In pregnancies of women with obesity or diabetes, neonates are often overgrown. Thus, the pregnancy period in these women offers a window of opportunity to reduce childhood obesity by preventing neonatal overgrowth. However, the focus has been almost exclusively on growth in late pregnancy. This perspective article addresses possible growth deviations earlier in pregnancy and their potential contribution to neonatal overgrowth. This narrative review focuses on six large-scale, longitudinal studies that included ∼14,400 pregnant women with at least three measurements of fetal growth. A biphasic pattern in growth deviation, including growth reduction in early pregnancy followed by overgrowth in late pregnancy, was found in fetuses of women with obesity, gestational diabetes mellitus (GDM), or type 1 diabetes compared with lean women and those with normal glucose tolerance. Fetuses of women with these conditions have reduced abdominal circumference (AC) and head circumference (HC) in early pregnancy (observed between 14 and 16 gestational weeks), while later in pregnancy they present the overgrown phenotype with larger AC and HC (from approximately 30 gestational weeks onwards). Fetuses with early-pregnancy growth reduction who end up overgrown presumably have undergone in utero catch-up growth. Similar to postnatal catch-up growth, this may confer a higher risk of obesity in later life. Potential long-term health consequences of early fetal growth reduction followed by in utero catch-up growth need to be explored.
A growing number of pregnancies are complicated by obesity or diabetes. Recent data from the U.S. Centers for Disease Control and Prevention National Vital Statistics Reports showed an alarming 30% rise in gestational diabetes rate from 2016 through 2020, worsened by the COVID-19 pandemic (1). Neonates born to women with obesity or diabetes are often characterized by increased accumulation of fat during the intrauterine period, which can manifest as large for gestational age (LGA) or “macrosomia” (2). Timing of the increase in fat is unknown (3), but the fetus can build up triglycerides from early in pregnancy (4). Since neonatal fat is related to the risk of childhood obesity (5), maternal obesity or diabetes indirectly contributes to the increase in prevalence of children with overweight or obesity (6).
Recently, large-scale, longitudinal studies with serial measurements of fetal growth from several thousand pregnant women reported growth reduction in early pregnancy, i.e., at the end of the first trimester of pregnancy, and a greater fetal size in late pregnancy in women with obesity or diagnosed with gestational diabetes mellitus (GDM) compared with lean women or those with normal glucose tolerance (7,8). This prompted us to hypothesize that growth reduction in early pregnancy in women with metabolic disturbances, as is seen in obesity and diabetes, is a more general phenomenon. Fetal growth deviations, both growth reduction and overgrowth, as well as fetal growth rate are related to long-term health of the offspring (5,9–13). Therefore, it is important to pay more clinical and scientific attention to this possible growth reduction in early pregnancy.
In this perspective article, we propose that the pattern of fetal growth deviation is biphasic in pregnancies complicated by maternal diabetes or obesity. In this scenario, early growth reduction is followed by in utero catch-up growth, potentially resulting in overgrowth at the end of pregnancy, the well-known phenotype of infants of women with obesity and/or diabetes.
Early Fetal Growth in Pregnancies Complicated by Maternal Obesity or Diabetes
We have focused on two measures of fetal size that are often routinely measured in clinical care: abdominal circumference (AC) and head circumference (HC). It is assumed that AC in early pregnancy is dictated mostly by organ size, whereas in late pregnancy it is predominantly determined by subcutaneous fat (14). Changes in HC presumably reflect skeletal growth. In a few instances, biparietal diameter (BPD) was used when HC was not available. Before 14 weeks of gestation, many studies, especially the older ones, on preexisting diabetes, presumably type 1 diabetes, only assessed crown-rump length (CRL) as a measure of fetal size.
Information on characteristics of the identified pertinent large longitudinal studies is provided in Table 1. Literature in English was searched in PubMed (until June 2022), and studies were considered pertinent when they included serial measurements (at least three) of fetal growth from early (<20 weeks) to late pregnancy in pregnancies complicated by obesity or diabetes, including GDM and type 1 and type 2 diabetes. The graphical representation of the results of these studies (Fig. 1) shows a biphasic profile of fetal growth deviation in pregnancies complicated by obesity (15,16) or diabetes (7,8,16,17), with statistically significant AC and HC reductions (undergrowth) between 14 and 16 weeks and statistically significant increases (overgrowth) after 30 (AC) or 33 (HC) weeks, respectively.
