Obesity and Pregnancy - Mechanisms of Short Term and Long Term Adverse Consequences For Mother and Child - PMC

01/04/2023, 16:30 State of the Art Review: Obesity and pregnancy: mechanisms of short term and long term
ong term adverse consequences for mother and child - PMC
BMJ. 2017; 356: j1. PMCID: PMC6888512

Published online 2017 Feb 8. doi: 10.1136/bmj.j1: 10.1136/bmj.j1 PMID: 28179267
State of the Art Review
Obesity and pregnancy: mechanisms of short term and long term adverse consequences
for mother and child
Patrick M Catalano, professor and director1 ,2 and Kartik Shankar, associate professor3 ,4
1
Department of Obstetrics and Gynecology, Center for Reproductive Health/MetroHealth Medical Center, Cleveland,
Ohio, USA
2
Case Western Reserve University, Cleveland, Ohio, USA
3
Arkansas Children’s Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
4
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
Correspondence to: P M Catalano pcatalano@metrohealth.org
Accepted 2016 Dec 5.
Copyright Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a
licence) please go to http://group.bmj.com/group/rights-licensing/permissions
Abstract
Obesity is the most common medical condition in women of reproductive age. Obesity during pregnan‐
cy has short term and long term adverse consequences for both mother and child. Obesity causes prob‐
lems with infertility, and in early gestation it causes spontaneous pregnancy loss and congenital anom‐
alies. Metabolically, obese women have increased insulin resistance in early pregnancy, which becomes
manifest clinically in late gestation as glucose intolerance and fetal overgrowth. At term, the risk of ce‐
sarean delivery and wound complications is increased. Postpartum, obese women have an increased
risk of venous thromboembolism, depression, and difficulty with breast feeding. Because 50-60% of
overweight or obese women gain more than recommended by Institute of Medicine gestational weight
guidelines, postpartum weight retention increases future cardiometabolic risks and prepregnancy obesi‐
ty in subsequent pregnancies. Neonates of obese women have increased body fat at birth, which in‐
creases the risk of childhood obesity. Although there is no unifying mechanism responsible for the ad‐
verse perinatal outcomes associated with maternal obesity, on the basis of the available data, increased
prepregnancy maternal insulin resistance and accompanying hyperinsulinemia, inflammation, and ox‐
idative stress seem to contribute to early placental and fetal dysfunction. We will review the pathophysi‐
ology underlying these data and try to shed light on the specific underlying mechanisms.
Introduction
Obesity is the most common problem in obstetrics that affects both the mother and her offspring.1 It
causes short term and long term problems for the mother, such as increasing her risk of gestational dia‐
betes (GDM) and pre-eclampsia.2 Because obese women are more likely to have excessive gestational
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01/04/2023, 16:30 State of the Art Review: Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child - PMC
weight gain (GWG),3 this further increases the risk of developing the metabolic syndrome in later life.
The offspring have an increased risk of obstetric morbidity and mortality,4 and, consistent with the de‐
velopmental origins of health and disease, a long term risk of childhood obesity and metabolic
dysfunction.5
Options for the management of obesity in non-pregnant women include lifestyle interventions, drugs to
achieve weight loss, and, because of sustained benefits, bariatric bypass surgery. During pregnancy
anti-obesity drugs and bariatric surgery are not options. Unfortunately, a large number of randomized
controlled trials (RCTs) have shown that lifestyle interventions have limited success in decreasing ex‐
cessive GWG or improving maternal or neonatal short term perinatal outcomes.6
In this review we will address why medical and lifestyle interventions during pregnancy have failed to
improve perinatal outcomes in obese women. We will focus on human data generated from epidemio‐
logic, genetic, and molecular research over the past 30 years, since the onset of the obesity epidemic in
developed countries. More than 10 700 PubMed citations (search terms obesity and pregnancy) have
been generated since the 1990s. Although the quality of the research is generally good, the problem of
obesity in pregnancy does not have its onset at conception or its resolution at delivery—it encompasses
the entire life cycle.
Prevalence of obesity and overweight in pregnancy
Obesity is classified according to World Health Organization (WHO) criteria of body mass index
(BMI=weight (kg)/height (m)2; table 1). 7 BMI estimates of body fat in non-pregnant women explain
50-70% of the variance in fat mass. During pregnancy, the significant increase in total body water
makes the correlation less robust.8 It is therefore not valid to use BMI to classify obesity during preg‐
nancy. Because of the differences in body composition among various racial groups, WHO has dis‐
cussed using different criteria for the classification of obesity in Asian women.9
The prevalence of obesity began to increase in the last decades of the 20th century in developed coun‐
tries. From 1999 to 2010, obesity increased from 28.4% to 34.0% in women of reproductive age (20-39
years) in the United States.10 According to the Centers for Disease Control and Prevention, the preva‐
lence of obesity in women of reproductive age did not change significantly between 2003-2004 and
2011-2012.11 However, 7.5% of women in this age group have class III obesity or BMI greater than
40.1 Currently in the US, 31.9% of reproductive age women are obese and 55.8% are overweight or
obese, with a higher prevalence in non-Hispanic black and Mexican American women (table 2). 1
The global age standardized mean BMI in women increased from 22.1 (credible intervals 21.7 to 22.5)
in 1975 to 24.4 (24.2 to 24.6) in 2014, with a doubling of the prevalence of obesity between 1980 and
2008.12 In 2000, WHO noted that obesity “is now so common that it is replacing the more traditional
public health concerns, including undernutrition and infectious disease, as one of the most significant
contributors to ill health.”7 In Europe, WHO estimates that more than 50% of men and women are over‐
weight or obese and 23% of women are obese. In South East Asia, 14% of the population are over‐
weight and 3% are obese.13 The prevalence of obesity in women is double that of men in Africa and
South East Asia.14 The increase in obesity is not confined to adults—there have been increases in obesi‐
ty in children13 and significant increases in birth weights among various populations.2 This review will
discuss the potential mechanisms by which maternal obesity in pregnancy propagates the vicious cycle
of obesity throughout the life course.
Sources and selection criteria
The references for this review were obtained from various sources including PubMed and
ClinicalTrials.gov. We searched PubMed from 1990 to July 2016 using the search terms pregnancy,
obesity, overweight, fertility, spontaneous abortion, congenital anomalies, stillbirth, placenta, maternal
metabolism, gestational diabetes and hypertension, pre-eclampsia, gestational weight gain, macroso‐
mia, neonatal body composition, lactation, diet composition, diet quality, lifestyle interventions, epige‐
netics, and microbiome. We prioritized RCTs, meta-analyses, longitudinal observational studies, and
cohort studies. We included only full text English language peer reviewed publications. We reviewed
Cochrane Reviews on preconception lifestyle for people with infertility, interventions for preventing ex‐
cessive weight gain during pregnancy, exercise in pregnant women for prevention of GDM, and diet or
exercise for weight reduction in women after childbirth. We used clinical guidelines from the American
Congress of Obstetricians and Gynecologists (ACOG), the Royal College of Obstetricians and
Gynaecologists (RCOG), the Royal Australian and New Zealand College of Obstetricians and
Gynaecologists (RANZCOG), the Society of Obstetricians and Gynaecologists of Canada (SOGC) and
the Institute of Medicine (IOM) for gestational weight guidelines in pregnancy. We prioritized the re‐
sults of guidelines in this review for quality according to the method outlined by the US Preventive
Services Task Force.
Effects of maternal metabolism on fertility and reproduction
Obesity and reproductive function
Obesity perturbs the hypothalamic-pituitary-ovarian axis and overweight women display shorter luteal
phases and lower levels of follicle stimulating hormone, luteinizing hormone, and progesterone.15 A
study of more than 45 000 assisted reproductive embryo transfers showed that a higher BMI correlated
with a reduced likelihood of successful pregnancy when autologous oocytes were used, but not when
