Gestational diabetes and ultrasound-assessed fetal growth in South Asian and White European women: findings from a prospective pregnancy cohort

Gestational diabetes (GDM), which affects up to 10% of pregnancies depending on the population under study and diagnostic criteria applied, is associated with excess fetal growth resulting in large size at birth, adverse perinatal outcomes, and offspring adiposity [1]. Consistent evidence shows that despite having a greater risk of developing GDM, South Asian women give birth to lower weight infants than women of White European origin [2, 3]. This ethnic difference in weight appears to be present in the fetus from as early as 20 weeks’ gestation based on fetal ultrasound scan assessment [4–6].

Emerging evidence suggests that fetuses whose mothers go on to be diagnosed with GDM may already show accelerated growth before this diagnosis is made. Diagnostic testing, usually with an oral glucose tolerance test (OGTT), is undertaken at 26–28 weeks, because this is the time in pregnancy when there are detectable increases in insulin resistance [7]. In a study of largely White European women, faster hyperglycemia-related fetal growth was observed between 20 and 28 weeks, i.e., prior to the diagnostic test [8]. As there are effective and safe treatments for GDM that reduce birth size and perinatal morbidity [7, 9, 10], this finding suggests that earlier diagnosis might have clinical benefit. Whether a similar pattern of early growth deviation by GDM status would be seen in South Asian women who differ from White European women in fetal growth characteristics and risk of developing GDM is unknown. Moreover, as GDM is the upper end of a continuum of linear associations of increasing gestational glucose with greater birth weight [11–13] it is plausible that glucose levels below the diagnostic threshold will be related to fetal growth. Understanding the joint associations of GDM and South Asian ethnicity, two key risk factors for variation in birthweight, on fetal growth is important for identifying mechanisms that might explain lower birthweight in South Asians despite their greater GDM risk, and also for determining whether hyperglycemia-related pathological growth in South Asians can be determined from fetal growth patterns.

The aim of this study was to determine the associations of GDM and gestational glucose with longitudinal fetal growth across different parameters [head circumference (HC), abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW)] in White European and South Asian women.

Table S2 in Additional file 1 summarizes the repeat anthropometric measurements included in the analyses. The median number of anthropometric measures per fetus was 3 (IQR 2–4; full-range 1–12) and the mean (SD) gestational age at first fetal anthropometric measurement was 18.8 (3.1) weeks. As might be expected, women with a third trimester scan were older, had a higher BMI, were more often multiparous, and were more likely to have diagnosis of GDM or hypertensive disorder of pregnancy (Table S4 in Additional file 1). Infants of women with a third trimester scan were delivered with an earlier gestational age and had a lower birthweight than infants of mothers who did not have a third trimester scan (Table S4 in Additional file 1). In total, 2341 participants did not have a CRL measurement for dating and fetal HC was used to date these women. Infants of the 2341 women who were “dated” on the basis of HC rather than CRL had similar gestational ages at delivery and birthweights; their mothers had similar mean BMI, height, fasting and postload glucose, and rates of GDM and hypertensive disorder of pregnancy. They were, however, more likely to be South Asian, have a higher parity, lower education, and less likely to smoke or drink alcohol in pregnancy (Table S5 in Additional file 1).

Joint associations of ethnicity and GDM with fetal growth

Figure 1 shows the observed mean differences in fetal size across gestation by GDM in each ethnic group. There was no evidence of effect modification by ethnicity, as the direction and magnitude of associations of GDM with fetal growth were similar in South Asians and White Europeans, as were associations with postload glucose in those not diagnosed with GDM (Figure S5 in Additional file 1). Positive associations of fasting glucose with fetal growth were somewhat stronger in White European than South Asian fetuses, but as with GDM, broadly similar in each ethnic group (Figure S6 in Additional file 1).