AC and HC or BPD in pregnancies complicated by obesity (black), GDM (red), or type 1 diabetes (green) and in pregnancies of comparison groups. Comparison groups consist either of women without diabetes (type 1 diabetes or GDM) or women with normal weight. Different symbols indicate different studies. Siddiqi et al. (17) did not measure HC but did measure BPD. Differences are the absolute differences in means between the two groups, in millimeters. Original data were taken from the main article (17) or from supplementary material (7,8,15,16). The boxes indicate the time periods when all the studies show statistically significant differences in fetal size between groups. Between the period in early pregnancy with growth reduction, i.e., undergrowth (14 and 16 weeks for AC and HC, respectively) and the period in late pregnancy with overgrowth (from 30 weeks for AC and 32 weeks for HC), there is a period where no consistent differences are found. In most studies, fetal growth profiles in women with obesity or diabetes cross the lines of those of women in the comparison group. This transition period between undergrowth, i.e., growth reduction, and overgrowth, i.e., increased growth, is shown in the figure with partially transparent lines and symbols. One study did not show a significant growth reduction, but the first ultrasound measurement was not conducted until 17 weeks (16). T1DM, type 1 diabetes mellitus.
AC and HC or BPD in pregnancies complicated by obesity (black), GDM (red), or type 1 diabetes (green) and in pregnancies of comparison groups. Comparison groups consist either of women without diabetes (type 1 diabetes or GDM) or women with normal weight. Different symbols indicate different studies. Siddiqi et al. (17) did not measure HC but did measure BPD. Differences are the absolute differences in means between the two groups, in millimeters. Original data were taken from the main article (17) or from supplementary material (7,8,15,16). The boxes indicate the time periods when all the studies show statistically significant differences in fetal size between groups. Between the period in early pregnancy with growth reduction, i.e., undergrowth (14 and 16 weeks for AC and HC, respectively) and the period in late pregnancy with overgrowth (from 30 weeks for AC and 32 weeks for HC), there is a period where no consistent differences are found. In most studies, fetal growth profiles in women with obesity or diabetes cross the lines of those of women in the comparison group. This transition period between undergrowth, i.e., growth reduction, and overgrowth, i.e., increased growth, is shown in the figure with partially transparent lines and symbols. One study did not show a significant growth reduction, but the first ultrasound measurement was not conducted until 17 weeks (16). T1DM, type 1 diabetes mellitus.
Characteristics of pertinent large longitudinal studies shown in Fig. 1
| Author, year (reference) | Participants | Timing of US | Exposure | Adjustments in analysis |
|---|---|---|---|---|
| Zhang et al., 2018 (15) | Women enrolled at 12 health care institutions in the U.S. with a singleton pregnancy between July 2009 and January 2013: comparison group N = 2,320 (4% [85] with GDM); women with obesity N = 443 (8% [37] with GDM) | US examinations every 4 weeks, from 16 to 41 weeks | Women without obesity (prepregnancy BMI 19–29.9 kg/m2) were compared with women with obesity (prepregnancy BMI >30 kg/m2) | Unadjusted |
| Li et al., 2020 (8) | Women enrolled at 12 health care institutions in the U.S. with a singleton pregnancy between July 2009 and January 2013: comparison group N = 2,020 (15% [307] with obesity); women with GDM N = 107 (33% [35] with obesity) | US examinations every 4 weeks, from 16 to 41 weeks | GDM diagnosed on average at 27.5 weeks; GDM defined as at least two values meeting or exceeding 95 mg/dL at fasting, 180 mg/dL at 1 h, 155 mg/dL at 2 h, and 140 mg/dL at 3 h or by receipt of gestational diabetes medications | Adjusted for race/ethnicity (White, Black, Asian, and Hispanic), age, parity, prepregnancy BMI, and infant sex |
