Introduction and definition

Fetal macrosomia may be arbitrarily defined as a birth weight >4000 g and occurs as a complication in more than 10% of all pregnancies in the United States of America . It is associated with increased risks of cesarean section and trauma to the birth canal and fetus. Prediction of fetal macrosomia may be 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 a customized chart, greater accuracy can potentially be obtained. Similarly, ultrasound estimation of 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, since early induction of labor to limit fetal growth may result in a substantial increase in the cesarean section rate because of failed inductions or respiratory complications in newborns. Hence, it is suggested that pregnancies complicated by fetal macrosomia might be best managed expectantly .

Generally, fetal macrosomia may be defined by a birth weight >4000 g or higher cutoffs . Since a clear-cut definition of fetal macrosomia has not yet been established, a clinical value independent of gestational age, such as large for gestational age (LGA), is preferable. LGA fetuses are usually defined as those with a birth weight >90th percentile for gestational age. One of the reasons for induction of labor in case of suspected macrosomia is to reduce the likelihood of cesarean section and of difficult operative delivery, possibly resulting in maternal or perinatal morbidity . Observational studies have raised concerns on the effectiveness of this management .

A direct correlation has been observed between maternal weight gain and the incidence of secondary cesarean section when vaginal delivery was initially planned; in addition, a direct correlation between increasing birth weight and a higher incidence of secondary cesarean section and assisted vaginal delivery has been reported.

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 cesarean section includes a potential reduction in perinatal complications, especially those related to macrosomia. Using multiple logistic regression models in 181,479 deliveries for comparing birth outcome of women with and without familial history of DM, it has been shown that women 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 cesarean section (p < 0.001) .

According to the National Vital Statistics in the United States, the prevalence of newborns 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 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 40% to 52% with clinical estimates. Among diabetic patients, the post-test probability of identifying a newborn weighing >4000 g clinically and by ultrasound is over 60%. Among uncomplicated pregnancies, there is sufficient evidence that suspected fetal macrosomia is not an indication for induction of labor or for elective cesarean section. For pregnancies complicated by diabetes, with a prior cesarean section or shoulder dystocia, delivery of a macrosomic fetus increases the risk of complications, but there is insufficient evidence on the threshold of EFW to prompt cesarean section .

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. 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 formulae for EFW had comparably poor accuracy for the prediction of macrosomia and that delivery decisions based on EFW will often result in an error .

Coomarasamy et al. have calculated the likelihood ratios for positive (LR+) and negative (LR-) test results for an ultrasound EFW of >4000 g and an abdominal circumference (AC) of 36 cm for predicting birth weight >4000 g. The authors reported that the area under the ROC curves for ultrasonographically determined EFW was no different from the area under the ROC curve for fetal AC in 19,117 pregnant women. Moreover, for predicting a birth weight >4000 g, the summary LRs 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 by using Hadlock’s formula. When fetal AC = 36 cm was considered, the LRs for predicting a birth weight >4000 g were 6.9 (95% CI: 5.2 to 9.0) and 0.37 (0.30–0.45), respectively. The authors’ conclusion was that no differences could be observed in accuracy between ultrasound EFW and AC in the prediction of a macrosomic baby at birth.

Vaginal delivery of a macrosomic fetus requires considered attention by an experienced clinical obstetrician to manage operative delivery, counteract shoulder dystocia, and prevent neonatal complications .

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 . Genetic, environmental, and constitutional factors as well as metabolic disorders, e.g. diabetes mellitus, have a 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 diabetes mellitus as well as GDM are recognized as independent risk factors for fetal macrosomia .

It has been demonstrated that fasting plasma glucose (FPG) in late pregnancy (30–32 weeks 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 women had a 4.5-fold increase in risk of newborn macrosomia . Among women with GDM, maternal FPG concentrations during pregnancy were significantly and positively associated with offspring birth size and overweight/obesity risk at 7 years, adjusting for maternal pre-pregnancy BMI .