oocytes from lean donors were used, suggesting a direct effect of obesity on the oocyte.16
Obesity is also associated with changes in ovarian granulosa cells and the follicular fluid surrounding
the oocyte. Differences in follicular fluid insulin, triglycerides, free fatty acids, proinflammatory cy‐
tokines, oxidized low density lipoprotein, and fatty acid composition have been observed in obese
women, suggesting that numerous mechanisms probably contribute to disruptions in oocyte develop‐
ment.17 18 19 Data from women undergoing in vitro fertilization (IVF) from a donated oocyte have been
used to isolate the role of the endometrium, but results have been conflicting. A meta-analysis of data
from six centers found no difference in the rate of pregnancy, implantation, or miscarriage between
obese versus non-obese women.20 A recent study of surrogate pregnancies also indicated that increas‐
ing BMI of the surrogate mother had no significant effect on IVF, embryo transfer, or neonatal out‐
comes.21 However, another study of 9587 women found that obesity in the recipient had negative ef‐
fects on implantation, pregnancy success, and live births,22 suggesting that obesity significantly alters
endometrial gene expression in women during the luteal phase.23 Thus, evidence suggests that both
uterine and ovarian changes associated with obesity contribute to reproductive dysfunction.
Increased risk of spontaneous abortion and congenital anomalies
Overweight and obese women have an increased risk of spontaneous miscarriage. A meta-analysis re‐
ported that women with a BMI ≥25 had a higher risk of miscarriage (odds ratio 1.67, 95% confidence
interval 1.25 to 2.25).24 A subgroup analysis suggested a higher risk of miscarriage after oocyte dona‐
tion (1.52, 1.10 to 2.09) and induction of ovulation (5.11, 1.76 to 14.83). An observational cohort study
of women with recurrent early pregnancy loss reported that obese women had a 58% risk of euploid
miscarriage compared with 37% in non-obese women.25
Obese women are at increased risk of pregnancy affected by congenital anomalies. A systematic review
and meta-analysis reported an increase in the following congenital anomalies in the offspring of obese
compared with non-obese women: spina bifida (2.24, 1.86 to 2.69), neural tube defects (1.87, 1.62 to
2.15), limb reduction anomalies (1.34, 1.03 to 1.73), cardiovascular anomalies (1.30, 1.12 to 1.51), and
cleft lip and palate (1.20, 1.03 to 1.40).26 A prospective observational cohort study reported a dose-re‐
sponse effect in relation to congenital heart defects with increasing BMI (overweight: 1.15, 1.01 to
1.32; obese: 1.26, 1.09 to 1.44; and morbidly obese: 1.34, 1.04 to 1.43).27 Although maternal folate sta‐
tus and glucose intolerance have been suggested, no definitive mechanism has been identified.28
Placental changes associated with maternal obesity
The placentas of obese women are significantly heavier at birth (mean 693 (standard deviation 184) g v
614 (152) g; P=0.002),29 and placental weight has a stronger correlation than maternal age, pre-preg‐
nancy BMI, and GWG with neonatal birth weight and fat mass.30 The maternal metabolic environment
affects early placental growth and gene expression, as well as later placental function, which become
clinically manifest in late pregnancy.31 A potential mechanism is that insulin receptors are more abun‐
dant on the maternal trophoblast surface in early gestation than in later gestation.32 The hyperinsuline‐
mia associated with obesity related insulin resistance results in differential responses in placental tro‐
phoblasts.31 One study reported a 30-fold decrease in insulin sensitive genes that regulate the cell cycle
and cholesterol homeostasis in placental villous tissue from obese women during the first trimester.
Maternal obesity, insulin resistance, and hyperinsulinemia together impaired global gene profiling relat‐
ed to mitochondrial dysfunction and decreased energy metabolism.31 For example, the maternal insulin
secretory response in early pregnancy is strongly correlated with placental weight and neonatal adiposi‐
ty at birth.33
The placentas of obese women at term are characterized by an increase in total lipid content and an ac‐
cumulation of macrophages and proinflammatory mediators compared with normal weight women.34 35
At a molecular level, the placental transcriptome of obese women with GDM shows activation of genes
36 Pregravid obesity is associated with a systemic low grade meta‐
related to lipid metabolism (fig 1).
bolic inflammatory state and subclinical endotoxemia, both of which may contribute to worsening of
pregnancy associated insulin resistance.37 Maternal obesity is associated with greater placental cy‐
tokine expression and greater vessel muscularity but little difference in other histological features such
as fibrin deposition or placental maturity.38 The precise mechanisms underlying the inflammatory re‐
sponses and role in fetal growth, however, remain unclear.
The placenta has been hypothesized to function as a “nutrient sensor,” whereby the placenta integrates
maternal and fetal nutritional cues, and through regulation of nutrient sensing pathways attempts to
match fetal demand and maternal supply.39 In support of this model, maternal obesity is associated with
increased placental expression of system A amino acid transporters 1 and 2 (SNAT1 and SNAT2) in
conjunction with greater activity of the mTOR (mechanistic target of rapamycin) and insulin growth
factor 1 (IGF-1) signaling pathways, which presumably contribute to fetal overgrowth.40 By contrast, a
recent report found that maternal obesity decreased placental taurine transporter activity in villous ex‐
plants, without changes in protein expression.41 Maternal obesity and GDM also affect lipid transport
across the placenta. Placental expression of fatty acid binding protein FABP4 and endothelial lipase is
raised in obese women with diabetes.42 43 Similarly, placentas from obese women show increased lipid
accumulation but lower concentrations of FABP5 and uptake of omega-6 polyunsaturated fatty acid
(oleic acid).34 44 45 Both increases and decreases in the long chain polyunsaturated fatty acid (PUFA)
transporter, CD36, have been reported in placenta from obese women.45 46 An important caveat of hu‐
man placental responses to obesity is that most information comes from studying late gestation
placentas.
In contrast to increased inflammatory markers, concentrations of placenta and plasma estradiol and
progesterone are lower in obese than in lean women.47 During pregnancy, estradiol and progesterone
are synthesized in placental mitochondria from cholesterol precursors. Although there are no significant
differences in circulating or placental cholesterol concentrations, mitochondrial cholesterol concentra‐
tions are 40% lower in the placentas of obese women, and this is related to decreases in the mitochondr‐
ial cholesterol translocator protein.47 The clinical significance of the decrease in placental steroid pro‐
duction is unknown but may be related to the adverse perinatal outcomes seen in obese women.
In summary, in early pregnancy the human placenta is responsive to the high concentrations of mater‐
nal insulin found in obese women. This results in altered gene expression in relation to mitochondrial
steroid hormone production and energy metabolism. Furthermore, placental size in early pregnancy is
strongly correlated with subsequent fetal adiposity at birth.33 The inflammatory milieu of late pregnan‐
cy may be an important factor affecting maternal insulin resistance.48
Differences in maternal metabolism in obese and normal weight women
Pregnancy is a unique metabolic condition because of the changes in maternal metabolism needed to
provide for fetal growth and increased maternal energy requirements. Insulin sensitivity decreases by
40-50% during the course of pregnancy but significantly improves within days of delivery.49 50 The fol‐
lowing data come from a secondary analysis of the longitudinal changes in metabolism in a small num‐
ber of lean (n=6) and obese (n=10) otherwise healthy women before a planned pregnancy and during
early and late gestation.51 52 53
Lean and fat mass increased significantly in both lean and obese women but the increase in fat mass
was greater in lean women (fig 2).
Although there was a significant 23% increase in resting energy ex‐
penditure, over time there was no significant difference between groups. Basal carbohydrate oxidation
increased 68% over time and was greater in obese women.
There was a 40% decrease in insulin sensitivity in lean and obese women over time and a trend
(P=0.07) for a greater decrease in obese women (fig 3). Because of decreases in insulin sensitivity over
time fat oxidation increased 220% in both lean and obese women (P=0.003).
There was decreased suppression of lipolysis during insulin infusion (hyperinsulinemic-euglycemic

