Environmental rather than genetic fetal overgrowth: defining the difference and hints for diagnosis and management

Abstract

Excessive fetal birth weight or macrosomia can be associated with traumatic delivery and both short-term and long-term neonatal complications. Moreover, evidence is accumulating that macrosomia/being large-for-gestational age (LGA) as a result of excessive and unbalanced intrauterine growth places the individual at increased risk for metabolic short-term complications and more importantly can influence metabolic disorders in adulthood1. Traditionally, maternal diabetes was considered as the main environmental (rather than genetic) cause of macrosomia, along with maternal obesity and accelerated maternal weight gain during pregnancy. In 1952, Pedersen2 was the first to postulate that maternal hyperglycemia was transmitted to the fetus, which, in turn, produced and released large amounts of insulin, resulting in fetal hyperinsulinemia. This would cause various aspects of diabetic fetopathy, including deposition of large amounts of body fat, giving the infant its characteristic appearance. Barker et al.3 later suggested that events during fetal life have implications for adult disease. This theory has effectively shifted focus from managing and preventing short-term complications at delivery to changing and modulating the uterine milieu in order to prevent excessive intrauterine growth and long-term complications such as obesity, Type 2 diabetes and the metabolic syndrome. It would seem logical to assume that the shorter the time a fetus is exposed to an unfavorable and metabolically ‘hostile’ environment, the lower its risk of later unfavorable consequences. Clinically, this approach implies a need to improve prenatal diagnostic capabilities as well as a need for intensive therapy during pregnancy. The terms macrosomia and LGA are used to describe excessive fetal weight. There is some controversy as to whether macrosomia should be defined as an actual birth weight of > 4000 or 4500 g. Macrosomia defined as a birth weight > 4500 g affects about 1.5% of all live-born infants. Decreasing the threshold for definition to 4000 g increases the prevalence of macrosomia to approximately 8% and may be associated with unnecessary obstetric intervention. LGA is usually defined as a birth weight or sonographic estimation of fetal weight above the 90th percentile. Metabolic (environmentally induced) macrosomia is distinguished from genetic or constitutional macrosomia and is defined as the growth of a fetus beyond its genetic potential. It is characterized by excessive fat accumulation during fetal life. The prediction of excessive intrauterine growth remote from term is difficult and inaccurate because it involves sonographic weight estimation and there are many different, as yet unstandardized, formulae for fetal weight calculation. Moreover, not all patterns of intrauterine fetal growth are well understood8. Gestational diabetes mellitus (GDM) is characterized by carbohydrate intolerance, with onset or first recognition during pregnancy. It is associated with a higher-than-normal rate of adverse pregnancy outcome and various neonatal complications, including macrosomia, birth injury, Cesarean delivery, neonatal hypoglycemia, polycythemia and bilirubinemia. The diagnostic criteria for GDM were published by O'Sullivan and Mahan9 more than 40 years ago and were based on maternal long-term complications (the appearance of Type 2 diabetes) rather than on perinatal outcome. Since then, however, despite extensive research and five international workshop conferences that were held in order to try and reach a universal agreement10, there have been no uniform international standards set for the ascertainment and diagnosis of GDM. While some data suggest that the current diagnostic criteria for GDM are too restrictive and that lesser degrees of hyperglycemia also increase risk, the risks associated with hyperglycemia that is less severe than that diagnostic of overt diabetes mellitus are uncertain. The HAPO study sought to resolve some of the diagnostic issues for carbohydrate intolerance during pregnancy4. The primary hypothesis was that pregnancy-related hyperglycemia, even at levels below the threshold for overt diabetes, is associated with increased maternal, fetal and neonatal adverse outcome. The aim of the HAPO study was to investigate the rate of adverse outcomes (the four primary outcomes being: birth weight > 90th percentile (LGA neonate), primary Cesarean section delivery (i.e. the first a woman had had), development of clinical neonatal hypoglycemia, and the presence of fetal hyperinsulinemia) associated with maternal glucose intolerance and to set evidence-based criteria for the diagnosis and classification of GDM. Women were recruited at 15 centers in nine countries worldwide