oct 1, Hospital Coffee, Telephone mg/day SGA
al., 12-19: 79, 745 648, 1997 - Tea, interview
20-24: 178,
(2014) 1671 25-29:
Control Dec 31, Caffeine
173, 2023 30- - 7295 2007
34: 119, 1878
>34: 99, 978
Hussen Mean age: Southern Cases - Mar 1 - Hospital Coffee Face to face mg/day LBW
& Desu, 26.5±5.1 Ethiopia 99, July 30, with pretested
(2020) Control 2019 structured
-296, questionnaire
Sindiani Mean age: Jordan Cases _ Hospital Coffee, Structured Cups/day Premature labor
et al., 29.18±6.11 314, Tea questionnaire
(2020) Control
796
30
Table 6.10 Characteristics of Included Studies (Cohort studies) (n=13)
method t method
Srisuphan ≤30: 2226, USA 3135 May, Hospital Coffee, Interview Cups/day Miscarriage
& Bracken, >30: 909 1980 - Tea
(1986) Mar, 1982
Martin & <20: 391 USA 3891 May 12, Hospital Caffeine Standardized mg/day LBW
Bracken, 20-24: 859 1980 - interview
(1987) 25-29: 1443 Mar 12,
30-34: 991 1982
>34: 207
Wisborg et 15-24: 2809 Demark 18478 Sep, 1989 Hospital Coffee Questionnaire Cups/day Stillbirth
al., (2003) 25-29: 7649 - Aug, with medical
30-50: 8020 1996 record
CARE, Mean age: UK 2635 Sep, 2003 Hospital Caffeine A validated mg/day SGA
(2008) 30±6.6 - June, assessment
2006 questionnaire
Weng et ≤24: 153 Italy 1063 Oct, 1996 Program Coffee, Person mg/day Miscarriage
al., (2008) 25-29: 294 - Oct, Tea, interview
30-34: 358 1998 Caffeine
>34: 258
Bakker et Mean age: Netherlands 7346 2001 - Community Caffeine Postal Units/day SGA, LBW,
al., (2010) 29.7±5.3 2005 questionnaire Preterm
31
Table 6.11 Characteristics of Included Studies (Cohort studies) (n=13) (Continued)
method t method
Greenwood Mean age: UK 2643 Sep, 2003 Hospital Coffee, Questionnaire mg/day Miscarriage
et al., 30±6.6(18 - - June, Tea, and electronic & Stillbirth
(2010) 45) 2006 Caffeine database
Potdar, Mean age: UK 1261 May, Hospital Caffeine Structured mg/day FGR
(2010) 29.7±5(18 - 2004 - questionnaire
44) Jun, 2006
Sengpiel et <25: 6688 Norway 59123 1999 - Nationwide Coffee, Self- reported mg/day Preterm, SGA
al., (2013) 25-29: 2009 Tea, semi-
20354 Caffeine quantitative
30-34: questionnaire
25213
>34: 6868
Bech et al., <25: 11662 Demark 89539 Mar 1, Clinics of Coffee, Telephone Cups/day & SGA, Birth
(2015) 25-29: 1996 - O&G Tea, interview mg/day weight
37328 30- Nov 1, Caffeine
34: 30344 2002
>34: 10205
Okubo et Mean age: Japan 858 Nov, 2001 Hospital Caffeine A validated mg/day SGA,
al., (2015) 30 (27-32) - Mar, self- Premature
2003 administrated labor, LBW
DHQ
32
Table 6.12 Characteristics of Included Studies (Cohort studies) (n=13) (Continued)
method t method
Chen et al., Mean age: Ireland 941 2001 - Hospital Caffeine A validated mg/day Birth weight
(2018) 30.1±5.8 2003 FFQ
Vitti et al., <20: 545 Brazil 7607 Jan 1 - Hospital Caffeine Standardized mg/day LBW,
(2018) 20-34: 3654 Dec 31, questionnaire Preterm
>34: 709 2010
(Jasim et ET group: Iraq 135, Jan 2, Hospital Tea Telephone mg/day SGA, Birth
al., 2021) 34.3±5.8, ET 41 2019 - interview weight
UT group: & UT Feb 1,
25.7±5.1 94 2020
33
6.3 Risk of Bias Assessment
The risk of bias assessment was independently performed by two reviewers,
(WZM and HPK) according to JBI critical appraisal tools. Disagreements between
two reviewers were solved by reaching a general agreement under supervision of third
reviewer, (LP).
6.3.1 Risk of Bias Assessment for Cohort Studies
In cohort studies, there was a low risk of bias as the most portions of appraisal
questions were denoted as “Yes” that produce more power to the quality of the
articles.
Table 6.13 Overview risk of bias assessment in cohort studies
No JBI Critical checklist question for Reviewer 1 Reviewer 2
Cohort study Ye No Un N Yes No Un N
s clear A clear A
Q1 Were the two groups similar and 12 1 12 1
recruited from the same population?
Q2 Were the exposures measured 13 13
similarly to assign people to both
exposed and unexposed groups?
Q3 Was the exposure measured in a 13 13
valid and reliable way?
Q4 Were the confounding factors 13 13
identified?
Q5 Were strategies to deal with 13 13
confounding factors stated?
Q6 Were the groups/participants free of 13 13
the outcome at the start of the study
(or at the moment of exposure)?
Q7 Were the outcomes measured in a 13 13
Q8 Was the follow up time reported 6 3 4 6 3 4
and sufficient to be long enough for
outcomes to occur?
Q9 Was follow up complete, and if not, 10 2 1 10 2 1
were the reasons to loss to follow
up described and explored?
Q10 Were strategies to address 11 1 1 11 1 1
incomplete follow up utilized?
Q11 Was appropriate statistical analysis 13 13
used?
34
Table 6.14 Detail description of risk of bias in cohort studies
No Reviewe Q Q Q Q Q Q Q Q Q Q1 Q1 Scor Percentag
Study Remark
. r 1 2 3 4 5 6 7 8 9 0 1 e e
Srisuphan & Bracken, WZM Y Y Y Y Y Y Y N Y Y Y
1 10 91% Included
(1986) HPK Y Y Y Y Y Y Y N Y Y Y
WZM Y Y Y Y Y Y Y Y Y Y Y
2 Martin & Bracken, (1987) 11 100% Included
HPK Y Y Y Y Y Y Y Y Y Y Y
WZM Y Y Y Y Y Y Y U N U Y
3 Wisborg, (2003) 8 73% Included
HPK Y Y Y Y Y Y Y U N U Y
4 CARE, (2008) 11 100% Included
5 Weng et al., (2008) 11 100% Included
6 Bakker et al., (2010) 11 100% Included
7 Greenwood et al., (2010) 11 100% Included
WZM Y Y Y Y Y Y Y U Y Y Y
8 Potdar, (2010) 10 91% Included
HPK Y Y Y Y Y Y Y U Y Y Y
9 Sengpiel et al., (2013) 11 100% Included
10 Bech et al., (2015) 11 100% Included
WZM U Y Y Y Y Y Y Y U N Y
11 Okubo et al., (2015) 8 73% Included
HPK U Y Y Y Y Y Y Y U N Y
WZM Y Y Y Y Y Y Y N N Y Y
12 Vitti et al., (2018) 9 82% Included
HPK Y Y Y Y Y Y Y N N Y Y
13 Jasim et al., (2021) WZM Y Y Y Y Y Y Y Y Y Y Y 11 100% Included
35
36
6.3.2 Risk of Bias Assessment for Case-Control Studies
In these included case-control studies, there was a low risk of bias as the most
portions of appraisal questions were denoted as “Yes” that produce more power to the
quality of the included articles.
Table 6.15 Overview risk of bias assessment in case-control studies
No. JBI Critical checklist question Reviewer 1 Reviewer 2
for Case-control study Yes No Un N Yes No Un N
clear A clear A
Q1 Were the groups comparable 5 1 5 1
other than the presence of
disease in cases or the absence
of disease in controls?
Q2 Were cases and controls 4 2 4 2

matched appropriately?
Q3 Were the same criteria used for 3 3 3 3

identification of cases and
controls?
Q4 Was exposure measured in a 5 1 5 1

standard, valid and reliable
way?
Q5 Was exposure measured in the 6 6

same way for cases and
controls?

identified?

Q8 Were outcomes assessed in a 6 6

standard, valid and reliable way
for cases and controls?
Q9 Was the exposure period of 6 6