| Macaulay et al., 2018 (16) | Black women from Soweto, South Africa, with a singleton pregnancy between June 2013 and July 2016: comparison group N = 658 (women with normal weight N = 228 and women with obesity N = 229); women with GDM N = 83 (percent with obesity unspecified) | US examinations measuring HC 1) at pregnancy dating (>14 but <20 weeks) and 2) every 5 weeks thereafter; HC and AC reported from 17 to 37 weeks | GDM diagnosed at 24–28 weeks with a 2-h 75-g OGTT after an overnight fast; GDM defined as fasting glucose 5.1–6.9 mmol/L, 1-h glucose ≥10.0 mmol/L, or 2-h glucose 8.5–11.0 mmol/L; women without GDM and with normal weight at enrollment (BMI <25 kg/m2) were compared with women without GDM and with obesity at enrollment (BMI >30 kg/m2); enrollment was, on average, at 12 weeks of gestation | Unadjusted |
| Brand et al., 2018 (7) | White European and South Asian women from Bradford, England, with a singleton pregnancy and expected delivery between March 2007 and December 2010: comparison group N = 9,873 (5,336 South Asian); women with GDM N = 832 (622 South Asian) | US examinations varying from 10 to 34 weeks; infant HC and AC measured within 24 h after birth; average predicted growth trajectories for HC and AC were stratified by GDM status | GDM diagnosed at 26–28 weeks with a 2-h 75-g OGTT after an overnight fast; GDM was defined as either fasting glucose ≥6.1 mmol/L or 2-h glucose ≥7.8 mmol/L | Adjusted for infant sex, maternal age at delivery, parity, height, BMI, education level, ethnicity, smoking, alcohol use during pregnancy, and hypertensive disorders of pregnancy; adjustment for infant sex only resulted in similar results |
| Siddiqi et al., 1989 (17) | Women enrolled at the Cincinnati Medical Center from 1979 and thereafter (end not specified): comparison group N = 117; women with type 1 diabetes N = 106 | US examination 1) at the initial visit, 2) to detect fetal cardiac activity between 16 and 20 weeks to detect malformations, and 3) every 4–5 weeks thereafter; BPD reported from 15 to 38 weeks | Women with type 1 diabetes defined as requiring insulin for survival, classes B through RT of the White classification; reference group had normal glucose tolerance as assessed with glucose challenge test at 26–28 weeks | Unadjusted |
| Author, year (reference) | Participants | Timing of US | Exposure | Adjustments in analysis |
|---|---|---|---|---|
| Zhang et al., 2018 (15) | Women enrolled at 12 health care institutions in the U.S. with a singleton pregnancy between July 2009 and January 2013: comparison group N = 2,320 (4% [85] with GDM); women with obesity N = 443 (8% [37] with GDM) | US examinations every 4 weeks, from 16 to 41 weeks | Women without obesity (prepregnancy BMI 19–29.9 kg/m2) were compared with women with obesity (prepregnancy BMI >30 kg/m2) | Unadjusted |
| Li et al., 2020 (8) | Women enrolled at 12 health care institutions in the U.S. with a singleton pregnancy between July 2009 and January 2013: comparison group N = 2,020 (15% [307] with obesity); women with GDM N = 107 (33% [35] with obesity) | US examinations every 4 weeks, from 16 to 41 weeks | GDM diagnosed on average at 27.5 weeks; GDM defined as at least two values meeting or exceeding 95 mg/dL at fasting, 180 mg/dL at 1 h, 155 mg/dL at 2 h, and 140 mg/dL at 3 h or by receipt of gestational diabetes medications | Adjusted for race/ethnicity (White, Black, Asian, and Hispanic), age, parity, prepregnancy BMI, and infant sex |
| Macaulay et al., 2018 (16) | Black women from Soweto, South Africa, with a singleton pregnancy between June 2013 and July 2016: comparison group N = 658 (women with normal weight N = 228 and women with obesity N = 229); women with GDM N = 83 (percent with obesity unspecified) | US examinations measuring HC 1) at pregnancy dating (>14 but <20 weeks) and 2) every 5 weeks thereafter; HC and AC reported from 17 to 37 weeks | GDM diagnosed at 24–28 weeks with a 2-h 75-g OGTT after an overnight fast; GDM defined as fasting glucose 5.1–6.9 mmol/L, 1-h glucose ≥10.0 mmol/L, or 2-h glucose 8.5–11.0 mmol/L; women without GDM and with normal weight at enrollment (BMI <25 kg/m2) were compared with women without GDM and with obesity at enrollment (BMI >30 kg/m2); enrollment was, on average, at 12 weeks of gestation | Unadjusted |