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 the IOM (Institute of Medicine, 2009) limit (7–11.5 kg) while the overall incidence of macrosomia was similar to that observed in a national survey in the East of China (6.5 and 8.2 %, respectively) . The study by Shi et al. confirmed that maternal overweight, gestational weight gain, and elevated FPG were significantly associated with fetal macrosomia after adjusting for maternal age and gestational weeks at delivery.

Primary prevention should aim to control nutritional behavior, physical activity, and BMI. 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 cesarean section .

A recent meta-analysis by He et al. 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 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) . 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 evidence that pre-pregnancy BMI may have a greater influence on fetal macrosomia than on gestational weight gain .

Increased placental levels of insulin growth factor (IGF) I, IGF-II, IGF-IR, and IGF-IIR mRNA are positively associated with fetal macrosomia as well as increased placental levels of apo-M, a high-density apoliproprotein that influences pre-beta 1 HDL formation and is thus an important regulator of HDL metabolism .

Consensus agreement of the diagnostic threshold for fetal macrosomia is not well established although the ACOG (American College of Obstetricians and Gynecologists) recommends a birth weight>4500 g as there are increased postnatal complications beyond this value . 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 is also influenced by gender and other factors such as ethnicity; in addition, specific nation-based reference ranges are not currently available in many cases or reference values need to be updated. A large number of formulae have been produced to calculate the EFW, either by using conventional two-dimensional (2D) or three-dimensional (3D) ultrasound equipment .

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 maintaining a measurement auditing system . Mongelli and Benzie 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. have demonstrated a diagnostic accuracy for fetal macrosomia in 34% women 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.

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 assessment, ultrasound findings, and absence/presence of comorbidities), the most dangerous obstetric complication associated with fetal macrosomia is shoulder dystocia and its related delivery consequences . The OR for shoulder dystocia is 21 for birth weight>4500 g versus normal birth weight and the perinatal mortality rate had an OR of 2.3 in case the birth weight exceeded the 97th percentile . In addition, the risk of postpartum hemorrhage and fourth-degree perineal tears are increased . Table 1 shows the clinical risk factors, pregnancy outcome, and ORs.

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 . Genetic, environmental, and constitutional factors as well as metabolic disorders, e.g. diabetes mellitus, have a 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 diabetes mellitus as well as GDM are recognized as independent risk factors for fetal macrosomia .

It has been demonstrated that fasting plasma glucose (FPG) in late pregnancy (30–32 weeks 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 women had a 4.5-fold increase in risk of newborn macrosomia . Among women with GDM, maternal FPG concentrations during pregnancy were significantly and positively associated with offspring birth size and overweight/obesity risk at 7 years, adjusting for maternal pre-pregnancy BMI .

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 the IOM (Institute of Medicine, 2009) limit (7–11.5 kg) while the overall incidence of macrosomia was similar to that observed in a national survey in the East of China (6.5 and 8.2 %, respectively) . The study by Shi et al. confirmed that maternal overweight, gestational weight gain, and elevated FPG were significantly associated with fetal macrosomia after adjusting for maternal age and gestational weeks at delivery.

Primary prevention should aim to control nutritional behavior, physical activity, and BMI. 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 cesarean section .

A recent meta-analysis by He et al. 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 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) . 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 evidence that pre-pregnancy BMI may have a greater influence on fetal macrosomia than on gestational weight gain .

Increased placental levels of insulin growth factor (IGF) I, IGF-II, IGF-IR, and IGF-IIR mRNA are positively associated with fetal macrosomia as well as increased placental levels of apo-M, a high-density apoliproprotein that influences pre-beta 1 HDL formation and is thus an important regulator of HDL metabolism .

