Accepted Manuscript

Macrosomia

Prof. Edward Araujo Júnior, PhD, Alberto Borges Peixoto, Ana Cristina Perez
Zamarian, Júlio Elito Júnior, Gabriele Tonni

PII: S1521-6934(16)30076-1
DOI: 10.1016/j.bpobgyn.2016.08.003
Reference: YBEOG 1635

To appear in: Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 30 March 2016

Revised Date: 16 August 2016
Accepted Date: 17 August 2016

Please cite this article as: Araujo Júnior E, Peixoto AB, Perez Zamarian AC, Elito Júnior J, Tonni
G, Macrosomia, Best Practice & Research Clinical Obstetrics & Gynaecology (2016), doi: 10.1016/
j.bpobgyn.2016.08.003.

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Title: Macrosomia

Authors: Edward Araujo Júnior 1, Alberto Borges Peixoto 1, Ana Cristina Perez Zamarian 1, Júlio
Elito Júnior 1, Gabriele Tonni 2

Institutions:

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1. Department of Obstetrics, Paulista School of Medicine - Federal University of São Paulo (EPM-
UNIFESP), São Paulo-SP, Brazil.

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2. Department of Obstetrics and Gynecology, Guastalla Civil Hospital, AUSL Reggio Emilia, Italy

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Address for correspondence:
Prof. Edward Araujo Júnior, PhD (Corresponding author)
Rua Belchior de Azevedo, 156 apto. 111 Torre Vitoria

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São Paulo–SP, Brazil
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CEP 05089-030
Phone/Fax: +55-11-37965944;
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E-mail: araujojred@terra.com.br
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Abstract

Fetal macrosomia is defined as birth weight >4000g and is associated with several maternal and

fetal complications such as maternal birth canal trauma, shoulder dystocia and perinatal asphyxia.

Early identification of risk factors could allow preventive measures to be taken so as to avoid

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adverse perinatal outcomes. Prenatal diagnosis is based on two-dimensional ultrasound formulae,

but accuracy is low, particularly at advanced gestation. Three-dimensional ultrasound could be an

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alternative to soft tissue monitoring allowing better prediction of birth weight than two-dimensional

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ultrasound. In this article, we describe the definition, risk factors, diagnosis, prevention, ultrasound

monitoring, prenatal care and delivery in fetal macrosomia cases.

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Key words: Fetal macrosomia; Gestational diabetes mellitus; Birth weight; Two-dimensional
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ultrasound; Three-dimensional ultrasound; Induction of labor; Shoulder dystocia.

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Highlights

Fetal macrosomia is defined as a birth weight >4000 g

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Gestational diabetes mellitus is an independent risk factor for fetal macrosomia

Ultrasound is a practical method for screening pregnant women for fetal macrosomia
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Fetal macrosomia is associated with higher rates of shoulder dystocia, perinatal

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trauma and Caesarean section

Scheduled early term birth for ultrasound diagnosed fetal macrosomia may confer benefits

to both the mother and baby

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Introduction and definition

Fetal macrosomia may be arbitrarily defined as a birth weight >4000 g and complicates over

10% of all pregnancies in the United States of America [1]. It is associated with increased risks of

Caesarean section and trauma to the birth canal and fetus. Prediction of fetal macrosomia may be

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performed using clinical and ultrasonographic evaluation. Clinical evaluation is based on maternal

fundal height assessment. When fundal height assessment is performed on an individual basis using

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a customized chart, greater accuracy can potentially be obtained. Similarly, ultrasound estimation of

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fetal weight (EFW) may not be accurate, resulting in an increased rate of false positive tests.

Inaccurate prediction of fetal macrosomia has resulted in a high number of unnecessary procedures,

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since early induction of labor to limit fetal growth may result in a substantial increase in the
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Caesarean section rate because of failed inductions [2] or respiratory complications in newborns.

For these reasons, it could be suggested that pregnancies complicated by fetal macrosomia might be
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best managed expectantly [1].

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Generally, fetal macrosomia may be defined by a birth weight >4000 g or higher cut-offs
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[3]. As a clear cut-off definition of fetal macrosomia has not yet been established, a clinical value

independent of gestational age like LGA (large for gestational age) is preferable. LGA fetuses are
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usually defined as those with a birth weight >90th percentile for gestational age. One of the reasons

for induction of labour in case of suspected macrosomia is to reduce the likelihood of Caesarean
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section and of difficult operative delivery, possibly resulting in maternal or perinatal morbidity [4].
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Observational studies have raised concerns on the effectiveness of this management [5,6].

A direct correlation has been observed between maternal weight gain and the incidence of

secondary Caesarean section when vaginal delivery was initially planned; in addition, a direct

correlation between increasing birth weight and a higher incidence of secondary Caesarean section

and assisted vaginal delivery has been reported.