clamp), but no significant difference between groups (P=0.30). Basal free fatty acids decreased 16%
over time (P=0.02) but free fatty acids increased by 62% during insulin infusion with the clamp over
the course of pregnancy (P=0.0004), although there was no significant difference between groups (fig 4
). There was a 61% increase in fasting cholesterol and 260% increase in triglycerides (P=0.0001) over
time, but no significant difference between lean and obese women. Others, however, have reported that
in late pregnancy obese women have increases in circulating triglycerides and very low density lipopro‐
tein cholesterol but a decrease in high density lipoprotein compared with lean women.54 55 56 57
A longitudinal study of amino acid concentrations in obese and normal weight pregnant women found a
decrease in leucine, methionine, phenylalanine, tyrosine, and valine from the second to the third
trimester. However, there were no changes in branched chain amino acids between lean and obese
women.58 At term there was a decrease in amino acid concentrations and fetal-maternal amino acid gra‐
dients in obese women who had small for gestational age neonates compared with normal or obese
women with average for gestational age neonates.59 The decreased fetal-maternal amino acid gradients
seen in some obese women may be related to altered placental amino acid transporter activity41 and de‐
creased placental SNAT activity.60
In summary, significant decreases in insulin sensitivity (increased insulin resistance) occur during preg‐
nancy, with obese women showing greater decreases in insulin sensitivity. In addition to affecting glu‐
cose metabolism, decreases in insulin sensitivity result in increases in various lipids and amino acids.
Hence, uniform metabolic changes seem to occur during pregnancy, and differences between lean and
obese women may relate more to the preconception metabolic condition of the mother rather than to
any specific effect of pregnancy.
Effects of maternal obesity on maternal and neonatal outcomes during the index pregnancy
Maternal implications
Maternal metabolism Subclinical metabolic dysfunctions in obese women, such as GDM and pre-
eclampsia, which are associated with adverse pregnancy outcomes, become clinically manifest later in
gestation.61 62 These metabolic disorders have a higher prevalence in certain racial or ethnic groups, in‐
cluding African-Americans and Southern Asians.63
Premature delivery and stillbirth Obese women have an increased risk of indicated preterm deliveries
because of the aforementioned antepartum complications, but they also have an increased risk of spon‐
taneous preterm births.64 The pathophysiology of preterm delivery is not well characterized, although
inflammation is associated with both maternal obesity and preterm labor.65 In a systematic review and
meta-analyses, the risk of perinatal mortality was related to increasing maternal BMI. The relative risk
for each five unit increase in maternal BMI in overweight and obese women was 1.21 for fetal death
(1.09 to 1.35), 1.24 for stillbirth (1.18 to 1.30), 1.16 for perinatal death (1.00 to 1.35), 1.15 for neonatal
death (1.07 to 1.23), and 1.18 for infant death (1.09 to 1.28).4
Intrapartum Obese women have an increased risk of a failed trial of labor, cesarean delivery, and en‐
dometritis; they also have double the risk of a composite measure of maternal morbidity and a fivefold
increased risk of neonatal injury.66 The length of labor in nulliparous women is inversely proportional
to maternal BMI.67 The unadjusted odds ratios of cesarean delivery are 1.46 (1.34 to 1.60) and 2.05
(1.86 to 2.27) in overweight and obese women, respectively, compared with normal weight women.68
The success rate of a trial of labor after cesarean is inversely related to BMI (BMI <19.8 (83.1%), BMI
19.8-26 (79.9%), BMI 26.1-29 (69.3%), and BMI >29 (68.2%); P<0.001). Obese women are also more
likely to undergo a repeat cesarean delivery before active labor.69 Similarly, gaining more than 18.14 kg
(40 lb) is associated with a decreased success rate of a trial of labor after cesarean (66.8% v 79.1%;
P<0.001).70
Anesthesia Maternal obesity significantly increases the risk of anesthetic complications. The Centre for
Maternal and Child Enquiries and RCOG recommend that women with a pregravid BMI >40 should
have an antenatal consultation with an obstetric anesthesiologist.71 The risk of epidural failure is greater
in obese women compared with normal weight and overweight women.72 Severely obese women have
significantly greater hypotension and prolonged fetal heart rate decelerations, after controlling for
epidural bolus dosing and hypertensive disorders, compared with normal weight women.73 The combi‐
nation of spinal anesthesia and obesity greatly impairs respiratory function for up to two hours.74
General anesthesia also poses a risk for obese pregnant women because of potential difficulties with en‐
dotracheal intubation75 and the increased prevalence of obstructive sleep apnea.76
Cesarean delivery Broad spectrum antimicrobial prophylaxis is recommended for all cesarean deliver‐
ies.77 However, there is no consensus regarding proper dosing on the basis of BMI. Compared with nor‐
mal weight women, there is an increased risk of surgical site infections after cesarean delivery in
women who are overweight (odds ratio 1.6, 1.2 to 2.2), obese class I (2.4, 1.7 to 3.4), and obese classes
II and III (3.7, 2.6 to 5.2).78 Different types of skin preparation, skin closure techniques, and supple‐
mental oxygen have not helped decrease the rate of post-cesarean infectious morbidity in overweight
and obese women.79 80 81 However, closure of subcutaneous tissue greater than 2 cm can significantly
decrease the incidence of wound disruption.82
Postpartum venous thromboembolism In the postpartum period, maternal obesity is a risk factor for ve‐
nous thromboembolism and a higher risk of pulmonary embolism (adjusted odds ratio 14.9, 3.0 to
74.8).83 The Pregnancy and Thrombosis Working Group in the US recommends considering thrombo‐
prophylaxis in selected patients only, noting that there are insufficient data to recommend routine phar‐
macologic prophylaxis with cesarean delivery.83 84 Because cesarean delivery increases the risk of ve‐
nous thromboembolism, ACOG recommends placement of pneumatic compression devices for all pa‐
tients before and after cesarean delivery.85 By contrast, the RCOG recommends considering prophylac‐
tic low molecular weight heparin for seven days after delivery in obese women who have one or more
additional risk factors, such as smoking, and considering low molecular weight heparin early in preg‐
nancy until six weeks postpartum for those with two or more risk factors.71
Breast feeding There are multiple barriers to successful breast feeding in obese women. These include
the physical problems of large size, increased risk of cesarean delivery, and the fact that neonates often
need to be evaluated in special care nurseries. Obese postpartum women may also have a decrease in
their first phase of milk production. Despite these obstacles, breast feeding should be encouraged, not
only because of the potential neonatal benefits, but because of potential maternal benefits relating to
postpartum weight reduction and decreased risk of diabetes in obese women who developed GDM.86
Mental health Postpartum depression affects one in seven women. ACOG recommends that all preg‐
nant women should be screened at least once for depression in the postpartum period using a validated
screening tool, because depressive disorders can affect both maternal and neonatal wellbeing. When
clinically significant depression is diagnosed, the obstetric care provider should start treatment or refer
the patient as needed.87
Neonatal implications
Neonates born to obese women have an increased risk of overgrowth. Fetal overgrowth has been classi‐
fied using various criteria. Macrosomia is defined as birth weight greater than 4000 g or 4500 g without
consideration for gestational age. Large for gestational age (LGA) is defined as birth weight greater
than the 90th centile for gestational age. However, many of the population based references fail to in‐
clude adjustment for factors that can affect fetal growth such as sex or race and ethnicity. Although the
ponderal index (weight/length9) has been used as a surrogate for BMI in neonates,88 our group and oth‐
ers have looked at measures of fetal growth that use estimates of body composition—fat-free or lean
body mass and fat mass. Although fat mass constitutes only 12-14% of birth weight, it accounts for
about 50% of the variance in term birth weight.89
Various techniques are available to estimate neonatal body composition including anthropometrics,
densitometry, magnetic resonance imaging, and dual energy x ray absorptiometry. It is difficult to esti‐
mate the various compartments of adiposity (such as visceral adipose tissue) in neonates and measures