interest long enough to be
meaningful?
Q10 Was appropriate statistical 6 6

analysis used?
37
Table 6.16 Detail description of risk of bias in case-control studies
No Percentag
Study Reviewer Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Score Remark
. e
WZM N Y U Y Y Y Y Y Y Y
1 Fenster et al., (1991b) 8 80% Included
HPK N Y U Y Y Y Y Y Y Y
WZM Y Y Y Y Y Y Y Y Y Y
2 Infante-Rivard et al., (1993) 10 100% Included
HPK Y Y Y Y Y Y Y Y Y Y
WZM Y Y Y U Y Y Y Y Y Y
3 Parazzini et al., (2005) 9 90% Included
HPK Y Y Y U Y Y Y Y Y Y
WZM Y N U Y Y Y Y Y Y Y
4 Hoyt et al., (2014) 8 80% Included
HPK Y N U Y Y Y Y Y Y Y
WZM Y Y U Y Y Y Y Y Y Y
5 Hussen & Desu, (2020) 9 90% Included
HPK Y Y U Y Y Y Y Y Y Y
WZM Y N Y Y Y Y Y Y Y Y
6 Sindiani et al., (2020) 9 90% Included
HPK Y N Y Y Y Y Y Y Y Y
Y - Yes, N - No and U - Unclear
38
6.3.3 Risk of Bias Assessment for Cross-Sectional Studies
In these included case-control studies, there was a low risk of bias as the most
portions of appraisal questions were denoted as “Yes” that produce more power to the
quality of the included articles.
Table 6.17 Overview risk of bias assessment in cross-sectional studies
No JBI Critical checklist Reviewer 1 Reviewer 2
. question for Cross-sectional
study Yes No Un N Yes No Un N
clear A clear A
Q1 Were the criteria for inclusion 3 3 3 3
in the sample clearly defined?
Q2 Were the study subjects and 5 1 5 1
the setting described in detail?
Q3 Was the exposure measured 6 6
in a valid and reliable way?
Q4 Were objective, standard 5 1 5 1
criteria used for measurement
of the condition?
identified?
Q7 Were the outcomes measured 6 6
in a valid and reliable way?
Q8 Was appropriate statistical 6 6
analysis used?
39
Table 6.18 Detail description of risk of bias in cross-sectional studies
No Percentag
Study Reviewer Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Score Remark
. e
WZM Y Y Y Y Y Y Y Y
1 Linn et al., (1982) 8 100% Included
HPK Y Y Y Y Y Y Y Y
WZM U N Y Y Y Y Y Y
2 Fenster et al., (1991a) 6 75% Included
HPK U N Y Y Y Y Y Y
WZM U Y Y Y Y Y Y Y
3 Fortier et al., (1993) 7 87% Included
HPK U Y Y Y Y Y Y Y
WZM Y Y Y Y Y Y Y Y
4 Jarosz et al., (2012) 8 100% Included
HPK Y Y Y Y Y Y Y Y
WZM Y Y Y U Y Y Y Y
5 Hoeven et al., (2017) 7 87% Included
HPK Y Y Y U Y Y Y Y
WZM U Y Y Y Y Y Y Y
6 Mannucci et al., (2020) 7 87% Included
HPK U Y Y Y Y Y Y Y
Y - Yes, N - No and U - Unclear
40
6.4 Qualitative Synthesis or Systematic Review
6.4.1 A Narrative Review of Included Studies
In this systematic review, studies related to maternal caffeine consumption and
pregnancy outcomes were published since 1982 and up to 2021. A total of 1225
articles published up to and including December 2021 were identified. After screening
for relevance and deletion of duplicates, the search yielded a total of 25 full-text
articles in final review and 22 studies moved forwards meta-analyses. The adverse
pregnancy outcomes were found to be comprehensively encompassed by five
categories: miscarriage, small for gestational age (SGA), preterm delivery (PB), low
birth weight (LBW) and stillbirth (SB).
6.4.1.1 A Narrative Review of Miscarriage
Finding of miscarriage relation to caffeine intake during pregnancy was shown
in Table (6.11) that summarized 5 observational studies conducted from 1986 to 2020.
The included studies in review of miscarriage were different study designs in which
the cross-sectional study, case-control study and cohort study were 1, 2 and 2 papers
respectively. A total of 7,313 participants were observed and the findings were in
strongly agreement, with reporting significant associations between caffeine and
increased risk of miscarriage.
Exposure level was varied from one study to another, but the greater the level
of exposure the higher the risk of outcome was increased in five studies of dose
response analysis and one study which is cross-sectional study (Mannucci et al., 2020)
was inconsistent result to level of exposure. Besides, one case-control study (Infante-
Rivard et al., 1993) and one cohort study (Weng et al., 2008) revealed that pregnant
women who consumed more than 200 mg of caffeine had a chance of risk of
miscarriage significantly, OR = 2.62 and OR = 2.23 with p value < 0.05.
6.4.1.2 A Narrative Review of Small for Gestational Age
Review of SGA regarded to caffeine consumption during pregnancy was
described in Table (6.12) in which 12 observational studies conducted from 1991 to
2017. The majority of included studies in review were cohort study design (n=7) and
remaining studies were cross-sectional study (n=3) and case-control study (n=2).
Sample size population in the included studies was from 135 to 71,000 participants.
Measure of effect in each articles were remarkably associations between caffeine
consumption and risk of SGA.
41
Changes in exposure level, the effect size was also changed and the more
exposure level the greater the risk of outcome was observed in all studies. One cohort
study (Jasim et al., 2021) conducted only on tea consumption and risk of excessive tea
consumption was more associated with SGA than usual tea consumption, OR usual tea =
1.03 and OR = 1.46 excessive tea with p value < 0.05.
6.4.1.3 A Narrative Review of Preterm Delivery
Regarding the risk of PB due to caffeine intake during pregnancy, findings of
10 observational studies were illustrated in Table (6.13) carried out from 1982 to 2020
and the study designs were cross-sectional study (n=4), case-control study (n=1) and
cohort study (n=5), respectively. Half of the studies were done in hospital setting and
others were taken in community health center and clinics. Seven articles were
conducted in Europe countries and the remaining three were performed in United
State of America, Brazil and Japan.
Preterm delivery was also related to maternal caffeine consumption in most
studies with dose response analysis but two studies, (Sengpiel et al., 2013) and
(Mannucci et al., 2020) showed that there was no association between maternal
caffeine intake and PB with OR strictly control group = 0.98, p value = 0.6 in (Sengpiel et al.,
2013) and OR122 mg=0.0.871, p value = 0.25; OR244 mg= 1.05, p value = 0.75; OR366 mg=
0.559, p value = 0.14 in (Mannucci et al., 2020). One cohort study (Okubo et al.,
2015) provided the strong association of exposure level to PB, OR 175-257 mg = 1.35,
OR258-372 mg= 2.34 and OR≥373 mg= 3.72 with p value <0.05.
6.4.1.4 A Narrative Review of Low Birth Weight
A total of 10 studies were included in this review for risk of LBW relation to
caffeine exposure during pregnancy was shown in Table (6.14). Half of these studies
were cohort studies, four studies were cross-sectional studies and one was case-
control study. As a country of review articles, three articles were studied in USA and
others were done in Canada, Netherlands, Poland, Japan, Brazil, Southern Ethiopia
and Italy. Hospitals and community health centers were mainly set in the included
studies.
The measure effect, OR for LBW in each studies was significantly associated
with caffeine consumption during pregnancy. For each exposure level, pregnant
mothers who drank more caffeine had a greater risk of low birth weight. But, one
cohort study (Okubo et al., 2015) and two cross-sectional studies (Fenster et al.,
1991a) and (Fortier et al., 1993) reported inconsistence effect size, OR258-372mg= 0.89,
42
OR1-150mg= 0.78, OR>300mg= 0.89, individually. In addition, (Martin & Bracken, 1987),
cohort study and (Hussen & Desu, 2020), case-control study showed the large effect
agreement of caffeine exposure to risk of LBW, OR = 1.4 for 1-150 mg, OR = 2.3 for
151-300 mg and 4.6 for more than 300 mg, p value < 0.05 (Martin & Bracken, 1987)
and OR= 4.1 for more than 300 mg, p value < 0.05 (Hussen & Desu, 2020).
6.4.1.5 A Narrative Review of Stillbirth
There were three studies for review of SB caused by maternal caffeine
consumption described in Table (6.15). Studies were done from 1982 to 2010 with a
sample range from 2,482 to 18,478. All the studies were conducted in hospital setting
and one study was cross-sectional study and two were cohort studies. The included
articles were performed in developed countries such as Demark, United Kingdom and
United State of America.
As a report of the studies, caffeine consumption during pregnancy and SB was
consistent agreement in all included studies. More than 200 mg of caffeine or 3 cups
of coffee was more significant association with stillbirths, OR 4-7cups= 1.4, OR≥8 cups=
2.2, p value < 0.05 (Wisborg et al., 2003) and OR ≥200 mg= 2.2, P value < 0.05
(Greenwood et al., 2010).
43
6.4.2 Tabular Synthesis for Included Studies
The included studies were illustrated in tabular synthesis relied on the different pregnancy outcomes.
6.4.2.1 Tabular Synthesis for Miscarriage
Table 6.19 Description of main outcomes on maternal caffeine in relation to miscarriage
Author/ Context Study Sampl Setting Exposure Comparison Effect Adjustment variables Remar
Year design e size type size k
Srisuphan USA Cohort 3135 Hospital Coffee, Moderately OR: 1.73 All confounding variables SR
& Tea heavy
Bracken, caffeine
(1986) users
Fenster et USA Case- 1891, Community Coffee, 0 mg OR: Age, race, marital status, SR &
al., control Cases: Tea, 1-150 mg 1.00 insurance, cigarette, MA
(1991b) 607, Caffeine 151-300 mg 1.02 alcohol and previous
Control >300 mg 1.17 abortion
: 1284 1.22
Infante- Canada Case- Cases: Hospital Caffeine <48 mg OR: Age, education, cigarette, SR &
Rivard et control 331, 48-162 mg 1.00 alcohol, uterine MA
al., (1993) Control 163-321 mg 1.15 abnormalities and work
: 993 >321 mg 1.95 schedule
2.62
Weng et Italy Cohort 1063, Program Coffee, 0 mg OR: 1.00 Maternal age, race, SR &
al., (2008) Events: Tea, <200 mg 1.42 education, income, marital MA
172 Caffeine ≥200 mg 2.23 status, nausea and
vomiting
Mannucci Italy Cross- 4719 Hospital Coffee Coffee OR: 1.21 Maternal BMI, alcohol and SR
et al., sectiona 122 mg 1.203 smoking
(2020) l 244 mg 1.085
44
366 mg 1.052
SR- Systematic Review, MA - Meta-analysis
6.4.2.2 Tabular Synthesis for Small for Gestational Age
Table 6.20 Description of main outcomes on maternal caffeine in relation to small for gestational age
Author/ Context Study Sample Setting Exposure Comparison Effect Adjustment variables Remark
Year design size type size
Fenster USA Cross- 1230, Community Caffeine 0 mg OR: 1.00 Age, race, parity, SR &
et al., sectiona Events: 1-150 mg 1.45 smoking and alcohol MA
(1991a) l 84 151-300 mg 1.58
>300 mg 2,90
Fortier et Canada Cross- 6731, Community Caffeine 0-10 mg OR: 1.00 Age, income, parity and SR &
al., sectiona Events: Health 11-150 mg 1.28 smoking MA
(1993) l 650 Department 151-300 mg 1,42
>300 mg 1.57
Parazzini Italy Case- Cases: Hospital Coffee 0 portion OR: 1.00 Age, education, parity SR &
et al., control 555, 1 portion 1.2 and smoking MA
(2005) Control: 2 portion 0.8
1966 3 portion 1.0
≥4 portion 1.3
CARE, UK Cohort 2536, Hospital Caffeine <100 mg OR: 1.0 Maternal age, weight, SR &
(2008) Events: 100-199 mg 1.2 height, parity and MA
338 200-299 mg 1.5 smoking
≥300 mg 1.4
45
Table 6.21 Description of main outcomes on maternal caffeine in relation to small for gestational age (Continued)
Bakker et Netherlands Cohort 7083, Community Caffeine <2 units OR: 1.0 Maternal age, education, SR &
al., Events: 2-3.9 units 1.38 parity, BMI, smoking MA
(2010) 354 4-5.9 units 1.50 and alcohol
≥6 units 1.87
Potdar, UK Cohort 964, Hospital Caffeine <100 mg OR: 1.0 Maternal age, parity, SR &
(2010) Events: 100-199 mg 1.2 smoking and alcohol MA
118 200-299 mg 1.5
≥300 mg 1.4
Sengpiel Norway Cohort 59123 Nationwide Coffee, 0-50 mg OR: 1.00 Maternal age, BMI, SR
et al., Tea, 51-200 mg 1.18 parity, nausea, smoking
(2013) Caffeine 201-300 mg 1.62 and alcohol
>300 mg 1.62
Hoyt et USA Case- Cases: Hospital Coffee, <10 mg OR: 1.00 Maternal age, education, SR &
al., control 648, Tea, 10-<100 0.96 high blood pressure and MA
(2014) Control: Caffeine 100-<200 1.18 smoking
7295 200-<300 1.24
≥300 mg 1.52
46
Table 6.22 Description of main outcomes on maternal caffeine in relation to small for gestational age (Continued)
Bech et Demark Cohort 71000, Clinics of Coffee, 0 mg OR: 1.00 Maternal age, BMI, SR &
al., Events: O&G Tea, 25-300 mg 1.09 parity, smoking and MA
(2015) 1764 Caffeine 325-775 mg 1.26 alcohol
≥800 mg 1.63
Okubo et Japan Cohort 858, Hospital Caffeine <175 mg OR: 1.00 Maternal age, BMI, SR &
al., Events: 175-257 mg 1.52 education, employment, MA
(2015) 67 258-372 mg 1.19 parity, smoking, alcohol
≥373 mg 1.11 and vitamin supplement
Hoeven Netherlands Cross- 887, Community Coffee, 100 mg OR: 0.92 Maternal age and SR &
et al., sectiona Events: Tea, smoking MA
(2017) l 39 Caffeine
Jasim et Iraq Cohort 135, Hospital Tea No intake Ref. Maternal age, parity, SR
al., ET ET group 1.46 BMI, education,
(2021) group: UT group 1.03 employment and
41 & smoking
UT
group:
94
47
6.4.2.3 Tabular Synthesis for Preterm Delivery
Table 6.23 Description of main outcomes on maternal caffeine in relation to preterm delivery
Author/ Context Study Sample Setting Exposure Comparison Effect size Adjustment variables Remar
Year design size type k
Linn et USA Cross- 12205, Hospital Coffee, 0 cup 7.3% Maternal age, parity and SR &
al., sectiona Events: Tea 1 cup 6.7% smoking MA
(1982) l 909 2 cups 8.0%
3 cups 8.5%
≥4 cups 9.0%
Fortier et Canada Cross- 6736, Community Caffeine 0-10 mg OR: 1.00 Maternal age, income, SR &
al., sectiona Events: Health 11-150 mg 1.08 parity and smoking MA
(1993) l 394 Department 151-300 mg 1.04
>300 mg 0.84
Bakker et Netherlands Cohort 7083, Community Caffeine <2 units OR: 1.00 Maternal age, SR &
al., Events: 2-3.9 units 0.92 education, ethnic, MA
(2010) 337 4-5.9 units 1.12 parity, BMI, smoking,
≥6 units 1.35 alcohol and vitamin
supplement
Jarosz et Poland Cross- 509, Clinics of Caffeine ≤100 mg OR: 1.0 Maternal age, SR &
al., sectiona Events O&G >100 mg education, place of MA
(2012) l 21 residence, smoking,
numbers of pregnancy
and vitamin supplement
Sengpiel Norway Cohort 59123 Nationwide Coffee, Strictly OR: 0.98 Maternal age, parity, SR
et al., Tea, control BMI, nausea, smoking
(2013) Caffeine group and alcohol
48
Table 6.24 Description of main outcomes on maternal caffeine in relation to preterm delivery (Continued)
Bech et Demark Cohort 71000, Clinics of Coffee, 0 mg 3.5% Maternal age, smoking, SR &
al., Events: O&G Tea, 25-300 mg 3.3% parity, BMI, occupation MA
(2015) 2486 Caffeine 325-775 mg 3.9% and alcohol
>800 mg 4.3%
Okubo et Japan Cohort 858, Hospital Caffeine <175 mg OR: 1.00 Maternal age, height, SR &
al., Events: 175-257 mg 1.35 BMI, education, parity, MA
(2015) 32 258-372 mg 2.34 smoking, alcohol and
≥373 mg 3.72 vitamin supplement
Vitti et Brazil Cohort 4908, Hospital Caffeine No intake OR: 1.00 Maternal age, SR &
al., (2018) Events: <300 mg 1.10 education, parity, MA
710 ≥300 mg 1.03 smoking, alcohol,
previous obstetric
history, and urinary
tract infection
Mannucci Italy Cross- 4719 Hospital Coffee Coffee OR: 1.016 Maternal BMI, smoking SR
et al., sectiona 122 mg 0.871 and alcohol
(2020) l 244 mg 1.055
366 mg 0.559
Sindiani Jordan Case- Cases Hospital Coffee, Coffee,Tea Maternal age, ethnic, SR &
et al., control 314, Tea No intake OR:1.0, education, occupation, MA
(2020) Control 1 cup 1.0 parity and smoking
796 2 cups 1.32, 1.12
3cups 1.47, 0.89
0.72, 1.43
49
6.4.2.4 Tabular Synthesis for Low Birth Weight
Table 6.25 Description of main outcomes on maternal caffeine in relation to low birth weight
Author/ Context Study Sampl Setting Exposure Comparison Effect Adjustment variables Remark
Year design e size type size
Linn et USA Cross- 12205, Hospital Coffee, Heavy coffee RR: 1.17 Maternal age, parity, SR &
al., sectiona Events: Tea consumption smoking, ethnic and MA
(1982) l 954 alcohol
Martin USA Cohort 3654, Hospital Caffeine 0 mg OR: 1.00 Maternal age, ethnic, parity SR &
& Events: 1-150 mg 1.4 and smoking MA
Bracken 70 151-300 mg 2.3
, (1987) >300 mg 4.6
Fenster USA Cross- 1230, Community Caffeine 0 mg OR: 1.00 Maternal age, parity, race, SR &
et al., sectiona Events: 1-150 mg 0.78 smoking and alcohol MA
(1991a) l 87 151-300 mg 1.07
>300 mg 2.05
Fortier Canada Cross- 6733, Community Caffeine 0-10 mg OR: 1.00 Maternal age, parity, SR &
et al., sectiona Events: Health 11-150 mg 1.27 income, previous history MA
(1993) l 321 Department 151-300 mg 1.25 and smoking
>300 mg 0.99
Bakker Netherlands Cohort 7083, Community Caffeine <2 units OR: 1.00 Maternal age, education, SR &
et al., Events: 2-3.9 units 1.08 ethnic, parity, BMI, MA
(2010) 329 4-5.9 units 1.19 nutrition, smoking and
≥6 units 2.58 alcohol
50
Table 6.26 Description of main outcomes on maternal caffeine in relation to low birth weight (Continued)
Author/ Context Study Sampl Setting Exposure Comparison Effect Adjustment variables Remark
Year design e size type size
Jarosz et Poland Cross- 509, Clinics of Caffeine <100 mg OR: 1.00 Maternal age, education, SR &
al., sectiona Events: O&G ≥100 mg 1.27 parity and smoking MA
(2012) l 10
Okubo Japan Cohort 858, Hospital Caffeine <175 mg OR: 1.00 Maternal age, BMI, SR &
et al., Events: 175-257 mg 2.07 education, employment, MA
(2015) 51 258-372 mg 0.89 parity, smoking, alcohol
≥373 mg 1.85 and nutrition supplement
Vitti et Brazil Cohort 4908, Hospital Caffeine No intake OR: 1.00 Maternal age, parity, SR &
al., Events: <300 mg 1.10 occupation, smoking and MA
(2018) 414 ≥300 mg 1.42 alcohol
Hussen Southern Case- Cases Hospital Coffee ≤300 mg OR: 1.00 Maternal age, education, SR &
& Desu, Ethiopia control 99, >300 mg 4.1 income, occupation and MA
(2020) Control BMI
296,
T: 395
Mannuc Italy Cross- 4719 Hospital Coffee <122 mg OR: 1.00 Maternal age, BMI, SR
ci et al., sectiona 122-243 mg 1.325 smoking and alcohol
(2020) l 244-365 mg 1.324
≤366 mg 1.566
51
6.4.2.5 Tabular Synthesis for Stillbirth
Table 6.27 Description of main outcomes on maternal caffeine in relation to stillbirth
Author/ Context Study Sampl Setting Exposure Comparison Effect size Adjustment variables Remark
Year design e size type
Linn et al., USA Cross- 12205, Hospital Coffee, 0 cup 0.5% Maternal age, parity, SR &
(1982) sectiona Events: Tea 1 cups 0.7% smoking and alcohol MA
l 69 2 cups 0.7%
3 cups 0.3%
≥4 cups 0.7%
Wisborg et Demark Cohort 18478, Hospital Coffee 0 cup OR: 1.00 Maternal age, education, SR &
al., Events: 1-3 cups 0.6 marital status, MA
(2003) 82 4-7 cups 1.4 employment, BMI,
≥8 cups 2.2 smoking and alcohol
Greenwoo UK Cohort 2482, Hospital Coffee, <200 mg Coffee,Tea Maternal age, parity, SR &
d et al., Events: Tea, ≥200 mg OR:1.0, smoking and alcohol MA
(2010) 25 Caffeine 1.0
1.2, 2.2
52
6.5 Meta-analysis or Quantitative Synthesis of Included Studies
Among of the studies in review, there were 21 studies included in the meta-
analysis or qualitative synthesis. Three articles were excluded from meta-analysis for
exclusion reason of insufficient data (n=3) and invalid exposure level and category
(n=1). There were five outcomes of interest analyzed in this section which were risk
of miscarriage, SGA, PB, LBW and SB.
6.5.1 Meta-analysis for Miscarriage
In the meta-analysis for risk of miscarriage, there were only three studies
included for eligibility. To find the pooled effect size for risk of miscarriage and
maternal caffeine consumption, these three studies were analyzed by Mantel-Haenszel
odds ratio using fixed effect model with 95% confident interval. To support the results
for risk of miscarriage, stratified analysis in subgroup was performed by caffeine
exposure level using random effect model. Begg’s funnel plot and Egger’s test to
assess the publication bias were not conducted in this analysis and sensitivity analysis
was also not performed because of limited articles (n=3).
6.5.1.1 Overall Pooled Effect for Miscarriage
To support the overall pooled effect of miscarriage, the included studies, one
cohort (Weng et al., 2008) and two case-control studies (Fenster et al., 1991b; Infante-
Rivard et al., 1993) were analyzed by Mantel-Haenszel odds ratio using fixed effect
model with 95% confident interval. The summary odds ratio of miscarriage was 1.54
(95% CI 1.30, 1.81; p value < 0.001) and there was no statistical heterogeneity
between the studies, shown in Figure (6.3).
Figure 6.4 Overall pooled effect of Miscarriage by caffeine exposure more than
200 mg
53
6.5.1.2 Stratified Meta-analysis of Exposure Level Relation to Risk of
Miscarriage
Although three studies were included in this meta-analysis, stratified analysis
was conducted as the exposure level was able to affect the risk of outcome. Three
level of exposure were applied to compare the reference level based on assigned
median value. But, in which high caffeine exposure data was not included due to data
availability shown in Figure (6.4).
Figure 6.5 Estimated risk of miscarriage by level of caffeine exposure