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Gestational diabetes mellitus (GDM) is a known clinical risk factor associated with fetal

macrosomia and represents 90% of all types of diabetes occurring in pregnancy. In women

diagnosed with GDM, the main complication is fetal macrosomia. The rationale for performing an

elective Caesarean section includes a potential reduction in perinatal complications, especially those

related to macrosomia. Using multiple logistic regression models in 181,479 deliveris, comparing

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birth outcome of women with and without familial history of DM, it has been shown that women

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with a familial history of DM (n= 13,813) had a higher rate of fetal macrosomia, defined as a birth

weight >4000 g, compared with controls (p < 0.001) and a 1.3-fold increase in the risk for

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Caesarean section (p < 0.001) [7].

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According to the National Vital Statistics in the United States, the prevalence of newborns
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weighing at least 4000 g has decreased by 10% in seven years (10.2% in 1996 and 9.2% in 2002)

and 19% for newborns weighing >5000 g (0.16% and 0.13%, respectively). Bayesian calculations
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indicate that the post-test probability of detecting a macrosomic fetus in an uncomplicated

pregnancy is variable, ranging from 15% to 79% with ultrasound estimation of birth weight, and
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40% to 52% with clinical estimates. Among diabetic patients the post-test probability of identifying
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a newborn weighing >4000 g clinically and by ultrasound is over 60%. Among uncomplicated
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pregnancies, there is sufficient evidence that suspected fetal macrosomia is not an indication for

induction of labour or for elective Caesarean section. For pregnancies complicated by diabetes, with
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a prior Caesarean section or shoulder dystocia, delivery of a macrosomic fetus increases the risk of
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complications, but there is insufficient evidence on the threshold of EFW to prompt Caesarean

section [8].

The accuracy of 31 published formulae for EFW in predicting macrosomia (birth weight

>4000 g) in infants of diabetic mothers has been reported in 165 women with GDM or pre-GDM

who had ultrasound for EFW > 36 weeks of gestation and within 2 weeks of delivery. Formulae

were ranked according to a scoring system based on three different outcome measurements.
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Furthermore, each rank score was summed up to give an overall score. The formula with the lowest

total score was considered the best to predict diabetic fetal macrosomia. Fetal macrosomia occurred

in 49 cases (30%). Areas under the receiver operator characteristics (ROC) curves ranged from

0.8361 to 0.8978. Using this ‘best’ formula, an EFW of ≥4000 g had a sensitivity of 45% to predict

macrosomia and a positive predictive value (PPV) of 81%. This study concluded that all 31

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formulae for EFW had comparably poor accuracy for prediction of macrosomia and that delivery

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decisions based on EFW will often result in error [9].

Coomarasamy et al. [10] have calculated the likelihood ratios for positive (LR+) and

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negative (LR-) test results for an ultrasound EFW of >4000 g and an abdominal circumference (AC)

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of 36 cm for predicting birth weight >4000 g. The authors reported that the area under the ROC
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curves for ultrasonographically EFW was no different from the area under the ROC curve for fetal

AC in 19117 pregnant women. Moreover, for predicting a birth weight >4000 g, the summary LRs
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were 5.7 (95% CI: 4.3 to 7.6) for a positive test and 0.48 (95% CI: 0.38 to 0.60) for a negative test,

using Hadlock's formula. When fetal AC=36 cm was considered, the LRs for predicting a birth
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weight >4000 g were 6.9 (95% CI: 5.2 to 9.0) and 0.37 (0.30-0.45), respectively. These authors’
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conclusion was that no differences in accuracy between ultrasound EFW and AC in the prediction
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of a macrosomic baby at birth could be observed.

Vaginal delivery of a macrosomic fetus requires considered attention by an experienced

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clinical obstetrician in order to manage operative delivery, counteract shoulder dystocia and prevent
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neonatal complications [11].

Risk Factors

Macrosomia defined as a fetal weight exceeding the 95th centile or > 2 standard deviations

(SD) above the mean for expected gestational age, has multifactorial causes [12,13]. Genetic,

environmental and constitutional factors as well as metabolic disorders, e.g. diabetes mellitus have a
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significant impact on the occurrence of fetal macrosomia. Constitutional factors like pre-gestational

body mass index (BMI), excessive weight gain during pregnancy and pre-gestational as well as

GDM are recognized as independent risk factors for fetal macrosomia [14-18].

It has been demonstrated that fasting plasma glucose (FPG) in late pregnancy (30-32 weeks

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of gestation) but not fasting plasma insulin or insulin resistance, is a determinant of newborn

macrosomia. Moreover, if an increase in FPG is observed from early to late pregnancy, these

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women had a 4.5-fold increase in risk of newborn macrosomia [19]. Among women with GDM,

maternal FPG concentrations during pregnancy were significantly and positively associated with

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offspring birth size and overweight/obesity risk at 7 years, adjusting for maternal pre-pregnancy

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BMI [20]. AN
In a population-based observational analysis performed on routinely-collected data in

Central China, more than 60% of overweight and obese women have excessive weight gain above
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the IOM (Institute of Medicine, 2009) limit (7–11.5 kg) [21] while the overall incidence of
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macrosomia was similar to that observed in a national survey or in the East of China (6.5 and 8.2 %,
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respectively) [22]. The study by Shi et al. [23] confirmed that maternal overweight, gestational

weight gain and elevated FPG were significantly associated with fetal macrosomia after adjusting
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for maternal age and gestational weeks at delivery.