| Brand et al., 2018 (7) | White European and South Asian women from Bradford, England, with a singleton pregnancy and expected delivery between March 2007 and December 2010: comparison group N = 9,873 (5,336 South Asian); women with GDM N = 832 (622 South Asian) | US examinations varying from 10 to 34 weeks; infant HC and AC measured within 24 h after birth; average predicted growth trajectories for HC and AC were stratified by GDM status | GDM diagnosed at 26–28 weeks with a 2-h 75-g OGTT after an overnight fast; GDM was defined as either fasting glucose ≥6.1 mmol/L or 2-h glucose ≥7.8 mmol/L | Adjusted for infant sex, maternal age at delivery, parity, height, BMI, education level, ethnicity, smoking, alcohol use during pregnancy, and hypertensive disorders of pregnancy; adjustment for infant sex only resulted in similar results |
| Siddiqi et al., 1989 (17) | Women enrolled at the Cincinnati Medical Center from 1979 and thereafter (end not specified): comparison group N = 117; women with type 1 diabetes N = 106 | US examination 1) at the initial visit, 2) to detect fetal cardiac activity between 16 and 20 weeks to detect malformations, and 3) every 4–5 weeks thereafter; BPD reported from 15 to 38 weeks | Women with type 1 diabetes defined as requiring insulin for survival, classes B through RT of the White classification; reference group had normal glucose tolerance as assessed with glucose challenge test at 26–28 weeks | Unadjusted |
Studies in English were selected when they included serial measurements (at least three) of fetal growth from early (<20 weeks) to late pregnancy in pregnancies complicated by obesity and diabetes, including GDM and type 1 diabetes. The data presented by Zhang et al. (15) and Li et al. (8) are based on the same cohort. OGTT, oral glucose tolerance test; US, ultrasound.
Not included in Fig. 1 is a U.K. cohort of >4,000 women for which investigators failed to find significant differences in fetal size between obesity or GDM and control pregnancies at 20 weeks of gestation (18). However, this study did not report values of AC or HC before 20 weeks of gestation, and growth reduction earlier in pregnancy might have been present in this cohort.
Obesity
A large U.S. study (15) showed that maternal obesity was related to significantly reduced AC between 12 and 21 weeks, reduced HC until 30 weeks, and overgrowth thereafter (Fig. 1). Others also found a reduction in AC and HC at 17 weeks and increased growth from 22 weeks onwards (16). In a large Danish cohort of over 9,000 women, a higher BMI was associated with shorter CRL and smaller HC in the first and second trimester, respectively (19). This study is not included in Fig. 1, because the necessary data were not provided in the article.
GDM
GDM is defined as hyperglycemia diagnosed in pregnancy that was not clearly overt diabetes prior to gestation (20–22).
Three large longitudinal studies measured fetal growth before 20 weeks in women who were later diagnosed with GDM (Fig. 1) (7,8,16). Two of these found a reduction in AC and HC between 14 and 17 weeks of gestation (7,8), while one South African study showed increased AC and HC at 17 weeks (16). All three studies found that, in the third trimester, AC was especially increased, but HC also was increased (7,8,16). In these studies, the higher maternal BMI of the women with GDM may have been a contributing factor despite adjustment for maternal BMI in some of the studies (7,8).
Overall, the available evidence combined indicates that although timing and extent of growth deviation vary between studies, on the whole a biphasic pattern of fetal growth deviation is apparent in fetuses of women with obesity or GDM. This was found for both AC and HC, indicating that both skeletal growth and soft-tissue growth are reduced in early pregnancy.
Type 2 Diabetes
During the last 20 years, type 2 diabetes has become increasingly common in women of reproductive age, and up to 60% of pregnant women with preexisting diabetes now have type 2 diabetes (23,24). Currently, no longitudinal data are available on the growth of fetuses of mothers with type 2 diabetes, but we expect that the growth pattern is similar to those of women with obesity or GDM, given the similarity in metabolic changes between these entities. Indeed, one longitudinal study in women with type 2 diabetes also found smaller AC and HC at 17 weeks and greater AC and HC at 37 weeks (25). However, further studies covering the whole pregnancy period in women with type 2 diabetes are needed.