The summary finding showed that the risk of low caffeine exposure was 1.46
(95% CI 1.13, 1.88; p value = 0.003) and moderate caffeine exposure was 1.63 (95%
CI 1.21, 2.20; p value = 0.001). There was heterogeneity within study in low caffeine
exposure with I2 = 52% and no heterogeneity in high caffeine exposure with I2 = 0,
using random effect model.
6.5.1.3 Sensitivity Analysis for Miscarriage
A statistical model and leave-one-out analysis were used to do sensitivity
analysis for the total effect size of miscarriage, and the results are summarized in
Tables (6.16) and (6.17). The total effect size of the fixed-effect model was somewhat
less significant than the random effect model, but the p value was statistically more
significant. The summary OR of the fixed effect model was more relevant than the
54
random method because of no heterogeneity across the included studies, as shown in
Table (6.16).
Table 6.28 Statistical models for miscarriage
Effect Overall ES
Model p value Heterogeneity
measure (95% CI)
Random-effect 1.59 (1.27,
Odds Ratio <0.001 I2 = 45%, p-value = 0.001
model 2.00)
1.54 (1.30,
Fixed-effect model Odds Ratio <0.001 I2 = 45%, p-value = 0.16
1.81)
The results of the leave-one-out analysis are shown in Table (6.14). It can be
seen that leaving out the study (Fenster et al., 1991b) caused the overall effect size to
increase, with a statistically significant OR of 1.78 (95% CI 1.41, 2.25) and a p value
of <0.001 when it was excluded from the analysis. The odds ratio and Mantel-
Haenszel fixed effect model were used in this outcome to determine the overall effect
size.
Table 6.29 leave-one-out analysis for miscarriage
Omitted Overall
No OR 95% CI p value 95% CI p value
studies OR
Fenster et
1 1.78 1.41 2.25 <0.001 1.54 1.30 1.81 <0.001
al.b
Infante-
2 1.48 1.21 1.8 0.001 1.54 1.30 1.81 <0.001
Rivard et al
3 Weng et al. 1.46 1.22 1.74 <0.001 1.54 1.30 1.81 <0.001
6.5.2 Meta-analysis for Small for Gestational Age

There were ten studies included in the meta-analysis for risk of small for
gestation age to assess the pooled effect of SGA and caffeine intake during
pregnancy. A meta-analysis of SGA was performed for pooled effect size including
subgroup analysis and stratified analysis. For publication bias, Begg’s funnel plot and
Egger’s test were used and leave-one-out analysis and statistical model were applied
to support the sensitivity analysis.
6.5.2.1 Overall Pooled Effect of Small for Gestational Age
As a result shown in Figure (6.5), the overall pooled effect of SGA was 1.43
(95% CI 1.24, 1.65; p value < 0.001) using Mantel-Haenszel random effect model in
55
which one study (Hoeven et al., 2017) showed no association between caffeine
exposure and SGA, but this study was smallest weight with 3.7% and OR = 0.97
(95% CI 0.50, 1.88), wide confident interval. Therefore the effect of this study could
not affect the overall pooled effect. There was substantial heterogeneity in this meta-
analysis of ten included studies with I2 = 64%, Chi- square test = 25.8, p value =
0.003. It may be confounding between study designs and undergo to subgroup
analysis.
Figure 6.6 Overall pooled effect of Small for gestational age of caffeine
consumption more than 200 mg
6.5.2.2 Subgroup Analysis of Small for Gestational Age
Subgroup analysis was done by study design as there was heterogeneity in the
meta-analysis. In this analysis, the included studies were five cohort studies, two case-
control studies and three cross-sectional studies shown in Figure (6.6).
56
Figure 6.7 Subgroup analysis of estimated risk of Small for gestational age by
study designs
This figure illustrated that there was more risk of SGA in cross-sectional study
than pooled effect with 1.56 (95% CI 1.21, 2.02; p value = 0.0006) and no
heterogeneity between these three studies with (I2 = 27%, Chi – square test = 2.24; p
value = 0.25) significantly.
In case-control study group, there were two studies included and the summary
OR for this group was 1.34 (95% CI 1.13, 1.58; p value = 0.007 with no heterogeneity
between the studies, I2 = 7%, Chi2 test = 1.08, p value = 0.30. In cohort study, the
summary OR was almost nearly the overall pooled effect with OR = 1.41 (95%1.11,
1.80; p value = 0.005) but there was substantial heterogeneity between these five
studies with I2 = 77%, Chi – square test = 17.13, p value = 0.002. However, it can be
seen that there was no heterogeneity between subgroup significantly with I2 = 0, Chi –
square test = 1.03, p value = 0.60.
57
6.5.2.3 Stratified Meta-analysis of Exposure Level Relation to Risk of Small for
Gestational Age
To find out the effect of exposure level on outcome, data were extracted based
on caffeine level by three groups in the included studies as available as possible and
compared with reference level of exposure. Stratified analysis was computed using
Mantel-Haenszel random effect model with 95% confident interval as shown in
Figure (6.7).
Figure 6.8 Estimated risk of Small for gestational age by level of caffeine
exposure
Results in the figure showed that there were ten studies included in low
caffeine exposure, seven studies in moderate caffeine exposure and two studies in
high caffeine exposure. The summary OR of low caffeine level was 1.21 (95% CI
58
1.09, 1.33; p value = 0.0003) and there was no heterogenity between the studies with
I2 = 37%, Chi - square test = 14.21, p value = 0.11. In moderate caffeine exposure,
there was more remarkable risk of SGA with summary OR = 1.63 (95% CI 1.28, 2.06;
p value < 0.001) but there was moderate hetreogenity between the studies with I2 =
54%, Chi - square test = 13.03, p value = 0.04. As a result of high caffeine exposure,
Standard error of effect size

the summary OR was 1.95 (95% CI 1.73, 2.21; p value < 0.001) and there was no
heterogenity between the studies with I2 = 0, Chi - square test = 0.55, p value = 0.46.
It can be seen that there was significant relationship of SGA and level of caffeine
exposure.
.1
.2
.3
.4
0
6.5.2.4 Assessment of Publication Bias for Small for Gestational Age
Funnel plot with pseudo 95% confidence limits