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Primary prevention should aim to control nutritional behaviour, physical activity and BMI.
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Family and patient history should also be investigated for diabetes mellitus and/or previous GDM.

Epidemiological studies have shown that females are more prone to develop overweight and

become obese than males. This has a great impact on maternal complications such as preeclampsia,

GDM, fetal macrosomia, operative delivery and/or need for elective Caesarean section [24].

A recent meta-analysis by He et al. [25] demonstrated that GDM is independently associated

with macrosomia with an adjusted odds ratio (aOR) of 1.71 (95% CI: 1.52-1.94). Clinical risk
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factors for macrosomia are delivery of a previous macrosomic baby (OR 13.1), maternal weight

gain (OR 10.2), parity (OR 4.8), father’s BMI (OR 3.7), male sex (OR 2.2), and post-term

pregnancy (OR 1.9) [26]. Pre-pregnancy overweight (adjusted aOR 1.27; 95% CI: 1.01-1.59),

obesity (adjusted aOR 1.63; 95 % CI: 1.29-2.07) and excessive gestational weight gain (adjusted

aOR 1.16; 95% CI: 1.13-1.20) were clinical risk factors associated with fetal macrosomia. There is

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evidence that pre-pregnancy BMI may have a greater influence on fetal macrosomia than

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gestational weight gain [27].

Increased placental levels of Insulin Growth Factor (IGF) I, IGF-II, IGF-IR and IGF-IIR

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mRNA are positively associated with fetal macrosomia as well as increased placental levels of apo-

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M, a high-density apoliproprotein that by influencing pre-beta 1 HDL formation is an important
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regulator of HDL metabolism [28].

Consensus agreement of the diagnostic threshold for fetal macrosomia is not well
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established although the ACOG (American College of Obstetricians and Gynecologists)

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recommends a birth weight >4500 g as there are increased postnatal complications beyond this
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value [29]. LGA is variously defined as above the 90th or the 95-97th centile for gestational age,

although centile has the advantage of being independent of gestational age. However, birth weight
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is also influenced by gender and other factors such ethnicity; in addition, specific nation-based

reference ranges are not currently available in many cases or reference values need to be updated. A
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large number of formulae have been produced to calculate the EFW, either by using conventional
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two-dimensional (2D) or 3D (three-dimensional) ultrasound equipment [30].

In order to increase ultrasound accuracy of EFW, standardization of the measurement

technique and EFW calculated on average measurements should be encouraged to reduce intra- and

inter-observer variability as well as keeping a measurement auditing system [31]. Mongelli and

Benzie [32] tested 18 formulae for fetal macrosomia and found that some formulae did not enable a

diagnosis of macrosomia while others showed high false positive rates. Interestingly, Poon et al.
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[33] have demonstrated a diagnostic accuracy for fetal macrosomia in 34% with a false positive rate

of 10% using the first trimester combined test to screen for common trisomies since nuchal

translucency, serum β-hCG and PAPP-A were significantly higher in macrosomic than in non-

macrosomic newborns.

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Although the mode of delivery is still under discussion and women with GDM now

generally undergo induction of labor at 39-40 weeks of gestation (depending on glucose metabolic

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assessment, ultrasound findings, and absence/presence of comorbidities), the most dangerous

obstetric complication associated with fetal macrosomia is shoulder dystocia and its related delivery

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consequences [34]. The OR for shoulder dystocia is 21 for birth weight >4500 g versus normal

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birth weight and the perinatal mortality rate had an OR of 2.3 in case the birth weight exceeded the
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97th percentile [35]. In addition, the risk of postpartum haemorrhage and fourth-degree perineal

tears are increased [36]. Table 1 shows the clinical risk factors, pregnancy outcome and ORs.
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Ultrasound monitoring
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Despite fetal macrosomia being associated with a 2-3 times increase of fetal death risk and
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an increase in the risk of neonatal and long-term maternal complications [11], there are not enough

studies in literature on how prenatal ultrasound monitoring should be performed in pregnancies with
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suspected fetal macrosomia, especially in non-diabetic patients. The difficulty of monitoring a fetus
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with macrosomia comes from the complexity of making a diagnosis, as well as the lack of quality
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evidence as to what should be done if it is suspected [37].

2D ultrasound is the most widely used method for the diagnosis and monitoring of

macrosomia, despite studies showing a lower accuracy in the prediction of LGA compared to

normal weight fetus [38]. Some studies show that performing serial ultrasound could provide more

accurate data on the EFW [39,40] in addition to the creation of an individual growth curve for that

fetus, increasing accuracy in the detection of macrosomia [38]. A new reassessment should be
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performed every 3-4 weeks following suspicion of LGA on ultrasound examination. Most often,

macrosomia can be predicted after two successive scans with an EFW or AC above the 90th

percentile, respectively. Moreover, if after two successive assessments, the EFW weight or AC is

below the 90th percentile, it is not necessary to perform further ultrasound examinations because

the predictive value does not increase [38].

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Regarding the optimal time for ultrasound examination for better prediction of macrosomia

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at birth, Souka et al. [41] showed that examination carried out late in the third trimester (between

34-37 weeks) has better accuracy than at the beginning of the third trimester (between 30-33 6/7).