of brown adipose tissue are available only as research tools. Infants of obese women are heavier at birth
because they have greater amounts of adipose tissue than those born to non-obese women.90 91 In our
population in Cleveland, Ohio, US, maternal pregravid BMI had the strongest correlation with neonatal
adiposity.92 This may relate to the large proportion of obese women in our population. By contrast,
GWG greater than the IOM guidelines recommend was significantly related to increased neonatal adi‐
posity in normal weight women.92 Other factors associated with fetal adiposity and cord blood markers
of metabolic dysfunction include maternal free fatty acids, insulin, cholesterol, and gestational age.93 94
95
Newborns of obese mothers have higher concentrations of umbilical cord leptin and interleukin 6 (IL-6)
than infants of lean mothers. Furthermore, neonates of obese mothers have greater insulin resistance
than those of lean mothers. Insulin resistance in obese infants significantly correlated with maternal in‐
sulin resistance and neonatal body fat.29 In both male and female neonates, placental weight had the
strongest correlation with neonatal fat mass (r2=0.20-0.39). However, in male infants, maternal BMI
and GWG were significant predictors of both lean mass and fat mass. By contrast, maternal plasma
markers of inflammation (IL-6 and C reactive protein) were independently associated with female body
fat and lean body mass.30
In summary, at term infants of obese mothers are significantly heavier than those of normal weight
women because of an increase in body fat, with pregravid maternal BMI and placental size being the
strongest correlates of infant weight in obese women. On the basis of variations in maternal pregravid
insulin sensitivity and early placental response to maternal insulin, we propose a model of fetal over‐
growth in obese women (fig 5). The decrease in insulin sensitivity in obese women leads to an increase
in the insulin response, which affects early placental growth and gene expression. This results in the re‐
lease of placental factors (cytokines, human placental lactogen, and others), which crosstalk with ma‐
ternal insulin sensitive tissue (skeletal muscle, liver, and adipose tissue), decreasing maternal insulin
sensitivity in these tissues. The result is an increase in nutrient availability, which contributes to the fe‐
tal adiposity that becomes manifest in late gestation.
Long term effects of maternal obesity on the mother and offspring
Maternal weight gain, postpartum weight retention, and childhood adiposity
Compared with normal weight women, childbearing in obese women increases postpartum weight re‐
tention, because a greater proportion of obese women than normal weight women have excessive GWG
and excessive GWG is related to postpartum weight retention.96 97 GWG over the course of pregnancy
has sharply increased over the past decades, along with the increase in the prevalence of obesity. Recent
studies suggest that postpartum weight gain is most strongly associated with weight gain during the first
trimester.98 99Substantial postpartum weight gain starts at six to 12 months after delivery. Findings
from the Danish National Birth Cohort show that in addition to GWG, weight retention at six months
and weight gain from six to 18 months postpartum contribute equally to adverse maternal weight status
seven years after delivery.100 Common adiposity associated variants of genes such as FTO (fat mass
and obesity associated protein) or MC4R (melanocortin 4 receptor) in either mother or child are not as‐
sociated with GWG.101 Mathematical models of dynamic weight change have been developed that pre‐
dict GWG on the basis of changes in energy intakes.102 Owing to the lack of high quality studies, an ex‐
tensive systematic review of the effect of dietary composition on GWG concluded that although energy
intake is associated with GWG, the contribution of specific macronutrients is unclear.103
Research into psychosocial aspects of behavior indicates that weight and healthy eating related self effi‐
cacy, or an individual’s perceived ability to undertake goal oriented behaviors despite potential barriers,
was inversely associated with body weight in both early pregnancy and two years postpartum.104
Several RCTs have evaluated physical activity and dietary interventions to reduce GWG. Meta-analyses
of these RCTs have reported conflicting evidence, with some studies finding significant beneficial ef‐
fects of physical activity on reducing maternal GWG105 but others reporting minimal effects.106 A re‐
cent systematic review found that diet or exercise or both interventions reduced the risk of excessive
GWG by 20% (average risk ratio 0.8, 0.73 to 0.87; n=7096 over 24 studies). Interestingly, dietary inter‐
ventions such as low glycemic diets and supervised or unsupervised exercise by itself or combined with
dietary changes led to similar reductions in the number of women with excessive GWG.107
Excessive GWG has also been proposed as a mediator of adverse health outcomes in a child’s long term
health and risk of obesity. In population based cohorts, greater GWG has been associated with greater
offspring weight in childhood,108 as well as higher BMI and systolic blood pressure in early
adulthood.109 Greater weight gain during pregnancy is associated with higher BMI z-score, sum of sub‐
scapular and triceps skinfold thicknesses, and systolic blood pressure in childhood.110 Similar associa‐
tions were seen between increased maternal BMI, greater GWG, and higher parity with greater waist
circumference, higher BMI, and greater fat mass index in the offspring.111
Efforts to improve nutrition and physical activity during pregnancy for parents and children during and
after delivery require not only a concerted effort on the part of the individuals but potentially consider‐
able fiscal resources and commitments of time. Populations in greatest need are often the ones least
able to afford the socioeconomic burden. Hence, obesity during pregnancy needs to be recognized as
not only an individual problem but also one of the larger community and society.
Obesity and metabolic dysfunction in the offspring
Observational studies provide a strong link between maternal body weight status and obesity and car‐
diometabolic risk factors in the offspring. LGA at birth significantly increases the risk of obesity in
adolescence and adulthood. In addition, children of obese mothers who are born LGA and who have
childhood obesity have double the risk of developing insulin resistance.5 Meta-analyses report that high
maternal BMI is unequivocally associated with LGA.112
These findings have been independently confirmed in the larger Hyperglycemia and Adverse Pregnancy
Outcomes (HAPO) study, which showed that, independent of glycemia, maternal BMI is strongly asso‐
ciated with excess fetal growth and adiposity.113 An American cohort of 854 participants showed that
parental obesity doubles the risk of adult obesity.114 Greater adiposity associated with maternal obesity
persists into childhood and adolescence, as shown by the Avon Longitudinal Study of Parents and
Children (ALSPAC) and Mater-University studies. Recently gestational fasting plasma glucose has
been positively associated with birth weight. Gestational fasting plasma glucose and prepregnancy obe‐
sity interacted significantly with the association of offspring growth and overweight status in the first 36
months of life.115 Therefore, there is considerable evidence that maternal obesity during pregnancy in‐
creases adiposity at multiple life stages in the offspring—at birth29 113 and during childhood, adoles‐
cence,116 117 and adulthood.101 These data suggest that the effects of a short period of overnutrition
during gestation can affect health throughout life.
Potential mechanisms linking maternal obesity to offspring susceptibility
Obesity is characterized by metabolic and endocrine derangements. Underlying these, lay a host of ge‐
netic, epigenetic, and lifestyle differences that directly or indirectly impinge on weight gain, adiposity,
and metabolism. Specific themes have been examined as mechanisms that potentially link maternal
obesity to offspring adiposity and metabolic health. Broadly, these studies point to a model whereby di‐
etary changes or exposure to one or more obesity associated metabolites or hormones during critical
stages of development can alter developmental pathways in the offspring and lead to greater accrual of
fat mass.118 119 120 121 122
Studies in experimental models and limited human data suggest that the earliest stages of development
(both preconception and periconception) are crucial.123 124 125 Although, developmental programming
associated with obesity probably occurs throughout gestation and neonatal life, understanding the cru‐
cial periods during which the major changes are initiated is key to devising effective interventions.