-2 of effect estimate
-.5 0 .5 1
Effect size
SND
2
0
Figure 6.9 Begg’s funnel plot for small for gestational age
Egger's intercept = -2.008, P value = 0.058
0 5 10 15 20
Precision
Study regression line

95% CI for intercept
Figure 6.10 Egger’s test for small for gestational age
59
To assess the publication bias, both Begg’s funnel plot and Egger’s test were
applied as shown in Fgures (6.8) and (6.9). In funnel plot, there was seen to be
publication bias in asymmetrical shape of plot in Figure (6.8) by eyeballing but
Egger’s test showed an intercept of -2.008 with statistically significant, p value =
0.058 in Figure (6.9). Therefore, there was small study effect in 9 included studies.
6.5.2.5 Sensitivity Analysis for Small for Gestational Age
The results of a sensitivity analysis for the total effect size of SGA were
presented in Table (6.15) and Figure (6.10) using a statistical model and leave-one-out
analysis. Compared to the random effect model, the fixed-effect model's total effect
size was somewhat more significant, but their p values were identical and statistically
significant. According to the heterogeneity among the included studies, the summary
OR of the random effect model was more pertinent than the fixed effect method, as
indicated in Table (6.14).
Table 6.30 Statistical models for small for gestational age
Model Effect Overall ES p value Heterogeneity
measure (95% CI)
Random-effect Odds Ratio 1.43 (1.24, < 0.001 I2 = 64%, p value =
model 1.65) 0.003
Fixed-effect model Odds Ratio 1.53 (1.42, <0.001 I2 = 64%, p value =
1.64) 0.003
OR 95% CI P value
Bakker et al. 1.49 1.3 1.71 <0.001
Bech et al. 1.44 1.25 1.67 <0.001
Fenster et al.a 1.4 1.21 1.63 <0.001
Fortier et al. 1.39 1.18 1.65 <0.001
CARE 1.4 1.2 1.65 <0.001
Hoeven et al. 1.45 1.26 1.67 <0.001
Hoyt et al. 1.43 1.21 1.68 <0.001
Okubo et al. 1.38 1.22 1.55 <0.001
Parazzini et al. 1.47 1.27 1.69 <0.001
Potdar et al. 1.46 1.26 1.68 <0.001
Overall 1.43 1.24 1.65 <0.001
0.9 11 1.1 1.2 1.3 1.4 1.5 1.6 1.7
Figure 6.11 Leave-one-out analysis for small for gestational age

In leave-one-out analysis there were no noteworthy changes in overall effect
size for each study when it was removed from analysis and all the p values were also
60
significant in same way. This analysis was performed by odds ratio and Mantel-
Haenszel random effect model as shown in Figure (6.10).
6.5.3 Meta-analysis for Preterm Delivery
To determine the risk of PB, meta-analysis was performed using seven
included studies. A meta-analysis of PB was computed for pooled effect size
including subgroup analysis by study design and stratified analysis for level of
exposure. For publication bias, Begg’s funnel plot and Egger’s test were used and
leave-one-out analysis and statistical model were applied to support the sensitivity
analysis.
6.5.3.1 Overall Pooled Effect for Preterm Delivery
There were seven studies included in meta-analysis for PB and the summary
OR was 1.19 (95% CI 1.09, 1.29; p value < 0.001), performed by Mantel-Haenszel
fixed effect model. Only one case-control study (Sindiani et al., 2020) revealed the
inconsistency of effect size for preterm delivery with OR = 0.85 (95% CI 0.52, 1.41; p
value = 0.54). However, there was no heterogeneity between the included studies with
I2 = 0, Chi – square test = 2.98, p value = 0.31, as shown in Figure (6.11).
Figure 6.12 Overall pooled effect of Preterm delivery of caffeine consumption

more than 200 mg
6.5.3.2 Subgroup Analysis for Preterm Delivery
In subgroup analysis for PB, seven studies were included to assess the source
of heterogeneity. The included studies were cross-sectional studies (n = 2), case-
control study (n =1) and cohort study (n = 4) and these studies were analyzed by
Mantel-Haenszel fixed effect model with 95% confident interval as shown in Figure
(6.12). In first group of cross-sectional study, the summary OR was 1.25 (95% CI
61
1.07, 1.47; p value = 0.005) and there was no heterogeneity between these two studies
with I2 = 0, Chi – square test = 0.07 with p value = 0.79.
Figure 6.13 Subgroup analysis of estimated risk of Preterm delivery by study

designs
As a second group in case-control study, there was only one study included in
analysis and OR was no association between caffeine consumption during pregnancy
and PB, OR = 0.85 (95% CI 0.52, 1.41) with no statistically significant, p value =
0.54 and the heterogeneity was not applicable for this group. In cohort study group,
although there were four studies included in meta-analysis, there was no heterogeneity
with statistically significant, I2 = 0, Chi – square test = 0.81, p value = 0.85). The
summary OR in cohort study group was 1.18 (95% CI 1.07, 1.30) with significant p
value = 0.0008.
62
6.5.3.3 Stratified Meta-analysis of Exposure Level Relation to Risk of Preterm
Delivery
To support the effect of exposure level on PB, there were three groups
included in analysis based on assigned median value to compare with reference level
of exposure. Stratified analysis was conducted by using Mantel-Haenszel random
effect model with 95% confident interval as shown in Figure (6.13). This figure
showed that there were eight studies included in low caffeine exposure, six studies in
moderate caffeine exposure and only one study in high caffeine exposure.
Figure 6.14 Estimated risk of Preterm delivery by level of caffeine exposure

As the data showed there was no remarkable association between maternal
caffeine intake and PB in low caffeine exposure group with summary OR = 1.02
(95% CI 0.93, 1.13; p value = 0.64). There was also no statistical heterogeneity in this
63
group with I2 = 37%, Chi – square test = 11.03 and p value = 0.14. In moderate
caffeine exposure group, the summary OR was weak association among exposure and
outcome with OR= 1.19 (95% CI 1.08, 1.32) and statistically significant p value =
0.0005. Heterogeneity between the studies was also not detected in analysis with I2 =
.4 error of effect size

0% Chi - square test = 4.82 and p value = 0.44. Only one study was included in high
caffeine exposure group and the summary OR revealed association between high
exposure and preterm delivery but no statistically significant with OR = 1.55 (95% CI
Standard
0.71, 3.38) and p value = 0.27. There was no applicable for heterogeneity.
.1
.2
.3
.5
0
6.5.3.4 Assessment of Publication Bias for Preterm Delivery

SND of effect estimate
-1 -.5 0 .5 1
Effect size
Figure 6.15 Begg’s funnel plot for preterm delivery

-2
2
Egger's intercept = 0.036, P value = 0.951
0 5 10 15 20
Precision

Figure 6.16 Egger’s test for preterm delivery
64
Both Begg’s funnel plot and Egger’s test were applied to evaluate the
publication bias, as shown in Figure (6.14) and Figure (6.15). In funnel plot, there was
seen to be no publication bias in symmetrical shape of plot by eyeballing and Egger’s
test also showed an intercept of 0.036 with p value = 0.951 and fail to reject null
hypothesis. Therefore, there was no small study effect in the included studies.
6.5.3.5 Sensitivity Analysis for Preterm Delivery
To determine the sensitivity for PB a statistical model and leave-one-out
analysis were conducted and detail information were described in Table (6.19) and
Figure (6.16). Both random and fixed effect models introduced the summary OR
identically and also no heterogeneity between the studies seen in Table (6.19).
Table 6.31 Statistical models for preterm delivery
measure (95% CI)
Random-effect Odds Ratio 1.19 (1.09, < 0.001 I2 = 0%, p value = 0.81
model 1.29)
Fixed-effect model Odds Ratio 1.19 (1.09, < 0.001 I2 = 0%, p value = 0.81
1.29)
The summary OR for each study that was excluded from the analysis was
roughly equal to the overall effect size, according to the leave-one-out approach, and
all p values were given in statistically significant levels. In this analysis, the odds ratio
and the Mantel-Haenszel fixed effect model were used, as illustrated in Figure (6.16).
OR 95% CI p value
1.1 1.0 1.3 0.001

Bakker et al. 9 9
1.1 1.0 1.2 0.002
Bech et al. 8 9 8
1.1 1.0 1.2 0.001
Fortier et al. 8 9 9
Linn et al. 1.1 1.0 1.2 0.005
7 7 8
Okubo et al. 1.2 1.0 1.3 <0.001
7 6
Sindiani et al. 1.2 1.1 1.3 <0.001
Vitti et al.
1.1 1.0 1.2 <0.001
Overall 9 9 9
1.1 1.0 1.2 <0.001
0.9 0.95 1 1.05 1.1 1.15 1.2 1.25
Figure 6.17 Leave-one-out analysis for preterm delivery
65
6.5.4 Meta-analysis for Low birth weight
A meta-analysis was performed for LBW using eight included studies. A
pooled effect size including subgroup analysis by study design and stratified analysis
for level of exposure were conducted by Mantel-Haenszel random effect model. For
publication bias, Begg’s funnel plot and Egger’s test were used and leave-one-out
analysis and statistical model were applied to support the sensitivity analysis.
6.5.4.1 Overall Pooled Effect for Low Birth Weight
To find out the overall pooled effect of caffeine exposure on LBW, a meta-
analysis was performed by Mantel-Haenszel random effect model using eight
included studies. The summary OR for low birth weight was 1.58 (95% CI 1.21, 2.06)
with significant p value < 0.001. There was substantial heterogeneity between the
included studies with I2 = 76%, Chi-square test = 29.29 and p value = 0.001, as shown
in Figure (6.17).
Figure 6.18 Overall pooled effect of Low birth weight of caffeine consumption
more than 200 mg
6.5.4.2 Subgroup Analysis for Low Birth Weight
According to the heterogeneity in the meta-analysis, subgroup analysis was
done by study design using Mantel-Haenszel random effect model. In this analysis,
the included studies were four cohort studies, one case-control studies and three cross-
sectional studies shown in Figure (6.18). There was less risk for LBW in cross-
sectional study than pooled effect with 1.39 (95% CI 1.13, 1.70; p value = 0.001) and
no heterogeneity between these three studies with I2 = 34%, Chi-square test = 3.03
and p value = 0.22) significantly.
66
Figure 6.19 Subgroup analysis of estimated risk of Low birth weight by study
designs
There was only one study included in case-control study group and the
summary OR for this group was strong association between caffeine exposure and
LBW with OR = 4.29 (95% CI 2.24, 8.20; p value < 0.001 and there was no
applicable heterogeneity. In cohort study, there was also less effect size than the
overall pooled effect with OR = 1.44 (95% CI 0.92, 2.26) and no statistically
significant, p value = 0.11). There was also substantial heterogeneity between these
four studies with I2 = 76%, Chi-square test = 12.32, p value = 0.006. There was
significant heterogeneity between subgroup with I2 = 81.3, Chi-square test = 10.68, p
value = 0.005.
67
6.5.4.3 Stratified Meta-analysis for Low Birth Weight
Stratified analysis was analyzed by Mantel-Haenszel random effect model
with 95% confident interval to find out the effect of caffeine exposure level on LBW.
Data were extracted based on assigned median value by three groups in the included
studies and compared with reference level of exposure. as shown in Figure (6.19).
There were eight studies included in low caffeine exposure, seven studies in moderate
caffeine exposure and one study in high caffeine exposure.
Figure 6.20 Estimated risk of Low birth weight by level of caffeine exposure
The summary OR of low caffeine level was 1.11 (95% CI 0.95, 1.29) with no
statistically significant, p value = 0.20 and there was no heterogenity between the
68
studies with I2 = 43%, Chi-square test = 12.32, p value = 0.09. In moderate caffeine
exposure, there was more remarkable risk of low birth weight with summary OR =
1.55 (95% CI 1.21, 1.99; p value = 0.005) and there was no hetreogenity between the
studies with I2 = 41%, Chi-square test = 10.20, p value = 0.12. In high caffeine
exposure, there was only one study included and the summary OR was 1.91 (95% CI
0.95, 3.83) and no significant p value = 0.07. There was no applicable heterogenity.
Standard error of effect size