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Another study found that ultrasound examinations performed up to 7 days before delivery had the

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best results in predicting birth weight [7]. Rigorous vitality monitoring should be performed in
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cases of suspected macrosomia and post-term pregnancy due to the increased risk of perinatal

morbidity and mortality [37].

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Diabetes mellitus is a leading cause of fetal macrosomia and shows a few peculiarities in
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prenatal monitoring. Fetal macrosomia in diabetic mothers is characterized by asymmetric growth

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of the AC, with an excess of muscle and fat accumulation in the fetal abdomen and the scapular

area of the fetus, increasing the risk of shoulder dystocia compared to the macrosomic fetus of
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pregnant women without diabetes [42]. In addition, to the increased risk of neonatal birth trauma,

the fetuses of diabetic mothers have an increased risk of metabolic disorders (anaerobic metabolism
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with lactate accumulation) and fetal death; therefore, these fetuses need more careful ultrasound
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monitoring [43]. Importantly, the NICE guidelines [44] consider the option of initiating

hypoglycemic therapy if ultrasound examination documents sign of impending fetal macrosomia

defined as an abdominal fetal circumference > 70th centile for expected gestational age. A meta-

analysis and systematic review of RCT compared conventional management to assess fetal growth

versus metabolic and ultrasound-based management prior to delivery in women with a wide range

of GDM severity. A total of 417 women were enrolled from two studies, 242 in the ultrasound-
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based group and 175 in the conventional group. Metabolic management was based on FPG and

HbA1c [43]. This RCT [43] concluded that ultrasound-based management was associated with

reductions of 42% in LGA, 36% in abnormal birth weight and 68% in macrosomia although 58%

more women would be treated with insulin.

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In patients with pre-gestational diabetes, ultrasound evaluation of amniotic fluid volume and

fetal growth is recommended every 4 weeks, starting in the 20th week, and every 2 weeks after the

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28th week. In patients with gestational diabetes, ultrasound monitoring is similar to that for patients

with pre-gestational diabetes; however, fetal monitoring may be less rigorous in cases treated only

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with diet who are maintaining normal blood glucose levels [43].

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Ultrasound can be used to measure soft tissue in the shoulder, abdomen, thigh and perioral
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region of the fetus. It is based on the fact that it is adipose tissue that undergoes the greatest change

in growth disorders. Although some studies have shown good correlation of this assessment with
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the evaluation of post-natal skin folds, a study comparing soft tissue evaluation with the EFW (head
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circumference - HC, AC and femur length - FL) has not demonstrated any advantage of such a
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technique in the detection of macrosomia. The combined use of soft tissue measurements with the

EFW could possibly improve the prediction of macrosomia compared to any isolated method [38].
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3D ultrasound provides a better assessment of fetal soft tissues. Studies to validate 3D ultrasound in

predicting birth weight showed similarity to the estimated weight using the 2D ultrasound method
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[45,46]. In a study which assessed the accuracy of 3D ultrasound fractional limb volume compared
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with conventional 2D ultrasound in GDM pregnant women, the 3D ultrasound method showed

better sensitivity for prediction of macrosomia than 2D ultrasound (84% vs. 63%) [47] (Figure 1).

Magnetic resonance imaging (MRI) provides a better evaluation of fetal fat. A systematic

review and meta-analysis showed that MRI is a more specific method than 2D ultrasound and is

apparently also more sensitive despite the limited number of studies and cases [48]. In addition, an

MRI study was conducted and showed good correlation of fetal shoulder measurement with
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shoulder width at birth; this may help in the prediction of shoulder dystocia in macrosomic fetuses

[38]. However, MRI is an expensive test and is not as accessible as ultrasound examination,

therefore, further studies are required before it can be recommended in clinical practice [48]. The

monitoring of fetal growth is an important part of prenatal care. Abnormal fetal growth has short-

and long-term consequences. Despite the lack of accuracy, ultrasound improves the monitoring of

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fetuses with abnormal growth and assists decisions around the timing of delivery [49].

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Fetal wellbeing

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Literature does not include many studies regarding fetal wellbeing in macrosomic fetuses

not associated with diabetes. Most papers focus on the timing and type of delivery for preventing

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birth trauma and dystocia. In addition to ultrasound monitoring for the assessment of fetal growth
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described above, fetal wellbeing can be assessed through the evaluation of amniotic fluid volume,

fetal movement counting by the pregnant woman, fetal biophysical profile (BPP), electronic fetal
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monitoring (EFM) and Doppler ultrasound.

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A study reports that the assessment of amniotic fluid volume together with the EFW
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increases the accuracy of prediction of macrosomia at birth [50]. The evaluation of amniotic fluid

volume should also be included in all ultrasound examinations, as polyhydramnios may be

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indicative of poor glycaemic control [42].

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The counting of fetal movements is no-cost method for assessing fetal well-being in the
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third trimester. There is no consensus on how to instruct the woman to perform this assessment and

there are not enough randomized studies to evaluate the various existing protocols; however,

maternal perception of 10 fetal movements in two hours is considered reassuring [51]. If the woman

perceives a decrease in fetal movements, another test such as EFM or BPP should be performed.