These persistent effects could be in part mediated through reprogramming of organ and tissue structure
and could function through epigenetic mechanisms in utero. Furthermore, developmental trajectories
are also likely to be modified in the postnatal period through signals in milk, changes in the microbio‐
me conferred by the mother, complementary feeding choices, and the home environment, which further
act on developmental changes (fig 6).
Dietary patterns and nutrient changes Recent observational studies have examined the association be‐
tween the composition and quality of the maternal diet and offspring outcomes (summarized in table 3
).118 126 127 128 129 130 131 132 133 Overall, although poor quality diets seem to have detrimental effects in
the offspring, they are unlikely to be mediators of changes associated with maternal obesity but proba‐
bly represent an independent risk factor. Studies have also evaluated the association between type of di‐
etary fat and child health outcomes. In the Project VIVA cohort, maternal omega-3 PUFA intake was
associated with lower childhood adiposity at 3 years of age.134 However, in a recent report from the
Southampton’s Women’s Survey, maternal plasma omega-6 PUFA levels at 34 weeks’ gestation were
positively correlated with childhood fat mass at 4 (β=0.14 standardized β coefficients, P=0.01) and 6
(β=0.11 standardized β coefficients, P=0.04) years of age, but no associations between maternal
omega-3 PUFA levels were seen.135 Variance in the nature of the cohorts, mean omega-3 PUFA and
omega-6 PUFA levels, and age of assessment of children may contribute to the differences.
The HAPO studies confirmed that there is a continuous association between maternal glucose levels in
pregnancy and neonatal fat mass.113 Glucose concentrations in pregnancy also predict fat and lean mass
of offspring in late childhood.136 Studies using continuous glucose monitoring report that despite con‐
trolled diets, obese women have a higher 24 hour glucose area under the curve than normal weight
women.137 Intake of carbohydrates may be associated with greater fetal overgrowth and adiposity. In
the Treatment of Obese Pregnant Women study, lower carbohydrate intake was associated with lower
neonatal fat mass. Conversely, high glycemic load during pregnancy was associated with greater GWG,
higher birth weight, and increased risk of LGA birth.138
Inflammation Low grade subclinical systemic and tissue specific inflammation is a hallmark of obesity
and is causally linked to insulin resistance. Several studies have examined the association between cir‐
culating maternal inflammatory markers and fetal, neonatal, and long term outcomes of adiposity in the
offspring. The studies found positive associations36 139 140 and a lack of association141 142 between
these parameters, depending on the markers assessed, time of assessment during pregnancy, and sample
size. In the Project Viva cohort, higher second trimester C reactive protein was associated with higher
mid-childhood adiposity.140
The mechanisms through which inflammatory signals in pregnancy lead to increased adiposity in the
offspring are not known. Recent studies indicate that the inflammatory state extends to the fetal side. A
gene expression study of umbilical cord tissue in term infants from healthy lean and obese women iden‐
tified a proinflammatory signature characterized by upregulation of acute phase response genes, includ‐
ing EGR1 and FOSB.143 However, the contribution of inflammation to developmental programming is
mainly associative and definitive mechanistic studies are lacking.
Epigenetic alterations in offspring A widely hypothesized overarching mechanism that links in utero ex‐
posure to health in later life is through epigenetic modification of offspring DNA or modification of
regulators of chromatin structure, such as histones, during crucial periods of development.144 In the
context of observational studies examining epigenetic mechanisms, DNA methylation is the most well
characterized epigenetic process. Although the epigenetic effects of fetal undernutrition have been
widely studied, fewer studies have focused on the effects of overnutrition or maternal obesity during
pregnancy.
The Epigenetic Birth Cohort from Boston studied 319 newborns and found no correlation between ma‐
ternal prepregnancy BMI and methylation of LINE-1 (long interspersed nuclear elements-1; a global
measure of DNA methylation) in placenta or umbilical cord blood DNA.145 However, in another cohort
maternal BMI positively correlated with DNA methylation of the PPARGC1A (peroxisome proliferator
activated receptor γ co-activator 1α) promoter in umbilical cord DNA.146 Infants born to obese mothers
with GDM have reduced methylation near the glucocorticoid receptor and the imprinted gene MEST
(encoding mesoderm specific transcript).147 Cord blood DNA of neonates from obese mothers showed
altered methylation of imprinted genes, MEG3 (maternally expressed 3) and PLAGL1.148 Associations
between DNA methylation and risk of disease in later life are primarily associative. One study found
that umbilical cord DNA methylation of the RXRA gene (retinoid X receptor α) was inversely correlated
with maternal carbohydrate consumption in early pregnancy and positively correlated with the child’s
adiposity at age 9.149 Furthermore, in a cohort of children born to obese mothers before or after
bariatric surgery, distinct changes in the DNA methylation of glucoregulatory genes was seen in chil‐
dren born after bariatric surgery. These changes resulted in improved fasting insulin and homeostatic
models of insulin resistance compared with siblings born before maternal bariatric surgery.150
Collectively, these studies suggest that maternal obesity can cause persistent loci and tissue specific epi‐
genetic disruption in the offspring.
Another area of research is the description of nutritional and environmental influences on metastable
epialleles (MEs)—loci where DNA methylation occurs stochastically early in embryogenesis and is
maintained and stably propagated during differentiation.144 151 This stochastic establishment of
epigenotype leads to systemic variability in DNA methylation between individuals that is neither cell
type specific nor genetically mediated. These MEs are sensitive to environmental influences, such as
maternal nutrition in early pregnancy. In humans, candidate MEs have been identified by comparing
genome scale methylation profiles of DNA between different tissue samples from the same individual
and from monozygotic twin studies. Moreover, nutritional status early in pregnancy has been linked to
persistent epigenetic changes in MEs in the offspring, as was elegantly shown in a study from rural
Gambia where seasonal fluctuations in dietary intake occur.152 However, the influence of maternal obe‐
sity, GWG, and dietary patterns on these MEs remains to be evaluated.
Alterations in neonatal nutrition and infant microbiome Long term associations between maternal obesi‐
ty and infant adiposity may also be mediated by signals that alter the offspring’s physiology through
early nutritional cues in breast milk. Breast milk from overweight and obese mothers has been reported
to have higher levels of insulin and leptin, lower levels of omega-3 PUFA, and higher omega-6:omega-
3 PUFA ratios,153 while showing no differences in macronutrient composition.154 155 156
Immunological modulators transforming growth factor β2 and sCD-14 have also been reported to be
lower in breast milk from obese women.157 Several other hormones and cytokines present in milk have
as yet uncharacterized biological effects on the gastrointestinal and immune systems of the offspring.
In addition to nutrients, human breast milk contains a variety of unconjugated glycans from the struc‐
turally diverse family known as human milk oligosaccharides (HMOs) which have specific structure re‐
lated bioactivity. HMOs are natural prebiotics that serve as an energy source for a diverse array of
colonic bacteria and hence shape and sustain the infant gut microbiome. Although studies have shown
that the composition, diversity, and abundance of specific HMOs is associated with infant growth and
adiposity,158 the effect of maternal obesity on the diversity of HMOs in milk is poorly understood.
The gut microbiota also plays a crucial role in regulating metabolism and adiposity, as shown by studies
in germ-free mice and studies of human twins who are discordant for obesity. Obesity and diets high in
fat are associated with a change in microbiome structure, most often an increase in Firmicutes and a de‐
crease in Bacteroidetes.159
Pregnancy has been suggested to induce shifts in the gut microbiome, but reports are conflicting.65 160
Importantly, the maternal microbiome is crucial in “seeding” the infant microbiome and the develop‐