As the association of GDM with fetal growth did not differ by ethnicity, and South Asians were consistently smaller in size than White Europeans across pregnancy for most growth measures (independently of GDM), South Asian fetuses exposed to GDM were smaller across gestation than White European fetuses not exposed to GDM (Fig. 2, Table 2). This difference was largest for AC and EFW and detectable from early pregnancy [difference in mean AC and EFW at 24 weeks comparing South Asians exposed to GDM to White Europeans not exposed to GDM = − 2.3 mm (− 3.4; − 1.2) and − 10 g (− 19; − 1) respectively] and increased as pregnancy progressed, such that by term (40 weeks) it was − 7.1 mm (− 9.4; − 4.8) for AC and − 45 g (− 86; − 4) for EFW.

All results presented above are from multivariable adjusted analyses following multiple imputation for missing covariable data; associations were similar in analyses with adjustment for infant sex only (Table S7 in Additional file 1) and in complete case analyses (Table S8 in Additional file 1). They were also similar when limited to women with ≤ 4 repeat ultrasound scans (Table S9 in Additional file 1) and when limited to women who completed the OGTT between 24 and 30 weeks’ gestation (Table S10 in Additional file 1).

In this prospective pregnancy cohort, we found that fetuses of women subsequently diagnosed with GDM were smaller at 12–16 weeks’ gestation but grew faster such that from 24 weeks to delivery time, they had greater AC and EFW compared with fetuses not exposed to GDM. The association of GDM with fetal growth was of similar magnitude in both ethnic groups and was also observed across the distribution of fasting and postload glucose levels in women without GDM. Growth trajectories differed by ethnicity irrespective of GDM status, with South Asian fetuses being smaller from 20 weeks’ gestation to term, than White European fetuses. Consequently, South Asian fetuses exposed to GDM were on average smaller across gestation than White European fetuses not exposed to GDM. These findings indicate that hyperglycemia-associated fetal growth deviations are detectable early in pregnancy prior to the usual time of GDM diagnostic testing and that universal criteria for fetal growth assessment may be inadequate for identifying GDM-associated pathological effects in South Asians.

The observation of South Asians having a smaller fetal size across gestation than White Europeans is consistent with observations in other population-based studies [4–6, 25]. Ethnic differences in fetal size increased as the pregnancy progressed and were relatively more profound for AC and EFW than for HC. It has been suggested that the slower fetal growth in South Asians represents compromised growth and development of abdominal visceral organs with relative sparing of the fetal brain to improve survival chances in environments where nutritional resources may be limited, with this being driven by fetal adaptations to generations of maternal undernutrition [6, 26]. The fact that we see larger ethnic differences for AC and EFW than HC provides some support for this hypothesized mechanism. South Asian infants are, however, more adipose at birth on an absolute scale and also relative to their birth weight compared to White European infants [27, 28]. This “thin-fat phenotype” has also been observed in South Asian infants born in the UK and compared with White European infants born in the UK (including from the same city and treated in the same antenatal care setting) [3, 29]. It appears to persist through infancy and early childhood [30]. Since our study was based on standard ultrasound anthropometric measurements, we were unable to distinguish fetal fat and lean mass growth trajectories.

While the impact of GDM on birthweight is well-established [12, 31], few studies have assessed the timing at which divergent growth patterns emerge in utero [8, 32, 33]. Our findings of a larger fetal AC at 24 weeks’ gestation in women later diagnosed with GDM is consistent with previous observations in White European women [8], and support the notion that glycemia-related fetal growth acceleration precedes the usual time of OGTT to diagnose GDM. For the first time, we demonstrate a similar pattern of increased fetal size preceding the GDM diagnosis in South Asian origin women. Consistent with previous data on offspring birth weight [11–13], associations with GDM were part of a continuum as gestational glucose levels were positively and linearly associated with fetal size from 24 weeks onwards. The continuous positive association of gestational glucose across the whole distribution with fetal growth and birth weight, including in two ethnic groups with very different body compositions, likely reflects the facilitated diffusion of glucose across the placenta and the fetal insulin secretion response to this. The diagnostic criteria for GDM aim to minimize LGA and associated adverse outcomes, while not compromising healthy fetal growth and development, and the associations of fasting and postload glucose with fetal growth and birth weight in women who do not meet criteria for a diagnosis of GDM do not imply the thresholds for diagnosing GDM should be reduced. Our results do support developing methods for identifying hyperglycemia-related adverse fetal growth in early pregnancy.