Some authors suggest this monitoring method can be carried out by the 26th to 28th week in
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pregnancies complicated by diabetes. Studies have demonstrated an increase in fetal activity

associated with increased glucose levels in maternal blood [52].

The BPP examination is usually used as a good predictor of fetal vitality, especially in

pregnancies that, in addition to macrosomia, have GDM or pre-gestational diabetes. The BPP has a

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high positive predictive value for an Apgar score > 7 at 5 minute; however when the test is

abnormal, it is not a good predictor of fetal acidaemia [53]. Kjos et al. [54] concluded that a fetal

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BPP evaluation carried out twice a week can prevent fetal death in diabetic pregnant women.

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Despite the lack of large randomized clinical trials, most protocols recommend that pregnant

women with pre-gestational diabetes perform an antepartum evaluation, including EFM.

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Researchers from USA have recommended that women affected by pre-gestational diabetes should
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undergo EFM weekly from the 32nd week and twice a week from the 36th week onwards [55].

However, EFM does not provide fetal wellbeing reassurance for no longer than 24 hours and this
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protocol does not represent a guideline in Europe or in many other countries. EFM can be combined
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with other non-invasive tests such as fetal biophysical profile. Normal results provide greater
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confidence for doctors and patients that pregnancy can continue for another week [51]. EFM can be

classified into reassuring, non reassuring or abnormal, according to NICE classification [56]. When
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it is classified as non-reassuring, it has a low predictive value for fetal distress (<50%) and should

be supplemented with BPP [57]. In diabetic pregnant women, loss of fetal heart rate variability at
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electronic tracing has a higher correlation with impending fetal risk than has decelerations with
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maintained baseline variability [58]. When computerized EFM was analyzed, an increase in the

baseline and short-term variability in diabetic patients was observed [59]. In these patients the

short-term variability may not be able to predict hypoxia [60].

Some studies have been conducted to demonstrate changes in patterns of arterial and venous

flow in macrosomic fetuses. Ebbing et al. [61] evaluated fetuses with isolated macrosomia and

showed increased umbilical vein flow, increased venous perfusion of the fetal liver, greater
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distribution of blood to the right liver lobe and decreased pulsatility index (PI) of the umbilical

artery. This increased blood flow to the fetal liver occurs by the end of pregnancy in macrosomic

fetuses, unlike that which occurs in fetuses of the appropriate weight for the gestational age.

Therefore, a correlation between fetal size and hepatic venous perfusion can be established [62]. It

has been shown that newborns with birth weight either >4000 g or > 90th centile have a lower mean

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umbilical artery PI compared to non-macrosomic fetuses [63]. Doppler study of umbilical artery

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and middle cerebral artery provides adequate monitoring of placental insufficiency in non-diabetic

pregnancies. However, most authors believe that we cannot use the same Doppler criteria of

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placental insufficiency to evaluate the fetuses of diabetic mothers, since the mechanism leading to

fetal death in these patients is of different aetiology [64].

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No randomized clinical trials have been published on the use of umbilical artery Doppler in

evaluating fetal wellbeing in diabetic patients. Current evidence recommends pregnancies

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complicated by preexisting diabetes should be monitored closely (twice a week) using EFM or BPP

or a combination of both. Moreover, Doppler ultrasound investigation should be carried out in

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women with diabetic vasculopahy or with complications of placental insufficiency such as

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pregnancy induced hypertension, intrauterine growth restriction (IUGR) [51]. Despite being a
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difficult vessel to assess and requiring training for insonation, the ductus venosus seems to have

potential in the evaluation of a jeopardized fetus. This is because hypoxia releases catecholamines
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and diverts more flow from the liver to the fetal heart, thus dilating the ductus venosus. The hepatic
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artery is another vessel that is worthy of further studies in the evaluation of the wellbeing of the

fetus of a diabetic mother, due to the large metabolic role of the liver in intrauterine life [64].

Prediction

Ultrasound is a practical method for screening pregnant women for fetal macrosomia. The

almost universal practice is to put the measurements of biparietal diameter (BPD), HC, AC and FL

into a regression model which calculates EFW [65]. The main components contributing to
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inaccuracy in ultrasound predictions are the following: (a) the inaccuracy of prediction formulae

and (b) inaccuracies of technical measurements, which can be reduced by taking repeated and

multiple fetal measurements and making certain that the sections of fetal anatomy have been

obtained accurately [66]. Other factors that increase random error are maternal obesity,

oligohydramnios, poor-quality equipment and inexperienced operators [65].