Type 1 Diabetes
The distinct pathophysiology of type 1 diabetes raises the question of whether fetal growth patterns would be similar to those of women with obesity, GDM, or type 2 diabetes.
More than 40 years ago, Pedersen and Mølsted-Pedersen identified early “growth retardation” in fetuses of women with type 1 diabetes (26), especially if glycemic control was poor, which may have entailed poor placentation (27). Thereafter, a number of studies in the 1980s and 1990s reported the same finding of reduced fetal growth, measured as CRL, in the first trimester in women with type 1 diabetes (17,28–35). However, with improving glycemic control in early pregnancy of women with type 1 diabetes, the issue of growth reduction seemed to be something of the past and has not received much attention in recent years. Instead, the focus has shifted toward prediction and prevention of overgrowth in late pregnancy of infants of mothers with type 1 diabetes. This, together with the smaller number of pregnancies complicated by type 1 diabetes compared with obesity or GDM, may explain the lack of longitudinal studies of a scale similar to that for women with obesity or GDM.
The largest longitudinal study of fetal growth from early to late pregnancy included 106 women with type 1 diabetes and 117 healthy control women (17). It measured BPD, which was smaller in fetuses of women with type 1 diabetes compared with controls at 16 weeks, with an even larger difference around 20 weeks of gestation (Fig. 1B). After 29 weeks, BPD was larger in fetuses of women with type 1 diabetes. In a study with measurements at only two time points (25), HC was smaller in fetuses of women with type 1 diabetes at 17 weeks and, interestingly, also smaller at 37 weeks compared with fetuses of control women.
The majority of studies focusing on fetal growth in early pregnancy in women with preexisting diabetes, likely type 1 diabetes, used CRL as a fetal growth measure before 14 weeks of gestation. Most of these studies (26,28–33,36–38), but not all (34,39), report shorter CRL in these pregnancies compared with either control women or reference charts. The largest cross-sectional study (35), with a total of 312 women with type 1 diabetes and 329 control women, found a reduction in CRL of fetuses of women with diabetes compared with controls. This difference was statistically significant at 12 weeks but not at 8 weeks of gestation. More recently, in 2005, a large Canadian study of >46,000 women (40) confirmed the findings of the older studies (i.e., those mentioned previously in this section) and reported early growth restriction of fetuses of women with diabetes.
Ethnic Variation and Sex Differences
Ethnic differences in fetal growth (41), as well as differences in susceptibility for type 2 diabetes (42,43) and GDM (21), are well established. A longitudinal U.K. study compared the influence of GDM on fetal growth patterns in self-reported White European women and South Asian women (7). Differences were seen in fetal growth, with South Asian women having smaller fetuses. However, in both ethnic groups, fetal size (AC and HC) in early pregnancy was similarly reduced in women later diagnosed with GDM (7). Further, in the U.S. study with mixed ethnicities, the effect of GDM on fetal growth was not significantly moderated by self-reported race or ethnicity, although small numbers of women with GDM in minority groups may have precluded significance (8). In a Norwegian cohort study (44), stronger growth reductions were observed at 24 weeks of gestation in South Asian women with GDM compared with White European women with GDM. In Black South African women with obesity or GDM, fetal growth was not reduced compared with that for control individuals (16). In the absence of other ethnic groups for comparison, it is unclear whether this is accounted for by ethnicity, self-reported in that study, or by differences in health care or study methodology. Studies are needed with larger numbers of women from different racial and ethnic groups to look into the ethnic differences in fetal growth pattern related to diabetes or obesity.
Although male and female fetuses follow different growth strategies (45,46) and respond differently to adverse conditions in utero (47,48), no information is available on sex differences in fetal growth in early pregnancy with diabetes or obesity. In the U.S. study, fetal sex did not significantly moderate the association of GDM (8) or obesity (15) with fetal growth profiles, but it is not clear whether this was also specifically assessed for the growth reduction in early pregnancy. One longitudinal study on embryonic growth found stronger growth reductions between 7 and 11 weeks in female compared with male fetuses of women with obesity (49). Other studies did not mention sex differences in growth.
Is Fetal Growth Reduction Related to Hyperglycemia in Pregnancy Real?