We further found evidence that fetuses of GDM complicated pregnancies were smaller at 12 and 16 weeks’ gestation prior to the onset of growth acceleration. This biphasic fetal growth pattern with early fetal growth restriction predating growth acceleration has previously been described in GDM [32], pre-gestational type 1 [34, 35], and type 2 diabetes [33] and has been attributed to transient oxygen tension in early pregnancy with oxidative and/or proinflammatory stress superimposed by hyperglycemia exerting a short-term inhibitory effect on trophoblast and placental growth [36]. In our cohort, there were too few women (67 in total; 36 South Asian, 24 White European, and 7 other ethnic origin) to be able to explore fetal growth trajectories by pre-gestational diabetes.

Oral glucose tolerance tests for diagnosis of GDM are undertaken at 26–28 weeks because this is the time in pregnancy when there are detectable increases in insulin resistance [7]. However, GDM is likely to reflect the unmasking of a predisposition to hyperglycemia and type 2 diabetes as a result of pregnancy changes mimicking a glucose stress test [37]. This would be in line with reports linking pregestational increased glucose levels [38] and reductions in peripheral insulin sensitivity [39, 40] to a GDM diagnosis later in pregnancy. The International Association of the Diabetes and Pregnancy Study Groups’ criteria recommend a random fasting glucose measure in the first antenatal clinic visit which could identify women with pre-existing hyperglycemia and support earlier monitoring and treatment. Given we have shown GDM-associated fetal growth alterations as early as 12–16 weeks’ gestation, and other studies show early growth retardation in relation to existing type 1 and type 2 diabetes [33–35], efforts to improve pre- and periconceptional maternal health deserve more attention in the prevention of adverse pregnancy outcomes including hyperglycemia-related fetal growth differences [41, 42].

Despite the fact that South Asian women have higher fasting and postload glucose levels and are more likely to develop GDM [11], their infants weigh on average less at birth than infants of White European mothers. Here, we show that the fetal growth difference between South Asians and White Europeans is substantial as, on average, infants of South Asian women with GDM were even smaller across gestation than infants of White Europeans without GDM. There are a number of implications that follow from this. First, this could result in South Asian fetuses and infants with glycemia-related pathological fetal growth not being identified as such. This can be seen by the proportions identified as LGA based on birth weight in this study. Applying the Intergrowth-21st standards, which assess the deviation in birth weight from an ideal size that would be obtained under extreme healthy pregnancy conditions (no complications, within a tightly defined age, height and BMI range, and healthy behaviors such as not smoking in pregnancy), showed higher proportions of LGA in infants of mothers with GDM compared to those without GDM in both ethnicities and also lower rates of LGA in South Asians compared with White Europeans, consistent with the differences in fetal growth that we find by GDM and ethnicity. By contrast, customized reference charts (which assume that maternal ethnicity, as well as height, weight, and parity are physiological causes of variation in birthweight and remove the effects of these characteristics on SGA and LGA) removed the ethnic difference in LGA, as expected given the standardization on ethnicity. Whatever standard or reference charts are used, it may be that lower thresholds for fetal growth and birth weight are necessary to identify South Asians at risk of LGA and potential future risk of obesity. However, such an approach could risk missing cases of SGA and the use of ethnic specific thresholds would only be justified if this would also improve the prediction of adverse neonatal outcomes related to SGA, which remains to be determined. In light of the ongoing debate around universal fetal growth standards vs. reference charts (whether customized or not), further studies addressing this important knowledge gap are warranted [43]. Second, our findings suggest that routine fetal ultrasound measures may be inadequate for the assessment of GDM pathological effects if these are largely driven by other anthropometric measures. Infants born to mothers with GDM have a higher fat to lean body mass [44, 45] and a predisposition to fat over fat-free mass has also been demonstrated in utero from 20 weeks’ gestation [46, 47]. Evidence from the BiB cohort further suggests that higher cord blood leptin levels, a proxy for fetal fat mass, in South Asian compared with White European infants is largely driven by the ethnic difference in maternal glucose levels [23]. Taken together, these data indicate that more detailed fetal body composition measures (distinguishing fetal fat from lean mass trajectories) may be important in identifying pathological effects of gestational hyperglycemia and to ascertain whether “normal” weight South Asian infants of GDM pregnancies might be a group at risk of adverse perinatal and long-term metabolic health.