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Fetal AC has the greatest impact on weight estimation. The maximum random error for

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weight prediction by ultrasound is 100 g/Kg (10%) [65]. Measurements should be performed in a

standardized manner on the basis of strict quality criteria to decrease variability [67]. For correct

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AC representation an axial cross-sectional view must be obtained. The kidneys should not be

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visible, and only one pair of ribs and the three ossification points of the vertebrae should be visible.
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Furthermore, according to Campbell and Wilkin [68] the correct transverse section includes the

stomach, and Hansmann [69] stated that the umbilical vein should be visualized at the level of the
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portal sinus and not be present at any stage. The AC is measured at the outer surface of the skin

line, either directly with ellipse calipers or calculated from linear measurements made perpendicular
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to each other, usually the anteroposterior abdominal diameter (APAD) and transverse abdominal
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diameter (TAD) (Figure 2). To measure the APAD, the calipers are placed on the outer borders of
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the body outline, from the posterior aspect (skin covering the spine) to the anterior abdominal wall.

To measure the TAD, the calipers are placed on the outer borders of the body outline, across the
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abdomen at the widest point. The AC is then calculated using the formula: AC = π (APAD +
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TAD)/2 = 1.57 (APAD + TAD) [70].

Estimation of fetal weight has a substantial impact on the further obstetric management as

both fetal and maternal risks rise with increasing fetal weight. The risk of shoulder dystocia is about

0.2% in average sized fetuses. With a birth weight of 4000–4500 g, this risk increases to about 5%

and is about 30% above 4500 g [71]. This makes it important to have other sonographic approaches

including a targeted formula for fetuses over 4500 g, to reduce systematic errors to a minimum [72].
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The majority of sonographic EFW formulae do not take body composition into account. Because

body composition can vary greatly, even in the fetus, there may be significant variation in birth

weight among fetuses with similar biometric parameters. On average, body fat accounts for 14

percent of the birth weight, but 46 percent of birth weight variance [73]. Adipose tissue is subject to

major changes when conditions associated with accelerated or decreased growth are present. For

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example, diabetic mothers with poor glycaemic control are at increased risk of having a

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macrosomic infant with a large volume of subcutaneous fat. Ultrasound has been used to assess

subcutaneous fat to provide better evaluation of normal and disturbed growth [74,75]. Scioscia et al.

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[76] proposed a linear measurement of the soft tissue above the external side of the fetal femur as a

straightforward method for assessing the amount of fat and muscular mass of the fetal thigh, and a

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new algorithm was calculated to predict birth weight. This method has two main advantages: first, it
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has good reproducibility and, second, it is based on linear 2D measurements that can be adequately
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obtained by non-expert sonographers (less experienced physicians/midwives).

Prevention
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Obesity, maternal weight gain and poor glycaemic control are the main risk factors for

macrosomia [77]. The prevalence of obesity is increasing both in developed countries and
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developing countries. An estimated one fifth of pregnant women in the United Kingdom and one

third of those in the United States are obese [78,79]. Obesity during pregnancy is associated with an
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increased risk of adverse short-term and long-term consequences for both mother and baby [80].
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Hyperglycaemia and increased insulin resistance occurring with obesity may explain the association

between obesity and fetal macrosomia, as well as other pregnancy complications [81].

Since metformin is associated with less gestational weight gain [82] and since birth weight

is related to both BMI and gestational weight gain [83], metformin appears to be an alternative

strategy for reducing insulin resistance and then reducing the risk of macrosomia. However, two

clinical trials performed recently, with pregnant women without diabetes and BMI > 30 and 35
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kg/m2, showed that daily administration of metformin from 12 to 18 weeks of gestation until

delivery did not reduce the median neonatal birth weight z-score or the incidence of LGA neonates

[84]. The use of metformin in women with GDM is an effective and safe treatment and it is not

associated with increased composite neonatal complications. Severe neonatal hypoglycemia is less

frequent in newborns whose mothers were treated with insulin, although 46.3% of women receiving

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metformin required supplemental insulin. A higher rate of spontaneous preterm birth however

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occurred in women with GDM treated with metformin, suggesting a possible active role of

metformin on the process of labour [82]. Pre-pregnancy counseling and public health initiatives

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should stress the importance of attaining a healthy weight prior to pregnancy and avoiding

excessive gestational weight gain following conception [77].

U
AN
However, the UK-UPBEAT (Pregnancies Better Eating and Activity Trial) multicenter

RCT has failed to demonstrate that lifestyle changes during pregnancy may be associated with
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significant effects on the incidence of LGA/macrosomia in women with obesity [85].

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Prenatal care
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The diagnosis of fetal macrosomia during pregnancy is a challenge, because prenatal

diagnostic methods based on clinical examination and ultrasound are imprecise for the estimation of
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fetal weight. A high index of suspicion of macrosomia should be maintained in women with risk
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factors such as a history of macrosomia, high maternal pre-pregnancy weight, increased weight gain
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during pregnancy, multiparity, male fetus, gestational age over 40 weeks, high maternal birth

weight, maternal age under 17 years, pre-gestational diabetes and GDM. Over and above these risk

factors, fetal macrosomia may be suspected following clinical examination which can estimate fetal

weight based on fundal height that is higher than expected for gestational age and abdominal

palpation (Leopold’s manoeuvres). Clinical examination is not accurate; several factors may affect

its accuracy such as obesity, uterine fibroids, multiple pregnancy and the amount of amniotic fluid

[86].
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The obstetrician should rule out or confirm diabetes. If diabetes is confirmed, the goal of

antepartum management is good glycaemic control throughout gestation with diet, exercise and

additional treatment (insulin or oral hypoglycaemic agents), if necessary [87]. Several reports

addressed an association between pre-gestational BMI, high maternal weight gain during pregnancy

and fetal macrosomia [14-18,23,28]. However, there is no evidence supporting clinical

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interventions for the treatment of suspected macrosomia in cases without diabetes. Once the

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diagnosis of macrosomia is suspected, concerns about birth trauma arise. Fetal macrosomia is a

significant risk for shoulder dystocia and its sequalae such as, fracture of the clavicle, brachial

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plexus injury and perinatal asphyxia [88]. During prenatal care the obstetrician should discuss the

risks and strategies for preventing birth trauma.