On the basis of small-scale studies, smaller fetal size in early pregnancy was argued not to reflect genuine reduction in growth but to be accounted for by delayed ovulation, especially in women with diabetes (50). Menstrual irregularities and delayed ovulation may occur in these women, resulting in misdating of gestational age. Hence, fetal growth measures may differ between women with and without diabetes because of different biological ages of pregnancy without true difference in growth. While this possibility cannot be fully disregarded, it is unlikely to account for reduced early intrauterine growth velocity (51) and delayed psychomotor development in 4-year-old offspring (52). Delayed ovulation also cannot explain a reduction in AC after only 12–14 weeks in women with either GDM or obesity (8,15), when in 9 or 10 weeks no reduction or even larger AC was found. Furthermore, growth reductions were also found in women with obesity who had a regular menstrual cycle and reliable last menstrual period (19,49) or when gestational age was confirmed by concentrations of human β-chorionic gonadotropin in women with type 1 diabetes (30). Collectively, these results argue against delayed ovulation as the only underlying reason for the observed early fetal growth reduction.
Methodological considerations include measurement precision, validity, and reliability, particularly in early pregnancy and in women with obesity. Ultrasound quality control data demonstrated high reproducibility of the measurement in women with and without obesity (15,53). In addition, a longitudinal study using advanced three-dimensional ultrasound measurements three times in the first trimester reported a reduction in embryonic/fetal growth trajectories between 7 and 11 weeks of gestation in women with obesity compared with women with a normal weight (49). Hence, there are no reasons to assume that there would be a systematic measurement error, which could account for smaller fetal size compared with control women. Gestational age variation within a study week (e.g., 12 weeks plus 1 day versus 12 weeks plus 6 days) could theoretically be unequally distributed between women with diabetes or obesity and control women. However, this is very unlikely.
Metabolic traits vary greatly in early pregnancy among women with obesity and women who are subsequently diagnosed with GDM. Some women with obesity may be metabolically healthy (54). Furthermore, each fetus will have an individual growth pattern (55,56). Therefore, growth reduction might only have been found in large cohort studies when there was sufficient statistical power to compare women with obesity or diabetes with control women.
Recently, two studies used an unsupervised, i.e., without principal assumptions underlying statistical analysis, approach for the analysis of longitudinal growth data in a large number of unselected pregnant women (12,57). Latent class trajectory analysis identified, among others, a biphasic growth pattern similar to the ones shown above. The women in this group were most likely to have pregestational diabetes (57) or to be overweight or obese or have developed GDM (12). The absence of selection bias and the unsupervised analyses lend further support to the concept of early growth reduction and later overgrowth.
Thus, in consideration of the methodological issues described above, the evidence accumulated over the past 40 years argues for the biphasic pattern of fetal growth deviation in pregnancies complicated by diabetes or obesity as a genuine biological manifestation of perturbations of the intrauterine environment. The question is what could be the pathophysiological underpinnings of the early growth reduction.
What Are the Reasons for Early Fetal Growth Reduction?
Animal experiments have demonstrated that exposure to diabetic conditions in the periconceptional period (58) can lead to early growth reduction in placenta and fetus (58–62). In human, embryos from women with overweight or obesity are phenotypically and metabolically different from those of lean women, with fewer cells at the blastocyst stage (63).
In both animal experiments and in human, diabetes and obesity affect early placental growth and function (27,62,64), which may constrain fetal growth in the early pregnancy period. Thus, the metabolic changes associated with diabetes and obesity appear to account for the reduced fetal growth in early pregnancy. Indeed, in women with diabetes, poorer glycemic control (higher HbA1c) in early pregnancy was associated with more pronounced fetal growth reduction (28,51). In women with normal glucose tolerance, higher early maternal random glucose levels also were associated with smaller AC and HC at 20 weeks of gestation and later overgrowth (LGA infants) (65). Thus, available data imply that metabolic dysregulation/hyperglycemia in early pregnancy is part of the reason for fetal growth deviation in both periods of pregnancy. Metabolic disturbances, the foremost of which is hyperglycemia, in early pregnancy are present in women with preexisting diabetes. Although to a lesser extent, early-pregnancy glycemic disturbances are also present in women who later develop GDM (66) as well as in a large proportion of women with obesity (66–69).
Why Does It Matter?