Therefore, it can be seen that there was association between caffeine exposure level
and risk of low birth weight.
6.5.4.4 Assessment of Publication Bias for Low Birth Weight
For the assessment of publication bias, both Begg’s funnel plot and Egger’s
.1
.2
.3
.4
0
test were applied as shown in Figures (6.20) and (6.21).

SND of effect estimate
-.5 0 .5 1 1.5
Effect size
-2
2
Figure 6.21 Begg’s funnel plot for low birth weight
Egger' intercept = 3.418, P value = 0.033
0 2 4 6 8 10
Precision

Figure 6.22 Egger’s test for low birth weight
69
There was seen to be publication bias in asymmetrical shape of plot in funnel
plot but Egger’s test interpreted an intercept of -2.008 with statistically significant, p
value = 0.058 in Figure (6.21). Therefore, there was small study effect in the included
studies.
6.5.4.5 Sensitivity Analysis for Low Birth Weight
Using a statistical model and a leave-one-out analysis, the findings of a
sensitivity analysis for the overall effect size of LBW were shown in Table (6.20) and
Figure (6.22). The total effect size of the fixed-effect model was slightly less
significant than that of the random effect model, but its p value was statistically more
significant. The summary OR of the random effect model was more relevant than the
fixed effect technique because of the heterogeneity among the included studies, as
shown in Table (6.20).
Table 6.32 Statistical models for low birth weight
measure (95% CI)
Random-effect Odds Ratio 1.58 (1.21, <0.001 I2 = 76%, p value = 0.001
model 2.06)
Fixed-effect model Odds Ratio 1.34 (1.20, <0.001 I2 = 76%, p value = 0.001
1.50)
OR 95% CI P value
1.69 1.2 2.37 0.002
1
1.5 1.1 1.97 0.003
4
1.56 1.1 2.08 0.003
7
1.62 1.1 2.24 0.003
8
1.73 1.3 2.25 <0.001
3
1.61 1.2 2.14 0.001
1
1.58 1.1 2.12 0.002
8
1.4 1.1 1.75 0.002
0.9 1 1.1 1.3 1.5 1.7 1.9
Figure 6.23 Leave-one-out analysis for low birth weight

The results of the leave-one-out analysis are shown in Figure (6.22). It can be
seen that leaving out the study (Linn et al., 1982) and (Bakker et al., 2010) resulted in
an increase in the overall effect size, the summary OR of 1.69 (95% CI 1.21, 2.37)
with a p value of 0.002 and OR of 1.73 (95% CI 1.33, 2.25) with a p value of <0.001,
70
while the study (Hussen & Desu, 2020) and (Martin & Bracken, 1987) provided the
smaller effect size, the summary OR of 1.4 (95% CI 1.13, 1.75) with a p value of
0.002 and OR of 1.5 (95% CI 1.14, 1.97) with a p value of 0.003 when each study was
excluded from the analysis. The overall effect size in this outcome was calculated
using the odds ratio and the Mantel-Haenszel fixed effect model.
6.5.5 Meta-analysis for Stillbirth
A meta-analysis for SB was done by using Mantel-Haenszel random effect
model with 95% confident interval. There were three studies included in the analysis
to assess the overall pooled effect. According to data availability there was no
subgroup analysis but stratified analysis for risk of stillbirth was conducted level of
caffeine exposure relied on assigned median value by three categories.
6.5.5.1 Overall Pooled Effect for Stillbirth
Figure 6.24 Overall pooled effects of Stillbirth of caffeine consumption more

than 200 mg
To evaluate the overall pooled effect size for SB, the included studies were
analyzed by Mantel-Haenszel random effect model and the summary OR was 1.66
(95% CI 0.90, 3.06) with no significant p value = 0.11. There was also statistical
heterogeneity between the studies with I2 = 60%, Chi-square test of 4.94 and p value =
0.08 as shown in Figure (6.23).
6.5.5.2 Stratified Meta-analysis of Exposure Level Relation to Risk of Stillbirth
Despite three were studies included in this meta-analysis, stratified analysis
was performed by the exposure level due to dose response gradients. Three level of
exposure were applied to compare the reference level based on assigned median
value. The summary findings showed that the risk of low caffeine exposure was not
associated with SB, OR = 0.94 (95% CI 0.61, 1.45) but no statically significant p
71
value = 0.78 and there was no heterogeneity between these studies with I2 = 15%, Chi-
square test = 2.35 and p value = 0.31.
In the moderate caffeine exposure the summary OR was 2.08 (95% CI 0.72,
5.95) with p value = 0.17 and there was heterogeneity between the studies with I2 =
52%, Chi-square test = 2.09, p value = 0.15. In the high caffeine exposure, there was
only one study included in analysis and OR was 2.05 (95% CI 1.26, 3.34; p value =
0.004). There was no applicable for heterogeneity in this group, as shown in Figure
(6.24).
Figure 6.25 Estimated risk of stillbirth by level of caffeine exposure

6.5.5.3 Sensitivity Analysis for Stillbirth
The results of a sensitivity analysis for the total effect size of SB were
displayed in Tables (6.21) and (6.22) using a statistical model and a leave-one-out
analysis. The total effect size of the fixed-effect model was slightly more significant
than that of the random effect model, but its p value was statistically significant.
However, the summary OR of the random effect model was more relevant than the
72
fixed effect technique because of the heterogeneity among the included studies, as
shown in Table (6.21).
Table 6.33 Statistical models for stillbirth
Effect Overall ES
Model p value Heterogeneity
measure (95% CI)
Random-effect 1.66 (0.90,
Odds Ratio 0.11 I2 = 60%, p value = 0.08
model 3.06)
1.81 (1.29,
Fixed-effect model Odds Ratio <0.001 I2 = 60%, p value = 0.08
2.55)
The results of the leave-one-out analysis are shown in Table (6.22). It can be
seen that leaving out the study (Linn et al., 1982) resulted in an increase in the overall
effect size, the summary OR of 2.24 (95% CI 1.52, 3.30) with a p value of <0.0001,
while the study (Wisborg et al., 2003) provided the smaller effect size, the summary
OR of 1.23 (95% CI 0.71, 2.14) with a no significant p value of 0.46 when each study
was excluded from the analysis. . The overall effect size in this outcome was
calculated using the odds ratio and the Mantel-Haenszel fixed effect model.
Table 6.34 Leave-one-out analysis for stillbirth
Overall
No Omitted studies OR 95% CI p value 95% CI p value
OR
1 Linn et al. 2.24 1.52 3.30 <0.001 1.81 1.29 2.55 <0.001
2 Wisborg et al. 1.23 0.71 2.14 0.46 1.81 1.29 2.55 <0.001
3 Greenwood et al. 1.80 1.24 2.63 0.002 1.81 1.29 2.55 <0.001
6.6 Assessment of The Certainty of A Body of Evidence

In order to support the evaluation of the certainty of a body of evidence or
quality of evidence, the GRADE technique [GRADEpro GDT] was used to generate
the complete quantity of data on the key outcomes and key conclusions of a review,
which was provided in the "Summary of Findings" table, Table
(6.23) (www.gradepro.org).
The summary table highlighted five review findings on maternal caffeine
consumption during pregnancy. Based on three observational studies including 4278
individuals, the first outcome, miscarriage, was given a "Moderate" rating for overall
certainty of the evidence. Seriousa indirectness (the assessment of exposure was
conducted through interviews using questionnaires) and seriousb imprecision
73
significantly lowered the degree of evidence's certainty (one research had a large
confident interval).
The second outcome of small for gestational age was downgraded due to
strongly suspected publication bias that was stated in the meta-analysis, serious c
inconsistency, seriousa indirectness, and seriousd imprecision, with a total of 101,717
patients included in ten observational studies. As a result, it was given a "Low" for
overall evidence.
With a total of 106,593 samples, preterm birth was the third outcome, and it
was downgraded from "Moderate" due to serious f inconsistencies, seriousa
indirectness, and seriousg imprecision.
The fourth outcome, low birth weight, was developed using eight
observational studies with a total of 39,765 participants and was rated as "Very low"
due to strongly suspected publication bias, serious c inconsistency, seriousa
indirectness, and serioush imprecision.
The 33,165 individuals from three observational studies' stillbirths were
included in the final outcome. The judgment's assessment of the overall certainty of
the evidence was downgraded to "Low" as a result of the serious c inconsistency,
seriousa indirectness, and seriousi imprecision.
The Summary of Confidence of a Body of Evidence (GRADE Evidence) for
each outcome is shown in Table 6, and it is broken up into two sections: a certainty
assessment that includes studies, participants, risk of bias, inconsistency, indirectness,
imprecision, and overall certainty of the evidence; and a summary of findings that
includes the study event rate, relative effect (95% CI), and anticipated absolute effect.
With footnotes and explanations, it was written in great depth.
74
Table 6.35 Summary findings of certainty of evidence
Certainty assessment Summary of findings

Study event rates (%) Anticipated absolute effects
Inconsistency
Indirectness
Imprecision
Risk of bias
Overall Relative
Participants Publicatio Caffeine Caffeine Risk with Risk difference
certainty effect
(studies) n bias level < level ≥ Caffeine level with Caffeine
of evidence (95% CI)
200 mg 200 mg < 200 mg level ≥ 200 mg
Miscarriage
4278 not not seriousa seriousb strong ⨁⨁⨁◯ 824/3428 286/850 OR 1.54 240 per 1,000 87 more per
(3 serious serious association Moderate (24.0%) (33.6%) (1.30 to 1,000
observational 1.81) (from 51 more to
studies) 124 more)
Small for Gestational Age

101717 not seriousc seriousa seriousd publication ⨁⨁◯◯ 17524/ 1179/ OR 1.43 208 per 1,000 65 more per
(10 serious bias Low 84193 17524 (1.24 to 1,000
observational strongly (20.8%) (6.7%) 1.65) (from 38 more to
studies) suspected 94 more)
Table 6.36 Summary findings of certainty of evidence (Continued)
75

Risk of bias
Indirectnes
Inconsisten
Imprecisio
Overall Relative
Participants Publicatio Caffeine Caffeine Risk with Risk difference
certainty effect
cy
n
s
(studies) n bias level < level ≥ Caffeine level with Caffeine
of evidence (95% CI)
200 mg 200 mg < 200 mg level ≥ 200 mg
Preterm Delivery
106593 not seriousf seriousa seriousg very strong ⨁⨁⨁◯ 4820/ 789/ OR 1.19 53 per 1,000 9 more per
(7 serious association Moderate 91128 15465 (1.09 to 1,000
observational (5.3%) (5.1%) 1.29) (from 4 more to
studies) 14 more)
Low Birth Weight
39765 not seriousc seriousa serioush publication ⨁◯◯◯ 2047/3219 524/7573 OR 1.58 64 per 1,000 33 more per
(8 serious bias Very low 2 (6.4%) (6.9%) (1.21 to 1,000
observational strongly 2.06) (from 12 more to
studies) suspected 59 more)
76