Strengths of this study are the large sample size, repeat ultrasound measurements of fetal growth from 12/16 weeks of gestation to birth, and the ability to examine joint effects of GDM and ethnicity. Our study was embedded in routine clinical practice with universal OGTT diagnostic testing, which allowed us to determine associations with gestational hyperglycemia across the entire glucose range. Third trimester ultrasound scans, however, were only available for a subset of the cohort. Nonetheless, ~ 30% of all third trimester scans were research scans and not done because of clinical indication, almost all infants had birth measurements as the fetal growth endpoint and exclusion of singletons with ≥ 4 ultrasound scans (which addresses the impact of clinical indications associated with multiple repeat scans) did not change the results. Moreover, all analyses were adjusted for a wide range of maternal characteristics, some of which were also predictive of having an additional third trimester scan. This means that the “missing at random” assumption is plausible, minimizing any potential bias.

Gestational age assessment in our study was based on fetal biometry which relies on the assumption that variation between fetuses is negligible during the dating period. This could have resulted in an underestimation of fetal size variation in early pregnancy and consequent inability to detect associations at this time, especially where fetal HC was used for dating. However, only 22% of all participants had missing CRL data, and it is unlikely that the use of HC for dating has resulted in major bias as mean gestational age at delivery, birth weight, GDM, and fasting and postload glucose were similar between those whose dates were derived from CRL and those from HC. However, the ethnic imbalance in dating method used could have masked the ethnic difference in fetal HC trajectory observed, especially during early gestation when fetal HC measurements are more closely correlated to the dating measure. Finally, we cannot exclude the possibility of a systematic over- or underestimation of early fetal size differences between women with and without GDM. This is an inherent source of potential bias related to the fact that pregnancy dating is performed without knowing whether or not a woman will or will not experience GDM. As fetal size is used to allocate a gestational age, a lower or higher gestational age may have been assigned to GDM cases if their fetus was already smaller or larger than fetuses of women without GDM at the dating scan. The consequence of pregnancy dating being pushed backward or forward in these women is that the actual size of their fetus at a given gestational age in early pregnancy (when fetal anthropometric measures are closely correlated to CRL and HC measures used for dating) could have been overestimated or underestimated relative to the fetal size of normoglycemic women. Finally, we were unable to assess associations with early pregnancy glucose, as this was not measured in the BiB cohort.

GDM is associated with fetal growth deviation in early pregnancy prior to diagnosis in both ethnic groups. This emphasizes the need for novel strategies to diagnose hyperglycemia-related growth accelerations earlier than current methods. Consistent with the hypothesis that South Asian fetuses adapt to generations of maternal undernutrition by compromising growth and development of abdominal visceral organs with relative sparing of the fetal brain, we found greater ethnic differences between AC and EFW than with HC, but further research is required to understand ethnic differences in fetal growth of fat, lean, and skeletal mass. Furthermore, as fetal growth trajectories differ considerably by ethnicity and this could potentially mask the detection of hyperglycemia-related pathological effects, further work is now needed to understand how this may influence perinatal and offspring health.