In a general population, smaller fetal size in early pregnancy is related to an adverse cardiovascular risk profile in childhood (70). In children of women with type 1 diabetes, smaller size in early gestation was related to poorer fetal functional development (33) and poorer cognitive outcomes at 4 years of age (52), although the latter may have also resulted from neonatal hypoglycemia. These associations are important but may not reflect the risk posed by the altered intrauterine growth dynamics in pregnancies complicated by diabetes and obesity. In view of the early-pregnancy growth reduction, fetuses of women with GDM, type 1 diabetes, and obesity who end up large at the end of pregnancy might have undergone in utero catch-up growth. Indeed, there are indications that LGA infants from women with type 1 diabetes were the smallest in early pregnancy (17). Moreover, LGA infants had accelerated AC and HC growth, i.e., increased growth velocity, at 18 weeks (71), supporting the concept of intrauterine catch-up growth leading to LGA in cases of early fetal growth reduction. Further support for this concept comes from a study in women with a high risk of SGA infants, which showed that fetuses with early growth restriction had the highest birth weight and subscapular skinfold thickness (72). Furthermore, infants exposed to the Dutch famine in 1944–1945 during the first trimester of pregnancy had a higher birth weight than infants exposed later in pregnancy (73). However, birth weight and LGA are not the best proxy measures for intrauterine catch-up growth, because even infants with an inconspicuous birth weight might have experienced catch-up growth (37). Importantly, rapid weight gain of fetuses with the lowest estimated fetal weight at 16–20 weeks (in utero catch-up growth) who ended up in the highest birth weight quartiles was associated with increased childhood obesity risk (13). Fetuses with a “late accelerating growth” trajectory, characterized by undergrowth in early pregnancy and overgrowth in later pregnancy, also had higher weight-to-length ratios at 1 and 2 years of age (12). We are not aware of other studies assessing the association of in utero catch-up growth with subsequent disease risk throughout the life span. Postnatal catch-up growth confers a higher risk of chronic disease such as insulin resistance and obesity in later life (11,74). Therefore, we propose that intrauterine catch-up growth, either directly or indirectly through the resulting fetal/neonatal overgrowth, increases the risk of childhood obesity (Fig. 2). This concept calls for testing in future studies.
Schematic of the proposed concept for the association of intrauterine catch-up growth with childhood obesity. Fetal overgrowth manifested by excessive fat accumulation is an established risk factor for childhood obesity (arrow 1) (5). Catch-up growth can result in fetal overgrowth and thus contribute to childhood obesity (arrow 2). However, it could also be a new risk factor, independent of fetal overgrowth, through biological pathways yet to be identified (arrow 3). The dotted line represents the comparison group throughout pregnancy. Its growth measures were set to zero to demonstrate the biphasic nature of the growth deviations in obesity and diabetes. Dashed lines represent different growth developments in the third trimester.
Schematic of the proposed concept for the association of intrauterine catch-up growth with childhood obesity. Fetal overgrowth manifested by excessive fat accumulation is an established risk factor for childhood obesity (arrow 1) (5). Catch-up growth can result in fetal overgrowth and thus contribute to childhood obesity (arrow 2). However, it could also be a new risk factor, independent of fetal overgrowth, through biological pathways yet to be identified (arrow 3). The dotted line represents the comparison group throughout pregnancy. Its growth measures were set to zero to demonstrate the biphasic nature of the growth deviations in obesity and diabetes. Dashed lines represent different growth developments in the third trimester.
What Now?
The bulk of current research focuses on size and weight at birth, especially as predictors of future health. However, based on the research presented here, spanning four decades, we propose that attention should be given to possible growth reduction in early pregnancy and in utero catch-up growth of fetuses of women with type 1 diabetes, type 2 diabetes, or obesity. Very early life history is gaining recognition as a determinant of later disease risk in the offspring. Increasing our knowledge about this particular period in the life span may motivate researchers to implement future intervention studies early on to prevent effects of intrauterine perturbations on the embryo and early fetus. This should enhance the prospect of reducing the incidence of overgrown babies and their long-term sequelae.