ment of the infant’s immune system.161 162 Few studies have evaluated the influence of obesity on the
maternal microbiome. More recently, the microbiome of exclusively breastfed infants from lean and
obese women was characterized at 2 weeks of age.156 These studies showed that both maternal obesity
status and milk insulin concentrations were associated with early changes in the infant’s microbiome.
The persistence of the changes in later life remains to be ascertained. However, it is clear that aspects of
developmental programming associated with maternal obesity may be mediated through interactions
between changes in the early diet (through alterations in breast milk) and reconfiguration of the
microbiome.
Why have lifestyle interventions had limited success in decreasing perinatal morbidity?
Several RCTs have examined lifestyle interventions for obese women during pregnancy. The primary
outcomes of these trials included avoiding excessive GWG and decreasing adverse perinatal outcomes,
such as GDM and LGA neonates.163 164 165 166 167 Unfortunately, other than decreasing GWG by 1-2
kg, these studies have not improved perinatal outcomes. Recent RCTs (UPBEAT and the Norwegian Fit
for Delivery Trial) suggest that behavioral lifestyle interventions do not prevent GDM or reduce the in‐
cidence of LGA babies despite increasing physical activity and reducing maternal dietary glycemic
load, GWG, and maternal skinfold measures.6 168 Investigators in the UK Pregnancies Better Eating
and Activity Trial (UPBEAT) noted that increasing the intensity and duration of the lifestyle interven‐
tion would probably be impractical for most obese women.6 At least five meta-analyses concluded that,
although lifestyle interventions started during pregnancy had some success in reducing excessive GWG,
they had little effect on adverse pregnancy outcomes including fetal overgrowth.169 170 171 172 173
Data from our group and others suggest that improvement in maternal metabolic function should begin
before conception to improve perinatal outcomes. We hypothesize that aspects of maternal metabolism
often associated with obesity, such as increased insulin resistance and hyperinsulinemia, affect placen‐
tal gene expression and function in early pregnancy before lifestyle interventions begin, although the re‐
sults of these changes are not clinically manifest until late gestation. Ongoing preconception lifestyle in‐
tervention trials have a decrease in the incidence of GDM and neonatal adiposity as their primary
outcomes.174
Although some individuals advocate weight loss in obese women during pregnancy, these recommen‐
dations are based on epidemiological data.175 176 177 In a perinatal database study in an affluent
European population, investigators reported that weight loss in obese pregnant women was associated
with reduced perinatal risk but not a higher risk of low birth weight or small for gestational age (SGA)
neonates.178 By contrast, a recent meta-analysis of six cohort studies reported that although women
who lost weight during pregnancy had a lower risk of having a LGA neonate, they also had a higher
risk of having an SGA neonate below than the 10th and third centiles.179 Furthermore, our group re‐
ported an increased risk of SGA and decreased lean body mass (head circumference and length) in
neonates of overweight or obese women with inadequate GWG.180 Therefore, unless new compelling
data become available, overweight and obese women should comply with IOM guidelines on GWG.
Interventions to mitigate the effects of maternal obesity on neonatal health
In retrospective cohort studies, 10-20% of overweight or obese women lost weight between
pregnancies.181 182 183 184 Inter-pregnancy weight loss in overweight and obese women was associated
with a decreased risk of GDM or pre-eclampsia in a subsequent pregnancy.178 179 180 181 182 183 184 185
Three studies reported a decreased incidence of LGA in overweight and obese women who had an in‐
ter-pregnancy weight loss of as little as 1-2 BMI units.178 182 186 The inter-pregnancy decrease in
weight was not associated with an increased risk of SGA infants.183 Four RCTs reported that a postpar‐
tum lifestyle intervention was effective in facilitating weight loss compared with a control group.187 188
189 190 A recent meta-analysis of 11 studies with 769 women reported a significant mean −2.57 kg
(−3.6 to −1.5) weight loss in the intervention group. In a subgroup analysis the most effective interven‐
tions were those with objective goals (use of heart rate monitors, pedometers, and exercise combined
with intensive dietary intervention), which produced a −4.1 kg (−5.2 to −3.5) weight loss.191
Therefore, supervised intensive lifestyle intervention in overweight and obese postpartum women is
feasible, efficacious, and safe even in lactating women. The idea that lifestyle intervention before preg‐
nancy is necessary to improve placental function and fetal development is gaining traction as a viable
paradigm to improve perinatal metabolic outcomes.174
Emerging treatments
Currently, 310 trials are listed on ClinicalTrials.gov under the heading of obesity and pregnancy. The
studies primarily use lifestyle interventions to decrease infertility, excessive GWG, and pregnancy com‐
plications such as GDM and pre-eclampsia. Nutrient supplements such as vitamin D, probiotics, and
omega-3 fatty acids are being tested to decrease the risk of GDM as well as allergic disease in infants.
Ongoing studies are using drugs such as orlistat to improve reproductive fitness in obese women and
metformin to decrease excessive weight gain and the risk of fetal macrosomia. Lastly, there are propos‐
als that discuss the potential of prepregnancy lifestyle interventions to decrease the risk of gestational
diabetes and fetal adiposity.
Guidelines
As noted previously, current guidelines for the management of obesity in pregnancy include those from
the ACOG, RCOG, SOGC, RANZGOG, and IOM. All recommend that obese women try to achieve a
healthy weight (based on BMI) before pregnancy. Obese women should receive counseling about GWG
based on good nutrition, food choices, and physical activity. The management of pregnancy complicat‐
ed by obesity should recognize the increased risk of medical and obstetric complications as outlined
here. All of the guidelines, however, acknowledge that the recommendations for management are large‐
ly based on less than level A data (data based on good and consistent scientific evidence). The most re‐
cent ACOG guidelines were published in December 2015.192 The following recommendations were
considered level A:
BMI calculated at the first antenatal visit should be used to provide diet and exercise counseling
guided by IOM recommendations for GWG during pregnancy
Subcutaneous drains increase the risk of postpartum cesarean complications and should not be used
routinely
Behavioral interventions using diet and exercise can improve postpartum weight reduction in
contrast to exercise alone.
The RCOG guidelines were published in 2010 and the only level A evidence was that women undergo‐
ing cesarean section who have more than 2 cm of subcutaneous fat should have suturing of the subcuta‐
neous tissue space to reduce the risk of wound infection and separation.71
Conclusions
The problems associated with obesity during pregnancy can be improved only with a comprehensive
approach. Behavioral lifestyle interventions of improved nutrition and increased physical activity dur‐
ing pregnancy have helped modestly to reduce excessive GWG in overweight and obese women but
have not decreased the risks of maternal metabolic dysfunction and fetal overgrowth. The perturbed
metabolic environment of obese women exerts its effect on reproductive function before conception.
To date, interventions aimed at improving perinatal outcomes in obese women have been started after
the first trimester, well after the feto-placental unit has been exposed to the adverse metabolic environ‐
ment. Preliminary data have reported changes in maternal and placental gene expression and function
before any phenotypic changes. Hence, just as optimal glucose control before conception is necessary
to decrease the risk of congenital anomalies in the offspring of women with pre-existing diabetes, the
metabolic environment of obese women—whether inflammation, insulin resistance, lipotoxicity, or hy‐
perinsulinemia—requires improvements to reduce the adverse obesogenic mediated effects on pregnan‐
cy. Importantly, improvement does not necessarily imply a return to the non-obese metabolic condition.
A 5% improvement in weight has been reported to be sufficient to exert positive metabolic effects in
non-pregnant obese people.193 Although ideally these measures should be initiated before a planned
pregnancy, it is still worth limiting excessive GWG and trying to improve metabolic conditioning
postpartum.
Glossary of abbreviations
ACOG=American Congress of Obstetricians and Gynecologists