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AN
Delivery

The mode of delivery- Caesarean section, induction of labour or expectant management- in

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women with suspected fetal macrosomia is very controversial in the medical literature. The value of
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elective Caesarean section in suspected fetal macrosomia is questionable [89]. Some authors
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demonstrated that the number of elective needed to prevent one permanent brachial plexus injury

was 3695 at a cost of 8.7 million dollars [90]. The ACOG recommends prophylactic Caesarean
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section for suspected fetal macrosomia with an EFW >5000 g in pregnant women without diabetes

and >4500 g in those with GDM [91].

C
AC

Induction of labour was proposed to prevent ongoing fetal growth, since the fetus gains

approximately 280 g per week at the end of gestation. This procedure theoretically reduces the risks

of shoulder dystocia, perinatal trauma and Caesarean section. Sanchez-Ramos et al. [92] performed

a systematic review and meta-analysis based on two RCTs and in 9 observational studies comparing

expectant management versus induction of labour for suspected fetal macrosomia and concluded

that induction of labour resulted in an increased Caesarean section rate without improving perinatal
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outcomes. The criticisms of this study are the small sample size and the fact that induction of labour

started at 40 weeks of gestation or more.

Boulvain et al. [86] did a multicentre RCT in 19 tertiary University hospitals in France,

Switzerland and Belgium comparing induction of labour with expectant management for LGA

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fetuses. The authors included women if the EFW was above the 95th percentile using Hadlock’s

formula. They allocated 407 women to induction of labour and 411 expectant management. Labour

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was induced between 37 and 38 6/7 weeks within 3 days of randomization. The primary outcome of

the study was shoulder dystocia, fracture of the clavicle or a long bone, brachial plexus injury,

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intracranial haemorrhage, or death. The authors demonstrated that induction of labour for women

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with suspected fetal macrosomia reduces the risk of shoulder dystocia and bone fracture, and
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increases the likelihood of vaginal delivery. However, this RCT demonstrated that induction of

labour increased the risk of Caesarean section. Despite some critics of the study by Boulvain et al.
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[86], such as the inclusion of women with diabetes and the induction of labour in the early-term of

gestation (37–39 weeks), the results of this work could change the management and mode of
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delivery of fetal macrosomia and could served as a basis for new guidelines.
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The incidence of shoulder dystocia ranges from 0.2 to 3.0% of all vaginal deliveries [93]. It
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is defined as birth with an interval of 60 seconds or more between delivery of the head and the body

[94]. Therefore, it is of great importance to reduce the time between delivery of the head and the
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body. The risk of shoulder dystocia seems to rise with increasing birth weight, however 40% to
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60% of shoulder dystocia happens in births with infants who weighing less than 4000 g [95].

Many manoeuvres for the management of shoulder dystocia alleviation have been described.

The majority of physicians employ the McRobert’s manoeuvre as their first step. The McRobert’s

is performed by removing the legs from the bed/stirrups and sharply flexing the maternal thighs up

onto her abdomen. This procedure results in a straightening of the woman sacrum relative to the

lumbar vertebrae with consequent cephalic rotation of the symphysis pubis [96]. Suprapubic
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pressure, commonly administered by an assistant, is given immediately before or in direct

conjunction with the McRobert’s manoeuvre. This pressure is usually directed posteriorly, in an

attempt to force the anterior shoulder under the symphysis pubis while downward traction is applied

to the fetal head [97]. In the Wood’s corkscrew manoeuvre, the physician attempts to rotate the

posterior shoulder through 180 degrees in a corkscrew fashion with the aim of delivering the

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posterior shoulder, and then the impacted anterior shoulder can be released. In the Rubin’s

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manoeuvre, pressure is applied to the most accessible part of the fetal shoulder, which is then

pushed toward the anterior surface of the chest. These rotational manoeuvres, however, may be

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difficult to perform when the anterior shoulder is tightly wedged underneath the symphysis pubis. It

may therefore be necessary to push the fetus upward slightly in order to facilitate the rotation [98].

U
AN
Delivery of the posterior fetal arm consists of sweeping out the posterior arm of the fetus

across the chest, followed by delivery of the arm. Rotation of the fetal trunk to one of the oblique
M

diameters of the pelvis helps with the subsequent delivery of the anterior shoulder [99]. Intentional

fracture of the clavicle can be achieved by pressing the anterior clavicle against the ramus of the
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pubis freeing the impacted shoulder. Usually, this can happen naturally when applying force to
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remove the anterior shoulder. The consequences of this type of fracture are less significant than
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those associated with brachial nerve injury [100]. The Zavanelli manoeuvre is considered a last

resort. This procedure consists of manual replacement of the fetal head into the vagina followed by
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Caesarean section. Other heroic techniques are symphysiotomy, hysterotomy and cleidotomy [101]
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(Figure 3).