What can we do in clinical practice? Evidence provided here again argues for improving maternal metabolism as early as possible, ideally in the preconception period. While progress has been made in women with type 1 diabetes and type 2 diabetes through intensified prepregnancy counseling, this may be difficult to achieve in women with obesity and even more difficult in those women later diagnosed with GDM, since general preconception counseling is still relatively rare. However, the interpregnancy period might provide chances for preconception counseling for a subsequent pregnancy (75). For the first pregnancy, a vision would be to start with the first ultrasound measurement in the first or early second trimester, perhaps combined with measurements of serum biomarkers in the mother, for the early identification of fetuses at high risk for later overgrowth. This may open a window of opportunity for the early identification of fetuses at risk for adverse development in childhood and adulthood.
A shift in focus of perinatal care to the early pregnancy period was already proposed a decade ago (76,77). However, the timing of the early ultrasound measurements may make a difference. Combined data (8,15,35) indicate that differences in fetal size are not detectable or are not present until 8 weeks of gestation, while after 10–12 weeks a reduction in fetal size is found in women with obesity or diabetes compared with controls. This means that in clinical practice, the timing of ultrasound measurement is important for finding an early growth reduction. In some institutions and health care systems, fetuses are screened by ultrasound at 11–13 weeks for genetic abnormalities. This screening could be combined with measurement of AC and HC. Should either parameter suggest growth reduction, women could be advised to follow a healthy lifestyle. There is evidence from a randomized clinical trial that recommending healthy eating and physical activity reduces neonatal fat deposits (78). Recommending a healthy life also limits gestational weight gain (79), which is especially important in women with type 1 diabetes. This approach is hampered by the current clinical practice of using ultrasound scans at around 12 weeks to determine gestational age on the basis of CRL measurements without taking into account regular/irregular menstrual cycles or metabolic, clinical, and other individual variables. Thus, more research is needed to determine potential cutoff limits for early growth reduction, including, e.g., sensitivity, specificity, and predictive value for later overgrowth, before this approach can be used in a daily clinical setting for the individual pregnant woman.
Until long-term follow-up data of the offspring/children with early growth reduction become available, the clinical applicability of these findings might be limited to identifying fetuses with the largest growth deviations in early pregnancy. Nevertheless, clinicians will be challenged to differentiate between true deviation in fetal size in early pregnancy and delayed ovulation/implantation when assessing ultrasound data (40,55,56), which often will be impossible if menstrual cycles are not very regular.
There is definitely a call for more research, especially for longitudinal studies in women with type 1 diabetes and type 2 diabetes beginning early in pregnancy. The increasing prevalence of pregnant women with type 1 diabetes and type 2 diabetes should make such studies feasible, especially in multicenter settings. By including measurements of AC and HC combined with metabolic phenotyping of the mothers, insights will be gained separately about the drivers of growth deviations for skeletal and soft tissue growth. This will also allow establishing z scores for different body compartments. Since women from some ethnic groups might be constitutionally smaller (e.g., South Asian women) and at the same time might be at higher risk for obesity or GDM, this characteristic might artificially drive differences in fetal size between GDM/obesity and controls. The few data available suggest that using universal criteria for fetal growth assessment would not be useful for identifying growth reductions in early pregnancy related to maternal diabetes or obesity in different ethnic groups (7). Indeed, growth charts differ between different ethnic groups (80). Hence, ethnicity-specific z scores or the use of a unified standard growth curve may be warranted (81).
Lastly, sex differences in response to in utero exposures are common, and whether male and female fetuses of women with diabetes or obesity differ in growth patterns in early pregnancy needs to be assessed systematically. Future studies with sufficient samples size are warranted to look into this.
In summary, by aggregating data from large-scale studies, we demonstrate that the overgrowth phenotype (LGA or macrosomia) in neonates of women with diabetes or obesity can be preceded by a growth reduction in early pregnancy. In our opinion, the early pregnancy period deserves more attention, and awareness of potential growth deviations in this period is needed. Future studies should confirm these findings in other populations and identify potential long-term consequences of early growth reduction for childhood health. Ideally, such studies should include assessment of influences of ethnicity and sex/gender.
Article Information
Funding. G.D. was supported by a visiting professorship grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. He also received funds from the Österreichische Nationalbank (Anniversary Fund, project number 17950).
Duality of Interest. C.Z. is an editorial board member of Diabetes Care. No other potential conflicts of interest relevant to this article were reported.