Table 6.37 Summary findings of certainty of evidence (Continued)
Risk of bias
Indirectnes
Inconsisten
Overall
Imprecisio
Relative
Participants Publication certainty Caffeine Caffeine Risk with Risk difference
effect
(studies) bias of level < level > Caffeine level with Caffeine
(95% CI)
evidence
cy
200 mg 200 mg < 200 mg level > 200 mg
n
s
Stillbirth
33165 not seriousc seriousa seriousi strong ⨁⨁◯◯ 124/26831 52/6334 OR 1.66 5 per 1,000 3 more per
(3 seriou association Low (0.5%) (0.8%) (0.90 to 1,000
observational s 3.06) (from 0 fewer to
studies) 9 more)
CI: confidence interval; OR: odds ratio

Explanations
a. Exposure assessment was done by interview using questionnaires.
b. One study was wide confident interval.
c. One study was inconsistency with others.
d. Four studies were wide confident intervals.
e. There was publication bias confirmed by Begg's funnel plot and Egger's test.
f. One study inconsistent with others.
77
g. Three studies were wide confident intervals.
h. Five studies were wide confident intervals.
i. Two studies were wide confident intervals.
78
7. DISCUSSION
The discussion section of the review was divided into five standard
subheadings that followed the Cochrane Handbook's guidelines, with the statements
of (1) Summary of main results, (2) Potential review process biases, (3) Overall
completeness and applicability of evidence, (4) Certainty of the evidence, and (5)
Agreements and disagreements with other reviews, and the addition of a component
of strengths and limitations of this review to provide a place to reflect and collaborate
(Higgins et al., 2019).
7.1 Summary of Main Results

To evaluate the complete body of research on the relationship between
caffeine consumption and the risk of unfavorable pregnancy outcomes, a systematic
review and meta-analysis of this review were conducted. This review was a risk
review or etiology review, and the PEO framework was used to create the research
question. Using meticulously planned and coordinated search tactics, the key studies
required for this review were investigated and located from several databases
There were 1225 studies discovered using the search engines PubMed, Google
Scholar, HINARI, and Hand search. Using the indicated eligibility criteria and
accurately noting the exclusion log, all of the chosen studies underwent screening
beginning with the title and abstract and continuing through the complete full text. 25
studies were chosen after screening and full-text retrieval that were eligible. The risk
of bias was then assessed using JBI Critical Appraisal Tools for each of the 25
research that were taken into consideration, comprising 6 case-control papers, 6 cross-
sectional analytical studies, and 13 cohort studies. The independent reviewer
determined that there was a low probability of bias in each of the included studies
The majority of these articles (n=6) were conducted in the United States of
America (USA), followed by the United Kingdom (UK) (n=3), Italy (n=3), Canada
(n=2), Denmark (n=2), and the Netherlands (n=2), and the remaining countries (n=1)
were Brazil, Iraq, Japan, Jordan, Norway, Poland, Southern Ethiopia, and Iraq,
respectively. To ensure the accuracy of the data, all of the investigations were carried
out in hospital and clinical settings utilizing a specific database and clinical records.
In this review, the outcomes of interest were: (1) miscarriage; (2) small for gestational
79
age; (3) preterm delivery; (4) low birth weight; and (5) stillbirth. Comprehensive
tabular synthesis was used to report on the characteristics of the included studies.
7.1.1 Risk of Miscarriage
The three studies, one cohort (Weng et al., 2008) and two case-control studies
(Fenster et al., 1991b; Infante-Rivard et al., 1993), combined effect of miscarriage
was 1.54 (95% CI 1.30, 1.81; p value < 0.001) and I2 = 45%, analyzed by Mantel-
Haenszel odds ratio using fixed effect model. There were strong consistent and no
heterogeneity between these studies and statistically significant in pooled effect (OR).
Thus, the result of this outcome was applicable in maternal caffeine consumption of
equal or more than 200 mg per day. As a result of data availability, the summary
finding of stratified analysis showed that the risk of low caffeine exposure was 1.46
(95% CI 1.13, 1.88; p value = 0.003; I2 = 52%) and moderate caffeine exposure was
1.63 (95% CI 1.21, 2.20; p value = 0.001; I2 = 0%). It can be seen that level of
exposure was positive relationship to the risk of miscarriage.
7.1.2 Risk of Small for Gestational Age
For the findings of SGA, the summary OR conducted by Mantel-Haenszel
random effect model stated the association with caffeine intake during pregnancy
significantly, but there was substantial heterogeneity in ten included studies with I2 =
64%, Chi-square test = 25.8, p value = 0.003. In subgroup analysis, there were no
remarkable changes of risk of outcome in all groups of study designs and the results
were proved that caffeine exposure equal or more than 200 mg has a chance for risk
of small for gestational age by statistically significant p values. Regarding the
stratified analysis, the risks of SGA was increased depend on more consumption of
caffeine exposure level. It can be seen that there was significant relationship of SGA
and level of caffeine exposure.
7.1.3 Risk of Preterm Delivery
From the analysis of included seven studies, the pooled risk (OR) of PB was
1.19 (95% CI 1.09, 1.29; p value < 0.001) and no heterogeneity between the studies
performed by Mantel-Haenszel fixed effect model. Although there was no
heterogeneity, the findings of subgroup analysis were inconsistent in different study
designs. The summary risk of preterm birth was similar effect with cross-sectional
and cohort groups and inconsistent with case-control group analyzed by one included
80
study and no statistically significant. There may be some potential bias such as recall
bias, interviewer bias and exposure assessment tool.
The stratified analysis data showed that the risk of preterm birth due to
caffeine consumption during pregnancy was no significant association to low and
high level of caffeine exposure [ OR = 1.02 (95% CI 0.93, 1.13; p value = 0.64) for
low exposure and OR = 1.55 (95% CI 0.71, 3.38; p value = 0.27) for high exposure].
However, the summary OR was association among exposure and outcome with OR=
1.19 (95% CI 1.08, 1.32) and statistically significant p value = 0.0005, in moderate
caffeine exposure group. Therefore, it can be said that the risk of preterm delivery
related to level of caffeine consumption from this review was not relevance to apply.
7.1.4 Risk of Low Birth Weight
The overall estimated effect of low birth weight in this review was 1.58 (95%
CI 1.21, 2.06) and p value = 0.0007. According to the heterogeneity (I2 = 76%, Chi-
square test = 29.29, p value = 0.0001) in the meta-analysis, subgroup analysis was
done by study design using Mantel-Haenszel random effect model. The summary
risks of low birth weight in subgroups were different where cross-sectional study
group was consistent with pooled effect while cohort group was no significant
association in analysis. In addition, case-control group included only one study in
analysis produced more estimated effect size with OR = 4.29 (95% CI 2.24, 8.20; p
value of < 0.001) and it can influence on overall pooled effect. Thus, there may be
some potential bias such as recall bias, interviewer bias and exposure assessment tool.
In stratified analysis, the summary OR of low and high caffeine level was no
statistically significant while there was more remarkable risk of low birth weight with
summary OR = 1.55 (95% CI 1.21, 1.99; p value < 0.001) in moderate consumption.
Therefore, it can be seen that there was no significant association between caffeine
exposure level and risk of low birth weight. However moderate caffeine consumption
(300-499 mg) had a chance of risk for low birth weight significantly.
7.1.5 Risk of Stillbirth
Using Mantel-Haenszel random effect model, the overall odds ratio of
stillbirth was 1.66 (95% CI 0.90, 3.06) with no significant p value = 0.11 and
statistical heterogeneity was also present between the included studies. Subgroup
analysis was not applicable because of three included articles therefore stratified
analysis was done by different level of caffeine exposure. There were also no
81
significant association between caffeine consumption and stillbirth in both low and
moderate exposure compared to reference level with OR = 0.94 (95% CI 0.61, 1.45; p
value = 0.78) and OR = 2.08 (95% CI 0.72, 5.95; p value = 0.17), respectively. In the
high caffeine exposure, there was only one study included and OR was 2.05 (95% CI
1.26, 3.34; p value = 0.004). Nevertheless, it may be said that there was no significant
association between the risk of stillbirth and maternal caffeine consumption.
7.2 Potential Bias in Review Process

The first step in the search procedure was to precisely create the search
strategy and key terms for the review framework and search to match all eligible
studies from various databases in order to reduce selection bias. However, due to the
reviewer's experience and the fact that some high-quality databases were not freely
accessible, some key words, mesh terms, and text words may be required to be
comprehensive. Therefore, this review only had a little amount of selection biases.
Second, the reviewers meticulously took the likelihood of bias into account
while assessing the outcomes of each study that was included in a systematic review.
A critical assessment of the included studies was conducted using the JBI Critical
Appraisal Tools and reported as a major indicator of quality in systematic reviews.
The two reviewers independently assessed both qualitatively and quantitatively
utilizing checklists of assessment techniques, and there was no disagreement between
them. In contrast, there was little potential for bias and misleading findings in any of
the studies that were included.
It is feasible to take into account the findings of the qualitative synthesis and
meta-analysis of the data from the included research for determining the third
potential bias. Two reviewers independently and accurately carried out the prescribed
data extraction procedure and eligible criteria in order to minimize observer bias.
However, there was significant heterogeneity in the results and findings in the
assessment of publication bias, which could be attributed to different study designs,
methodological and clinical variation, context variation, different exposure levels,
different assessment methods, the study's setting, and selective under- and non-
reporting of results.
The evaluation was not started, directed, sponsored, or financially supported
by any specific individual, group, organization, or other legal entity. There were no
financial conflicts of interest because this review was conducted as part of a Master's
82
degree. Because the team members (WZM and HPK) were coworkers pursuing a
Master of Public Health, and the third reviewer (LP) was a lecturer and supervisor
from the department of preventive and social medicine, there were no conflicts of
interest among the reviewers. Conflicts could not arise from interpersonal
relationships, academic competition, intellectual passion, or any other circumstance
that could result in a real or perceived unjust impact on judgments.
7.3 Overall Completeness and Applicability of Evidence

No single participant could be completely matched to the group analyzed in
the included research because the population of interest consisted of pregnant women
of reproductive age who appeared healthy or low risk. Because the studies were
picked based on strict qualifying requirements, it's possible that there weren't any
noticeable differences between the population of interest and the population to whom
the evidence was applied at the time of the selection.
When assessing whether exposure and non-exposure effects were actually
applied to all participants, population biological variance, exposure variation in
different caffeine-containing beverages, and other factors may have an impact on a
result's application. In this review, coffee and tea were cited as the two most
important terms, but they weren't discussed in detail in terms of their varieties, levels
of caffeine, or the materials needed to manufacture them. In light of this, the findings
of this review may have some bearing on how useful the data is, but each outcome of
interest may be affected by the level of exposure.
The primary emphasis of the review was caffeine exposure during pregnancy
and adverse pregnancy outcomes, and its findings included the effect magnitude for
each outcome and the relationship between exposure level and outcome risk. The
findings weren't convincing enough to justify an answer to the query. Additional
exposures may also be taken into account in order to virtually completely complete
the study.
7.4 Certainty of the Evidence

The inclusion of a variety of study designs in this review may have some
impact on the body of evidence. Depending on the review question under
investigation, they comprised observational studies such as cross-sectional studies,
case-control studies, and cohort studies. Each had its own advantages and drawbacks.
83
The capacity to optimize internal validity and research design were frequently linked
to the ranking of effectiveness evidence. Observational studies' evidence of outcomes'
certainty was rated less highly than studies' evidence of outcomes based on
randomized control trials.
Five outcomes were used to address the research question; two of them,
miscarriage and preterm delivery, were rated as "Moderate," two of them, small for
gestational age and stillbirth, were rated as "Low," and the one, low birth weight, was
rated as "Very Low" in terms of overall certainty of evidence. It might be argued that
the evaluation's results have some issues for "Low" and "Very low" grading but are
acceptable for "Moderate" grade.
7.5 Agreements and Disagreements with Other Reviews