There is a clear association between shoulder dystocia and fetal macrosomia. Tsur et al.

[102], in a review of 240,189 deliveries, stated that fetal macrosomia is an important risk factor for

shoulder dystocia (OR: 16.1). Fetal brachial plexus injury is the most frequent fetal complication.

The incidence ranges from 4% to 40% in literature. Fortunately, only 10% or less cases of brachial
 20
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plexus injury result in permanent injury. Fractures of the clavicle and humerus occur in

approximately 10.6% of cases of shoulder dystocia and usually recover without sequelae.

Hypoxic-ischaemic brain injury can occur in 0.5-23% of cases of shoulder dystocia. The

duration of head-to-body delivery is a critical point and the risk increases if the duration is over 5

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minutes [103]. Perinatal mortality is not frequent and is reported in 0.4% of cases, usually when all

the manoeuvres applied to release the shoulder fail. Neonates with macrosomia have a high oxygen

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demand and subsequently have increased erythropoiesis and polycythemia. Therefore, when these

cells break down, bilirubin increases resulting in neonatal jaundice [104].

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Summary

U
AN
Fetal macrosomia is an obstetric complication that affects 10% of all pregnancies and is associated

with severe maternal-fetal complications such as maternal birth canal trauma, fracture of the
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clavicle, brachial plexus injury and perinatal asphyxia. Early identification of risk factors such as

pre-gestational BMI, excessive weight gain during pregnancy, pre-gestational and GDM can allow
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the early application of measures to prevent adverse perinatal outcomes. The diagnosis of fetal
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macrosomia is based on 2D ultrasound formulae in which the EFW is >4000 g. Furthermore, 3D

ultrasound could monitor the soft tissue allowing better prediction of birth weight than 2D
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ultrasound. Elective Caesarean section does not improve the perinatal outcomes in fetal macrosomia
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cases and induction of labour seems to be better than expectant management for the risk of shoulder
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dystocia.
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Practice points

Fetal macrosomia may be defined as a birth weight >4000 g.

Fetal macrosomia is a clinical risk factor for shoulder dystocia and is associated with
increased risks of Caesarean section, trauma to the birth canal and adverse perinatal

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outcomes such as fracture of the clavicle, brachial plexus injury and perinatal asphyxia.

Fetal macrosomia may be predicted using clinical and ultrasonographic data.

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Pre-gestational body mass index, excessive weight gain during pregnancy and pre-

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gestational diabetes mellitus are recognized as independent risk factors for fetal

macrosomia.

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Biophysical profile examination is usually the best test of fetal wellbeing in assessing
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pregnant women with a high a risk of macrosomia in pregnancies with gestational or pre-

gestational diabetes.
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Three-dimensional ultrasound could monitor the fetal soft tissues and predict macrosomia
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with better sensitivity than two-dimensional ultrasound.

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Metformin is an effective and safe treatment and it is not associated with increased
composite neonatal complications.
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Research agenda
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Two- and three-dimensional ultrasound formulae for the prediction of birth weight with
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more accuracy in cases at high risk of fetal macrosomia.

Maternal biochemical markers for prediction of fetal macrosomia.

Fetal wellbeing tests for monitoring pregnant women at high risk of fetal macrosomia.

Induction of labour versus expectant management in pregnant women with a suspicion of

fetal macrosomia.

Prediction of shoulder dystocia in pregnant women with fetal macrosomia.

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Conflict of Interest Statement

The authors declare no conflict of interest.

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Figure Legends

Figure 1. Fractional fetal humerus volume by three-dimensional ultrasound. The fetal limb is

automatically divided into five similar cross-sectional areas and its areas are manually delineated.

Figure 2. Standard axial view for fetal abdominal circumference measurement. S: spine; St:

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stomach; UV: umbilical vein.

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Figure 3. Flow chart for obstetrical manoeuvres in shoulder dystocia cases.

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Table 1. Clinical risk factors, pregnancy outcome and odds ratios (OR).

Clinical Risk Factors Outcome OR (odd ratio)

Familial DM7 Risk of CS 1.2

GDM25 Macrosomia 1.71

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Previous macrosomia26 Macrosomia 13.1

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Maternal weight gain26 Macrosomia 10.2

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Parity26 Macrosomia 4.8

Father BMI26 Macrosomia 3.7

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Male sex26 Macrosomia 2.2

Post-term pregnancy26 Macrosomia 1.9

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LGA35 Preterm delivery 1.9

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BW >97th centile35 Perinatal mortality 2.3

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Fetal macrosomia98 Shoulder dystocia 16.1

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(Legend: BMI, body mass index; BW, birth weight; CS, Caesarean section; GDM, gestational diabetes

mellitus; LGA, large for gestational age.)

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