BMI=body mass index
FABP=fatty acid binding protein
GDM=gestational diabetes
GWG=gestational weight gain
HAPO=Hyperglycemia and Adverse Pregnancy Outcomes
HMO=human milk oligosaccharide
IL-6=interleukin 6
IOM=Institute of Medicine
IVF=in vitro fertilization
LGA=large for gestational age
ME=metastable epiallele
PUFA=polyunsaturated fatty acid
RANZCOG=Royal Australian and New Zealand College of Obstetricians and
Gynaecologists
RCOG=Royal College of Obstetricians and Gynaecologists
RCT=randomized controlled trial
SGA=small for gestational age
SNAT=system A amino acid transporters
SOGC=Society of Obstetricians and Gynaecologists of Canada
Further research is needed to improve our understanding of how obesity in pregnancy is related to short
term and long term adverse outcomes in the offspring. Meanwhile, only through the concerted and sus‐
tained efforts of healthcare providers and the community, as well as public health endeavors, will we
begin to improve the long term health of obese women and their children.
Questions for future research
What is the paternal epigenetic contribution to metabolic dysfunction in the offspring?

Is there a differential metabolic response of fetal sex to the environment of obese
pregnancy?
At term, do umbilical cord stem cells reflect the crosstalk between the maternal metabolic
environment and the fetus in relation to developmental programming?
What are the mechanisms in the preconception and periconception window that affect
oocyte development and have long term effects on developmental programming?
Notes
The authors are supported in part by the following grants: Eunice Kennedy Shriver National Institute of
Child Health and development HD-11089-19 (PMC) and USDA Agricultural Research Service CRIS
6251-51000-010-05S (KS).
Contributors: PMC and KS both performed the literature search, wrote the draft article, and revised the
manuscript. They are both guarantors.
Competing interests: The authors have read and understood BMJ policy on declaration of interests and
have no conflicts to declare.
Provenance and peer review: Commissioned; externally peer reviewed.
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Figures and Tables
Table 1
World Health Organization body mass index (BMI) categories7
Category BMI*
Underweight Less than 18.5
Normal weight 18.5-24.9
Overweight 25.0-29.9
Obesity class I 30.0-34.9
Obesity class II 35.0-39.9
Obesity class III 40 or greater
Table 2
Prevalence of obesity (measured by body mass index; BMI) by race or ethnicity in women of reproductive age1
All race/ethnic groups Non-Hispanic white Non-Hispanic black Hispanic Mexican-American
BMI ≥30
20-39 years 31.9 (28.6-35.5) 26.9 (23.0-31.3) 56.2 (44.3-67.5) 34.4 (30.9-38.2) 37.8 (33.2-42.7)
BMI ≥25
20-39 years 55.8 (49.6-61.9) 50.7 (43.1-58.2) 74.2 (65.9-81.1) 65.4 (59.9-70.5) 68.8 (62.1-74.8)
Fig 1
Differential expression of placental metabolic genes in lean women with type 1 diabetes and obese women with gestational dia‐
betes (gene expression increases as the color changes from blue (downregulated) to red (upregulated). Unsupervised hierarchical
clustering of metabolic genes that are modified in the placenta of obese women with gestational diabetes (GDM) and lean women
with type 1 diabetes (type 1 DM). When the placental transcriptome at term was compared between lean women with type 1 DM
and obese women with GDM, genes related to lipid metabolism were preferentially activated in obese women with GDM. Eleven
genes related to lipid transport and activation and seven genes related to lipid metabolism were enhanced36
Fig 2
Longitudinal changes in body composition in lean and obese women before pregnancy through to late gestation. (A) Changes in
lean body mass (kg; mean and standard deviation) in lean (n=5) and obese (n=6) women: prepregnancy, early pregnancy (12-14
weeks), and late pregnancy (34-36 weeks). Change over time, P=0.0001 and between groups, P=0.34. (B) Longitudinal changes
over time (kg; mean and standard deviation) of fat mass in lean (n=5) and obese (n=6) women: prepregnancy, early pregnancy
(12-14 weeks) and late pregnancy (34-36 weeks). Change over time, P=0.0001 and between groups, P=0.0253
Fig 3
Longitudinal changes in insulin sensitivity in lean and obese women before pregnancy through to late gestation. Longitudinal
changes over time in insulin sensitivity (mean and standard deviation) as estimated by the hyperinsulinemic-euglycemic clamp
(mg/kg.ffm/min) in lean (n=5) and obese (n=6) women: prepregnancy, early pregnancy (12-14 weeks) and late pregnancy (34-36
weeks). Change over time, P=0.0001 and between groups, P=0.0753
Fig 4
Longitudinal changes in free fatty acid concentrations in lean and obese women before pregnancy through to late gestation. (A)
Longitudinal changes over time in basal free fatty acid concentration (mE/L; mean and standard deviation) in lean (n=5) and
obese (n=6) women: prepregnancy, early pregnancy (12-14 weeks), and late pregnancy (34-36 weeks). Change over time, P=0.02
and between groups, P=0.30. (B) Longitudinal changes over time in free fatty acid concentration (mE/L; mean and standard devi‐
ation) during the hyperinsulinemic-euglycemic clamp in lean (n=5) and obese (n=6) women: prepregnancy, early pregnancy (12-
14 weeks) and late pregnancy (34-36 weeks). Change over time, P=0.0004 and between groups, P=0.8253
Fig 5
Maternal-placental crosstalk and fetal growth. Because of the reduced insulin sensitivity in obese compared with lean women,
there is an increase in the insulin response in early pregnancy which affects early placental growth and gene expression. This then
results in the release of placental factors that decrease insulin sensitivity in maternal tissue (skeletal muscle, liver, and adipose tis‐
sue), thereby resulting in increased nutrient availability for feto-placental growth. Increased availability of nutrients such as glu‐
cose and lipids thereby contributes to fetal adiposity, which becomes manifest only in late gestation
Fig 6
Overview of potential mechanisms influencing the risk of obesity in the offspring of obese mothers. Pregravid obesity has impor‐
tant effects on reproductive function and the development of the oocyte. Persistent effects of maternal obesity can be mediated
through resetting of epigenetic marks in early developmental stages, which may influence the commitment and renewal of stem
cells. Maternal obesity and high energy diets also alter the growth of the offspring by altering nutrient transport through the pla‐
centa, perhaps as a result of altered placental development caused by placental inflammation and alterations in nutrient sensing
pathways. Effects of maternal obesity and poor diets may also be perpetuated in the offspring through programming of neonatal
growth, with alterations in milk composition and restructuring of the infant’s microbiome having pleiotropic effects on the off‐
spring’s health
Table 3
Summary of studies examining maternal dietary patterns in pregnancy on offspring growth and obesity risk*
Ref (1st author) N Study design Country Main findings
Masalova118 965 Prospective Denmark Maternal fat intake was associated with higher BMI among
observational male offspring at 20 years of age
Yin126 264 Observational Australia Maternal total energy intake and antenatal meat intake was
positively associated with offspring fat mass at 16 years of
age
Knudsen127 44 612 Prospective cohort Denmark Western style dietary pattern high in red meat and dairy fat
study increased risk for SGA birth weight
Rodriquez- 787 Observational Spain High quality maternal diet in the first trimester assessed by
128
Bernal the Alternative Healthy Eating Index was positively
associated with birth weight and lower risk of fetal growth
restriction
Blumfield129 179 Observational Australia Dietary patterns of intermediate protein (18-20% energy),
fat (28-30% energy), and carbohydrate (50-54% energy)
optimized micronutrient intakes in pregnant women
Shapiro130 1079 Prospective USA Poor quality diet (dichotomized healthy eating index-2010
observational (HEI-2010) score of <57) was significantly associated with
higher neonatal fat mass percentage and fat mass measured
within 72 hours of birth
Fernandez- 1827 Observational Spain Adherence to a Mediterranean type diet during pregnancy
131
Barres did not alter risk of overweight in childhood at 4 years but
was inversely associated with waist circumference
Leermakers132 2592 Population based Netherlands Maternal dietary patterns with higher vegetables and fish
cohort study or those with nuts and dietary fiber were not associated
with serum lipids or insulin levels in offspring at 6 years of
age
Van der Broek133 2695 Population based Netherlands Healthier dietary patterns were not associated with lower
cohort study BMI or fat mass index after adjusting for
sociodemographic and lifestyle factors of mothers
*Abbreviations: BMI=body mass index; SGA= small for gestational age.