This review revealed that there was a direct correlation between maternal
caffeine use and all unfavorable pregnancy outcomes. This review stated the
consistent agreement with previous systematic reviews and meta-analyses on the
subject of miscarriage outcomes, including those by (Li et al., 2015) who found that
maternal caffeine consumption was linked to an increased risk of miscarriage (OR
1.32, 95% CI 1.24, 1.40), and (Ayoub & Yaseen, 2022), who found that the pooled
estimated effect (RR) for pregnant mother in the caffeine exposed group was 1.65
(95% CI 1.46, 1.87) and both studies were analyzed by cutoff point of exposure (>150
mg/day). Moreover, although exposure categories were different, findings in
increasing the level of exposure related to miscarriage was also in line with the result
of study (Chen et al., 2015) in which the summary RR of miscarriage was 1.02 (95%
CI 0.85, 1.24) for low consumption (50-149 mg/day), 1.16 (95% CI 0.94, 1.41) for
moderate exposure (150-349 mg/day), 1.40 (95% CI 1.16, 1.68) for high exposure
(350-699 mg/d) and 1.72 (95% CI 1.40, 2.13) for very high consumption (≥700
mg/d).
The pooled estimated risk of this review was strongly associated with maternal
caffeine consumption in relation to the outcome of small for gestational age, and the
level of exposure was also correlated with a dosage response relationship. This result
showed no discrepancy with earlier systematic review findings (Greenwood et al.,
2014), which showed that the pooled effect of the risk ratio (RR) from a linear dose-
response meta-analysis was 1.10 (95% CI 1.06, 1.14) per 100 mg/day of caffeine (p
value <0.001).
84
For the results of preterm delivery, the overall pooled effect size was
inconsistent with other review. The finding of this review was significantly
association with maternal caffeine consumption although primary article (Mannucci et
al., 2020) in which the risk of preterm birth (OR) for women who drank coffee during
pregnancy was 1.01 (95% CI 0.72, 1.54; p value = 0.939) for overall coffee drinking,
0.871(95% CI 0.76, 1.47; p value = 0.248) for caffeine 122 mg/day, 1.05 (95% CI
0.72, 1.54; p value = 0.751) for caffeine 244 mg/day and 0.559 (95% CI 0.26, 1.21; p
value = 0.14) for caffeine 366 mg/day. But the findings of stratified analysis showed
the agreement results of the previous study (Greenwood et al., 2014) stated that the
pooled estimate of outcome was no approvable association from linear dose- response
meta-analysis with RR = 1.02 (95 % CI .98–1.06) per 100 mg/day of caffeine (p value
= 0.42).
Regarding the outcome of low birth weight, the summary odds ratio in this
study was significantly associated to maternal caffeine intake during pregnancy and
there were strong agreements with other reviews. In one study, a systematic review
and meta-analysis by (Chen et al., 2014) showed the pooled relative risk (RR) of low
birth weight was 1.13 (95% CI 1.06, 1.21) for low exposure (50-149 mg), 1.38 (95%
CI 1.18-1.62) for moderate consumption (150-349 mg), and 1.6 (95% CI 1.24, 2.08)
for high exposure. In another review, (Jin & Qiao, 2021) found that the summary
relative risk (RR) for low birth weight was 1.33 (95% CI 1.12, 1.57) in comparison of
highest caffeine intake to lowest caffeine level.
The last pregnancy outcome, risk of stillbirth in the analysis mentioned that
the pooled estimated effect size of three included studies was 1.66 (95% CI 0.90,
3.06) and this result was no incompatibility with primary studies except (Linn et al.,
1982) in which stillbirth was not the main outcome of the study. Findings concerning
the exposure level were also consistent with the review of (Greenwood et al., 2014)
by the summary effect size (RR) was 1.19 (95% CI 1.05, 1.35) per 100 mg/day of
caffeine in dose-response relation analysis.
7.6 Strengths and Limitations

The systematic review and meta-analysis highlighted, among other things, the
following strengths:
85
1. This study used a rigorous methodology, statistical analysis by two
independent reviewers, and an evidence-based systematic review and
analysis to ensure good internal validity.
2. The simultaneous observation of a narrative review and a tabular synthesis
in this review, which may simultaneously supply additional information
3. The demographic of interest was deliberately defined as looking healthy or
low-risk pregnant women of reproductive age in order to maximize the
review's generalizability or external validity.
4. The pooled effect sizes for each outcome will be more accurate and
precise, enhancing external validity, despite the fact that many primary
studies produced inconsistent results when a particular sample size was
taken into consideration.
5. This study found strong evidence for certainty regarding miscarriage and
preterm delivery and fair evidence regarding small for gestational age and
stillbirths, and findings would be acceptable for practice due to
"Moderate" and "Low" grade for each outcome.
However, the review included the following limitations:
1. Due to the reviewers' limited experience and the accessibility of the
databases, there may be a slight weakness in the search words and search
technique.
2. Because of recall bias, the interview approach of exposure evaluation
made it impossible to identify the actual caffeine amount in individual
included studies.
3. When determining the exposure status for caffeine, other forms of
caffeinated beverages (rather than coffee and tea) and drugs are excluded
in the included studies.
4. Based on the original research findings from primary studies that each
employed a different cutoff point level, this review made an assumption
based on the assigned median value.
5. Not all of outcomes from protocol were provided.
6. It is challenging to compile ongoing results given the diversity of the
studies that were evaluated.
7. Publication bias was discovered in relation to evaluate the pooled effect
size of small for gestational age and low birth weight.
86
8. For the sensitivity analysis, only leave-one-out and statistical model
analysis were used; meta-regression was not.
87
8. CONCLUSION
This systematic review and meta-analysis supports the research question that
maternal caffeine intake during pregnancy is associated with the risk of adverse
pregnancy outcomes. In this meta-analysis based on assigned median value and
categories of caffeine consumption, the risk for miscarriage, small for gestational age,
preterm delivery and low birth weight were significantly associated with maternal
caffeine consumption of equal or more than 200 mg compared to caffeine exposure
less than 200 mg but the risk for stillbirth was not associated with maternal caffeine
intake during pregnancy. In stratified analysis of exposure level, the risks for
miscarriage and small for gestational age also increased by increasing levels of
caffeine exposure however the risks for preterm delivery, low birth weight and
stillbirth were unclear. Nonetheless the risks for all adverse pregnancy outcomes
except stillbirth were associated with maternal caffeine consumption of equal or more
than 200 mg per day during pregnancy compared to caffeine consumption of less than
200 mg per day. In real practice, pregnant mothers should be taken into account the
risks of adverse reproductive outcomes caused by caffeine consumption during
pregnancy and should be avoid from consuming caffeine (especially coffee) in
amounts greater than or equal to 200 mg (2-3 cups) per day.
88
9. RECOMMENDATIONS
The following recommendations are suggested for the application of the

results from this review and the improvement of further primary and secondary
research regarding the maternal caffeine consumption and adverse pregnancy
outcomes-
1. According to this analysis, caffeine intakes below the recommended maximum
limit of the current recommendations for pregnant women (200 mg/day by the
Nordic Nutrition Guidelines and 300 mg/day by the World Health
Organization) may increase the risk of miscarriage and small for gestational
age.
2. This finding does add to the body of evidence that suggests pregnant women
should consume no more than 100 mg of caffeine per day however it would be
ideal to see this result confirmed in larger randomized controlled trials.
3. Further in-depth studies are needed to clarify the harmful consequences of
maternal caffeine usage during pregnancy, notably on preterm delivery and
stillbirth.
4. The next systematic review ought to focus on a certain sub-population, such as
women of a certain age who are primigravida or multigravida, and on a
specific gestational period, such as the first, second, and third trimesters.
5. To minimize the differences between the included studies and to enhance the
internal validity of the review, it is necessary to highlight the specific type of
exposure and advanced exposure assessment method in future reviews.
6. The data from this evaluation is supporting evidence-based practice for the
policy-maker in making decisions and disseminating information about
antenatal care and maternal and child health care programs.
89
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100
11. APPENDICES
Appendix 1: Administrative information

Named contact – Dr Win Zaw Maung
Named contact email – drwinzm1986@gmail.com
Named contact address – No. (10) Basic Military Training Unit, Ayartaw, Monywa,
Myanmar
Named contact phone number – +959 251 309 411
Organizational affiliation of the review – Defence Services Medical Academy,
Myanmar
Review team members and organizational affiliations –
1. Dr Win Zaw Maung (WZM), Defence Services Medical Academy, Myanmar.
2. Dr Hpone Pji Kyaw (HPK), Defence Services Medical Academy, Myanmar.
3. Dr Linn Pyae (LP), Defence Services Medical Academy, Myanmar.
Funding sources/sponsors –
There will not be individuals, organizations, groups or other legal entities who take
responsibility for initiating, managing, sponsoring and/or financing the review. This
review is intended for the partial fulfillment of a Master degree.
Conflicts of interest –
There will not be conflicts of interest among the reviewers because the team members
are colleagues attending the degree of Master in Public Health and the third reviewer
has just accomplished a systematic review for partial fulfillment of the requirement
for the Degree of Master. Therefore, conflicts cannot occur for the reasons, such as
personal relationships, academic competition, and intellectual passion and any
conditions that could lead to actual or perceived undue influence on judgments cannot
occur.
Collaborators –
1. Professor Kyaw Myo Tun, Directorate of Medical Services
2. Dr Tun Tun Win, Defence Services Medical Academy
101
Appendix 2: Search Strategies
Appendix 2.1.Search Strategy in PUBMED
Search Strategy
Domains Searc Details Filter Results
h
((("Pregnancy"[Mesh]) OR "Pregnant Women"[Mesh]) OR "Gestational Sac"[Mesh]
Abstract,
AND ((fha[Filter]) AND (observational study[Filter]) AND (fft[Filter]))) OR
Full text,
Populatio ((((((pregnancy[Title/Abstract]) OR ("pregnant women"[Title/Abstract])) OR
#1 and 13,637
n (P) ("gestational mother"[Title/Abstract])) OR ("pregnant mother"[Title/Abstract])) OR
Observational
("gestational women"[Title/Abstract])) OR (healthy[Title/Abstract]) AND ((fha[Filter])
Study
AND (observational study[Filter]) AND (fft[Filter])))
Abstract,
(("Coffee"[Mesh]) OR "Caffeine"[Mesh] AND ((fha[Filter]) AND (observational
Full text,
Exposure study[Filter]))) OR (((((coffee[Title/Abstract]) OR (caffeine[Title/Abstract])) OR
#2 and 19,512
(E) (level[Title/Abstract])) OR (amount[Title/Abstract])) OR (dosage[Title/Abstract]) AND
Observational
((fha[Filter]) AND (observational study[Filter]) AND (fft[Filter])))
Study
102
Search Strategy
Domains Searc
Details Filter Results
h
(((((((((((((((((((("pregnancy outcomes"[Title/Abstract]) OR ("pregnancy
complications"[Title/Abstract])) OR ("adverse birth outcomes"[Title/Abstract])) OR
(miscarriage[Title/Abstract])) OR (abortion[Title/Abstract])) OR ("spontaneous
abortion"[Title/Abstract])) OR ("miss abortion"[Title/Abstract])) OR ("incomplete
abortion"[Title/Abstract])) OR ("complete abortion"[Title/Abstract])) OR ("small for
gestational age"[Title/Abstract])) OR (SGA[Title/Abstract])) OR
(preterm[Title/Abstract])) OR ("preterm delivery"[Title/Abstract])) OR ("preterm Abstract,
labor"[Title/Abstract])) OR ("premature birth"[Title/Abstract])) OR ("preterm Full text,
Outcomes birth"[Title/Abstract])) OR (stillbirth[Title/Abstract])) OR ("fetal death"[Title/Abstract]))
#3 OR ("low birth weight"[Title/Abstract])) OR ("birth weight"[Title/Abstract]) AND and 6,317
(O)
((fha[Filter]) AND (observational study[Filter]) AND (fft[Filter]))) OR Observational
((((((((((("Pregnancy Outcome"[Mesh]) OR "Pregnancy Complications"[Mesh]) OR Study
( "Abortion, Spontaneous"[Mesh] OR "Abortion, Threatened"[Mesh] )) OR "Abortion,
Missed"[Mesh]) OR "Infant, Small for Gestational Age"[Mesh]) OR "Premature
Birth"[Mesh]) OR "Obstetric Labor, Premature"[Mesh]) OR "Fetal Death"[Mesh]) OR
"Stillbirth"[Mesh]) OR ( "Infant, Low Birth Weight"[Mesh] OR "Infant, Extremely Low
Birth Weight"[Mesh] OR "Infant, Very Low Birth Weight"[Mesh] )) OR "Birth
Weight"[Mesh] AND ((fha[Filter]) AND (observational study[Filter]) AND (fft[Filter])))
#4 #1 AND #2 AND #3 795