Consensus agreement of the diagnostic threshold for fetal macrosomia is not well established although the ACOG (American College of Obstetricians and Gynecologists) recommends a birth weight>4500 g as there are increased postnatal complications beyond this value . 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 is also influenced by gender and other factors such as ethnicity; in addition, specific nation-based reference ranges are not currently available in many cases or reference values need to be updated. A large number of formulae have been produced to calculate the EFW, either by using conventional two-dimensional (2D) or three-dimensional (3D) ultrasound equipment .

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 maintaining a measurement auditing system . Mongelli and Benzie 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. have demonstrated a diagnostic accuracy for fetal macrosomia in 34% women 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.

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 assessment, ultrasound findings, and absence/presence of comorbidities), the most dangerous obstetric complication associated with fetal macrosomia is shoulder dystocia and its related delivery consequences . The OR for shoulder dystocia is 21 for birth weight>4500 g versus normal birth weight and the perinatal mortality rate had an OR of 2.3 in case the birth weight exceeded the 97th percentile . In addition, the risk of postpartum hemorrhage and fourth-degree perineal tears are increased . Table 1 shows the clinical risk factors, pregnancy outcome, and ORs.

Ultrasound monitoring

Despite fetal macrosomia being associated with a 2–3 times increase in fetal death risk and an increase in the risk of neonatal and long-term maternal complications , there are not enough studies in literature on how prenatal ultrasound monitoring should be performed in pregnancies with suspected fetal macrosomia, especially in non-diabetic patients. The difficulty of monitoring a fetus with macrosomia comes from the complexity of making a diagnosis as well as from the lack of quality evidence on the next steps if it is suspected .

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 than in normal weight fetus . Some studies show that performing serial ultrasound could provide more accurate data on the EFW in addition to the creation of an individual growth curve for that fetus, increasing accuracy in the detection of macrosomia . A new reassessment should be 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 .

Regarding the optimal time for ultrasound examination for better prediction of macrosomia at birth, Souka et al. 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). Another study found that ultrasound examinations performed up to 7 days before delivery had the best results in predicting birth weight . Rigorous vitality monitoring should be performed in cases of suspected macrosomia and post-term pregnancy due to the increased risk of perinatal morbidity and mortality .

Diabetes mellitus is a leading cause of fetal macrosomia and shows a few peculiarities in prenatal monitoring. Fetal macrosomia in diabetic mothers is characterized by asymmetric growth 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 pregnant women without diabetes . In addition to the increased risk of neonatal birth trauma, the fetuses of diabetic mothers have an increased risk of metabolic disorders (anaerobic metabolism with lactate accumulation) and fetal death; therefore, these fetuses need more careful ultrasound monitoring . Importantly, the NICE guidelines consider the option of initiating hypoglycemic therapy if ultrasound examination documents sign of impending fetal macrosomia defined as an abdominal fetal circumference > 70 ^th 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-based group and 175 in the conventional group. Metabolic management was based on FPG and HbA1c . This RCT 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.

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 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 patients treated only with diet who are maintaining normal blood glucose levels .

Ultrasound can be used to measure soft tissue in the shoulder, abdomen, thigh, and perioral region of the fetus. It is based on the fact that the adipose tissue undergoes the greatest change in growth disorders. Although some studies have shown good correlation of this assessment with the evaluation of post-natal skin folds, a study comparing soft tissue evaluation with the EFW (head circumference – HC, AC, and femur length – FL) has not demonstrated any advantage of such a technique in the detection of macrosomia. The combined use of soft tissue measurements with the EFW could possibly improve the prediction of macrosomia compared with any isolated method . 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 . In a study that assessed the accuracy of 3D ultrasound fractional limb volume compared with conventional 2D ultrasound in GDM pregnant women, the 3D ultrasound method showed better sensitivity for the prediction of macrosomia than 2D ultrasound (84% vs. 63%) ( 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.

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 . In addition, an MRI study was conducted and showed good correlation of fetal shoulder measurement with shoulder width at birth; this may help in the prediction of shoulder dystocia in macrosomic fetuses . 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 . 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 fetuses with abnormal growth and assists decisions around the timing of delivery .