between July 2000 and April 2006. At about 28 weeks' gestation (range, 24–32 weeks) they presented for a 75-g oral glucose tolerance test (OGTT). A fasting plasma glucose sample was collected, and additional samples were collected 1 and 2 hours after glucose consumption. Weight, height and blood pressure were recorded. To avoid influencing clinical decisions, caregivers and participants were blinded to the test results unless they exceeded any of the predefined cut-off values; results were only unblinded if the fasting plasma glucose level was > 5.8 mmol/L (105 mg/dL), if the 2-hour OGTT plasma glucose level was > 11.1 mmol/L (200 mg/dL), if the random plasma glucose level was ≥ 8.9 mmol/L (160 mg/dL) or if any plasma glucose value was < 2.5 mmol/L (45 mg/dL). Only women whose results remained blinded and who had no additional glucose testing outside the HAPO protocol were included in the data analyses. Prenatal care and the timing of delivery were determined by standard practice at each of the 15 field centers. Cord blood was collected at delivery for measurement of C-peptide (as an index of fetal plasma insulin concentration) and glucose. Following delivery, routine neonatal care was carried out at each center. A total of around 28 500 women agreed to participate and more than 25 000 completed an OGTT. About 3% of these had their results unblinded, and 6% dropped out of the study. A total of 23 316 women completed the study. The primary endpoints of the HAPO study showed associations between increased levels of fasting and 1-hour and 2-hour plasma glucose levels obtained on OGTT and: birth weight > 90th percentile and cord blood serum C-peptide level > 90th percentile. There were weaker associations between glucose levels and primary Cesarean delivery and clinical neonatal hypoglycemia5. The study also found positive associations between increasing plasma glucose levels and each of the five secondary outcomes examined: premature delivery, shoulder dystocia or birth injury, intensive neonatal care, hyperbilirubinemia and pre-eclampsia. Confirming the Pedersen hypothesis first proposed 50 years ago2, the HAPO data also provided the ‘missing link’ between maternal glycemia, fetal insulin response and neonatal growth: specifically, neonatal adiposity6. Cord serum C-peptide results were available for 19 885 babies and skin-fold measurements were available for 19 389. For measures of neonatal adiposity, there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. However, whether the observed associations of the maternal metabolic environment with fetal growth are indicative of long-term effects on the increasing prevalence of obesity and diabetes in both adolescents and adults remains to be investigated. Thus, physiologically, the HAPO study results support the old Pedersen hypothesis that the link between maternal hyperglycemia and fetal hyperglycemia and hyperinsulinemia is the mechanism underlying fetal overgrowth and its resulting complications. The results also support the hypothesis that increased glucose concentration to a level less severe than that indicating diabetes is associated with fetal overgrowth, specifically adiposity. This pattern is similar to that reported for maternal glucose and birth weight ≥ 90th percentile6 and was also seen for the association with fetal fat free mass, a parameter derived by subtracting fat mass from total body weight. In February 2009 at the annual meeting of the Society for Maternal-Fetal Medicine, the MFMU network presented for the first time a prospective multicenter randomized treatment trial of mild GDM7. The objective of the study was to evaluate if treatment of mild GDM reduces perinatal morbidity. Women underwent a blinded OGTT (at 24–31 weeks' gestation). Those meeting the criteria for mild GDM (abnormal OGTT with fasting < 95 mg %) were randomized into one of two groups: the untreated GDM group received the usual prenatal care and the treated GDM group underwent dietary intervention, self blood glucose monitoring and insulin administration if necessary. A cohort of women with normal OGTT was also enrolled to mask the status of the untreated GDM group. The primary outcome was a composite of neonatal morbidity: stillbirth/perinatal death, hyperbilirubinemia, hypoglycemia, hyperinsulinemia and birth trauma. Of the 958 women enrolled, 485 were treated and 473 were in the untreated GDM group. There was no difference in composite morbidity in the treated GDM (32.4%) vs. the untreated GDM (37.0%) group (P = 0.14). Neonatal hypoglycemia, hyperbilirubinemia, birth trauma and hyperinsulinemia (cord C-peptide > 90%) were no different. However, mean birth weight (3302 ± 502 g vs. 3408 ± 589 g, P = 0.0005) and neonatal fat mass (427 ± 198 g vs. 464 ± 222 g, P = 0.003) and rates of birth weight > 4000 g, LGA, shoulder dystocia and Cesarean section