Last search was done on 15.1.2023 (11:00 AM).
103
Appendix 2.2.Search Strategy in Google Scholar
Search Strategy
Domains Searc
Details Filter Results
h
English
Populatio Pregnancy OR "pregnant women" OR "gestational mother" OR "pregnant mother" OR
#1 "gestational women" OR healthy language, and 525,000
n (P)
no citation
English
Exposure
#2 Coffee OR tea OR caffeine OR level OR amount OR dosage language, and 808,000
(E)
no citation
"Pregnancy outcomes" OR "pregnancy complications" OR "adverse birth outcomes" OR
miscarriage OR abortion OR "spontaneous abortion" OR "miss abortion" OR English
Outcomes
#3 "incomplete abortion" OR "complete abortion" OR "small for gestational age" OR language, and 2,310
(O) (SGA) OR preterm OR "preterm delivery" OR "preterm labor" OR "premature birth" OR
no citation
"preterm birth" OR stillbirth OR "fetal death" OR "low birth weight" OR "birth weight"
#4 #1 AND #2 AND #3 87
104
Appendix 2.3.Search Strategy in HINARI via Research4life
Search Strategy
Domains
Search Details Filter Results
Population Pregnancy OR "pregnant women" OR "gestational mother" OR "pregnant mother" OR
#1 "gestational women" OR healthy 2,058,046
(P)
Exposure 11,331,88
#2 Coffee OR caffeine OR level OR amount OR dosage
(E) 9
Outcomes
#3 "Pregnancy outcomes" OR "pregnancy complications" OR "adverse birth outcomes" 175,993
(O)
#1 AND #2 AND #3 338
105
106
Appendix 3: JBI Critical Appraisal Checklists
Appendix 3.1 JBI Critical Appraisal Checklist for Cohort Study
Reviewer Date
Author Year Record Number
No Reason for check Yes No unclear Not
Applicable
1. Were the two groups similar and recruited

from the same population?
2. Were the exposures measured similarly to
assign people to both exposed and
unexposed groups?
3. Was the exposure measured in a valid and
reliable way?
4. Were confounding factors identified?
5. Were strategies to deal with confounding

factors stated?
6. Were the groups/participants free of the
outcome at the start of the study (or at the
moment of exposure)?
7. Were the outcomes measured in a valid and
reliable way?
8. Was the follow up time reported and
sufficient to be long enough for outcomes to
occur?
9. Was follow up complete, and if not, were
the reasons to loss to follow up described
and explored?
10 Were strategies to address incomplete
follow up utilized?
.
11 Was appropriate statistical analysis used?

.
Overall appraisal: Include Exclude Seek further info
Comments (Including reason for exclusion)
107
_____________________________________________________________________
_____________________________________________________________________
Appendix 3.2 JBI Critical Appraisal Checklist for Case-control Study

Reviewer Date
No Reason for check Yes No unclear Not
Applicabl
e
1. Were the groups comparable other than

the presence of disease in cases or the
absence of disease in controls?
2. Were cases and controls matched

appropriately?
3. Were the same criteria used for

identification of cases and controls?
4. Was exposure measured in a standard,

5. Was exposure measured in the same way

for cases and controls?

factors stated?
8. Were outcomes assessed in a standard,

valid and reliable way for cases and
controls?
9. Was the exposure period of interest long

enough to be meaningful?
10. Was appropriate statistical analysis used?
108
_____________________________________________________________________
_____________________________________________________________________
_____________________________________________________________________
109
Appendix 3.3 JBI Critical Appraisal Checklist for Cross-sectional study
Reviewer Date
Yes No Unclear Not
applicable
1. Were the criteria for inclusion in the

sample clearly defined?
2. Were the study subjects and the setting

described in detail?
3. Was the exposure measured in a valid and

reliable way?
4. Were objective, standard criteria used for

measurement of the condition?

factors stated?
7. Were the outcomes measured in a valid

and reliable way?
8. Was appropriate statistical analysis used?
_____________________________________________________________________
_____________________________________________________________________
_____________________________________________________________________
110
Appendix 4: PRISMA (2020) Checklist
PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) (2020) checklist
Section and Ite Checklist item Reported

topic m Remark
No ( /)
ADMINISTRATIVE INFORMATION
Title:
Identification 1a Identify the report as a protocol of a systematic review  Cover sheet
Update 1b If the protocol is for an update of a previous systematic review, identify as such  Section 1.2
Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration
 Section 5.2
number
Authors:
Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide  Appendix 1
physical mailing address of corresponding author
Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review  Appendix 1
Amendment 4 If the protocol represents an amendment of a previously completed or published protocol, 
s identify as such and list changes; otherwise, state plan for documenting important
protocol amendments
Support:
Sources 5a Indicate sources of financial or other support for the review  Appendix 1
Sponsor 5b Provide name for the review funder and/or sponsor  Appendix 1
Role of 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the  Appendix 1
sponsor protocol
INTRODUCTION
111
Rationale 6 Describe the rationale for the review in the context of what is already known  Section 1.3
Section and Ite Checklist item Reported Remark
topic m ( /)
No
Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to  Section 3, 4
participants, interventions, comparators, and outcomes (PICO) & 5.1
METHODS
Eligibility 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and  Section 5.4
criteria report characteristics (such as years considered, language, publication status) to be used as
criteria for eligibility for the review
Information 9 Describe all intended information sources (such as electronic databases, contact with  Section 5.5
sources study authors, trial registers or other grey literature sources) with planned dates of
coverage
Search 10 Present draft of search strategy to be used for at least one electronic database, including  Section 5.5.2
strategy planned limits, such that it could be repeated Appendix 2
Study
records:
Data 11a Describe the mechanism(s) that will be used to manage records and data throughout the  Section 5.6
management review
Selection 11b State the process that will be used for selecting studies (such as two independent  Section 5.6
process reviewers) through each phase of the review (that is, screening, eligibility and inclusion in
meta-analysis)
Data 11c Describe planned method of extracting data from reports (such as piloting forms, done  Section 5.7
collection independently, in duplicate), any processes for obtaining and confirming data from
process investigators
112
Data items 12 List and define all variables for which data will be sought (such as PICO items, funding  Section 5.9
sources), any pre-planned data assumptions and simplifications Section 6
Section and Ite Checklist item Reported Remark

topic m ( /)
No
Outcomes 13 List and define all outcomes for which data will be sought, including prioritization of  Section 5.4.5
and main and additional outcomes, with rationale
prioritization
Risk of bias 14 Describe anticipated methods for assessing risk of bias of individual studies, including  Section 5.8
in individual whether this will be done at the outcome or study level, or both; state how this Appendix 3
studies information will be used in data synthesis
Data 15a Describe criteria under which study data will be quantitatively synthesised  Section
synthesis 5.10.1
15b If data are appropriate for quantitative synthesis, describe planned summary measures,  Section
methods of handling data and methods of combining data from studies, including any 5.10.3
planned exploration of consistency (such as I2, Kendall’s τ)
15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses,  Section
meta-regression) 5.10.4
15d If quantitative synthesis is not appropriate, describe the type of summary planned  Section 5.9
Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies,  Section
selective reporting within studies) 5.10.5
Confidence in 17 Describe how the strength of the body of evidence will be assessed (such as GRADE)  Section 5.11
cumulative
evidence
113
* It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available)
for important clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including
checklist) is held by the PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0 (Shamseer et al., 2015).
Appendix 5: PRISMA (2020) for Abstract Checklist

Section and Reported
Item # Checklist item
Topic (✓ / X)
TITLE
Title 1 Identify the report as a systematic review. ✓
BACKGROUND
Objectives 2 Provide an explicit statement of the main objective(s) or question(s) the review addresses. ✓
METHODS
Eligibility 3 Specify the inclusion and exclusion criteria for the review. ✓
criteria
Information 4 Specify the information sources (e.g. databases, registers) used to identify studies and the date ✓
sources when each was last searched.
Risk of bias 5 Specify the methods used to assess risk of bias in the included studies. ✓
Synthesis of 6 Specify the methods used to present and synthesise results. ✓
results
RESULTS
Included studies 7 Give the total number of included studies and participants and summarise relevant ✓
characteristics of studies.
Synthesis of 8 Present results for main outcomes, preferably indicating the number of included studies and ✓
114
Topic (✓ / X)
results participants for each. If meta-analysis was done, report the summary estimate and
confidence/credible interval. If comparing groups, indicate the direction of the effect (i.e. which
group is favoured).
PRISMA (2020) for Abstract Checklist (Continued)

Topic (✓ / X)
DISCUSSION
Limitations of 9 Provide a brief summary of the limitations of the evidence included in the review (e.g. study risk ✓
evidence of bias, inconsistency and imprecision).
Interpretation 10 Provide a general interpretation of the results and important implications. ✓
OTHER
Funding 11 Specify the primary source of funding for the review. ✓
Registration 12 Provide the register name and registration number. ✓
115
Appendix 6: Gantt Chart
2022 2023
Time
Activity Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr
Protocol preparation
Protocol defence
Protocol registration
Identification and
screening process
Quality appraisal
Data extraction
Data synthesis and

data analysis
Review writing
Conclusion
Thesis defence
116
117

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MATERNAL CAFFEINE CONSUMPTION AND

ADVERSE PREGNANCY OUTCOMES:

A thesis submitted in partial fulfillment of the requirement for the

WIN ZAW MAUNG

1.1 Background Information 1

2.1 Overview of Caffeine 6

5.1 Research Design 13

6.1 Summary of Selection Process 25

7.1 Summary of Main Results 77

Appendix 1: Administrative information 99

ACOG - American College of Obstetricians and Gynecologists

1.1 Background Information

Pregnant women Pregnancy

Figure 1.1 Analytical framework

2.1 Overview of Caffeine

2.2 Caffeine Contents in Different Types of Beverages

Coffee drinks Size in oz. (mL) Caffeine (mg)

Brewed, decaf 8 (237) 2

Espresso, decaf 1 (30) 0

Instant, decaf 8 (237) 2

Teas Size in oz. (mL) Caffeine (mg)

Brewed black 8 (237) 47

Brewed black, decaf 8 (237) 2

Brewed green 8 (237) 28

Ready-to-drink, bottled 8 (237) 19

Table 2.3 Caffeine contents in sodas

Sodas Size in oz. (mL) Caffeine (mg)

Citrus (most brands) 8 (237) 0

Root beer (most brands) 8 (237) 0

Table 2.4 Caffeine contents in energy drinks

Energy drinks Size in oz. (mL) Caffeine (mg)

Energy drink 8 (237) 71.9

Energy shot 2 (60) 215

2.4 Pregnancy Outcomes

5.1 Research Design

5.2 Process of Registration

5.3 Study Period

5.4 Eligibility Criteria

5.5 Information Sources and Search Strategy

In this evaluation, two independent reviewers, (WZM and HPK) developed a

5.6 Identification and Selection of Studies

5.7 Data Collection Process

5.8 Risk of Bias Assessment

5.9 Data Extraction

5.10 Data Synthesis and Analysis

5.11 Confidence in Cumulative Evidence

5.13 Ethical Consideration

6.1 Summary of Selection Process

Cohort studies (n=13)

Figure 6.2 Included Studies in Review

Identification of studies via databases and registers

Studies identified from:

Databases (n=1225) Studies removed before

Studies not retrieved (n =28):

Studies excluded (n=17):

Studies assessed for eligibility

Studies excluded (n=4):

Figure 6.3 PRISMA Flow Diagram

Table 6.9 Characteristics of Included Studies (Case-control studies) (n=6)

Q2 Were cases and controls 4 2 4 2

Q3 Were the same criteria used for 3 3 3 3

Q4 Was exposure measured in a 5 1 5 1

Q5 Was exposure measured in the 6 6