Obesity and Pregnancy - Mechanisms of Short Term and Long Term Adverse Consequences For Mother and Child - PMC

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01/04/2023, 16:30 State of the Art Review: Obesity and pregnancy: mechanisms of short term and long term

ong term adverse consequences for mother and child - PMC

BMJ. 2017; 356: j1. PMCID: PMC6888512

State of the Art Review

Accepted 2016 Dec 5.

Prevalence of obesity and overweight in pregnancy

Sources and selection criteria

Effects of maternal metabolism on fertility and reproduction

Obesity and reproductive function

Increased risk of spontaneous abortion and congenital anomalies

Placental changes associated with maternal obesity

Differences in maternal metabolism in obese and normal weight women

There was decreased suppression of lipolysis during insulin infusion (hyperinsulinemic-euglycemic

Long term effects of maternal obesity on the mother and offspring

Maternal weight gain, postpartum weight retention, and childhood adiposity

Obesity and metabolic dysfunction in the offspring

Potential mechanisms linking maternal obesity to offspring susceptibility

Interventions to mitigate the effects of maternal obesity on neonatal health

ACOG=American Congress of Obstetricians and Gynecologists

Questions for future research

What is the paternal epigenetic contribution to metabolic dysfunction in the offspring?

Provenance and peer review: Commissioned; externally peer reviewed.

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