were reduced in the treatment group. The rate of pre-eclampsia (5.5% vs. 2.5%) and gestational hypertension (13.6% vs. 8.6%) was significantly greater in the untreated GDM group (P = 0.02 for both). The authors concluded that while treatment of mild GDM does not reduce the frequency of several commonly observed neonatal morbidities associated with diabetic pregnancy, it does lower the risk for fetal overgrowth, shoulder dystocia, hypertensive disorders and Cesarean delivery7. The isolation of fetuses with metabolic overgrowth within the subgroup of LGA fetuses is complicated, and depends on various biophysical parameters identified mainly by sonographic evaluation. In addition, because the sonographic findings are not always conclusive, maternal parameters must be taken into consideration. These include maternal obesity, low level of physical activity and accelerated maternal weight gain even with no evidence of diabetes. In some cases, the correct diagnosis is possible only after delivery. Ultrasound assessment of the fetus has become a common procedure in the evaluation of all pregnancies and especially in those affected by GDM. Many investigators have evaluated the use of different anthropometric measurements by ultrasound for both treatment assessment and for prediction of deviant fetal growth. It has been suggested that experienced sonographers can assess fetal weight to within 10% of the actual weight in 80% of cases, but in the remaining 20% of cases, the accuracy is only to within 20% of the actual weight11, 12. The best method or formula has not yet been agreed, although the difference between various methods is not always clinically significant. However, the accurate estimation of birth weight alone does not separate metabolically induced macrosomia from constitutional LGA and other means of evaluation should be incorporated. Percentiles should be calculated for each population individually, taking into consideration demographic measures. Sonographic evaluation of soft tissue thickness by measuring cheek-to-cheek diameter may predict abnormal fetal growth13. In comparison to estimated fetal weight, this measure was found to have higher sensitivity but lower specificity13. However, this approach has not gained wide popularity. Others suggested that measuring subcutaneous fetal fat tissue (e.g. femur width/femur length ratio) achieves high sensitivity and specificity14. Sonographic markers for deviant fetal soft tissue development, such as subcutaneous fat layers of the fetal limb and abdomen, have also been described15-18; all these methods were limited in their success and have yet to achieve wide clinical acceptance. New 3D techniques have the potential to improve the measurement of subcutaneous fetal fat19-23. Some researchers have reported that incorporating fractional limb volume measurements improves weight prediction to within 5% of the actual weight, but this technique is not yet in practical use24. Additionally, a comparative study of antenatal magnetic resonance imaging (MRI) and sonography showed that MRI had better predictive value in terms of fetal weight estimation, although the limited availability of MRI and the consideration of cost effectiveness prevents its routine use in the diagnosis of macrosomia25. Finally, Hackmon and colleagues recently described a possible association between severe neonatal macrosomia and larger than expected crown–rump length from the first or early second trimester of pregnancy26; however, larger prospective studies are needed to confirm this finding. Differentiation between constitutional (genetic-based) and metabolic (environmental-based) macrosomia during fetal life is a novel idea. A better understanding of sonographic findings and their combination with maternal risk factors offers the possibility of identifying metabolic macrosomia. The HAPO study has provided sufficient data to allow us to better understand the associations between adverse pregnancy outcome and ‘non-diabetic’ hyperglycemia, hopefully leading us towards a universal consensus (agreed by all leading international authorities—WHO, CDC, FIGO, ACOG, ADA, EASD and EAPM) to accept new (probably less stringent) diagnostic criteria for GDM, and more efficient management during pregnancy. A management approach which focuses on early, efficient and universally accepted diagnostic criteria of GDM, combined with advances in imaging technologies, may facilitate early and efficient diagnosis of fetal overgrowth. Combining the data from the HAPO and MFMU studies as well as sonographic data with the recent proof supporting intensive maternal treatment for even the mildest forms of carbohydrate intolerance provides further evidence not only that this approach may reduce birth trauma and short-term complications but that it may overcome long-term complications for the offspring.