As expected, early pregnancy BMI in our sibling cohort was higher in second compared with first pregnancies (+0.5 kg/m2), while total pregnancy weight gain was approximately 1 kg less in second pregnancies (Table 2). Risk of small-for-gestational-age birth was lower in second births, while the risk of large-for-gestational-age birth was increased. For 52% of women in the sibling cohort, weight gain between pregnancies differed by more than 2 kg, and more than 4 kg for 33% of women. Weight gain differences within women were balanced across birth order (i.e., the proportion of women experiencing higher weight gain in their first pregnancy was comparable to the proportion experiencing higher weight gain in their second pregnancy).
Figure 2 shows the estimated effect of each 1 z-score increase in pregnancy weight gain on fetal size using the sibling comparison and conventional regression (between pregnancies) approaches (values provided in eAppendix 2; http://links.lww.com/EDE/B447). In the simple sibling comparison model, birthweight was an average 66 g (95% CI = 60, 73 g) higher for every 1 z-score change in pregnancy weight gain for a woman with a BMI of 25. After adjusting for confounders, associations became more pronounced (e.g., 89 g [95% CI = 82, 95 g] for a woman with a BMI of 25). The changes between the crude and adjusted estimates were driven primarily by the adjustment for parity. In the conventional analysis, the simple model estimated that for every 1 z-score difference in pregnancy weight gain, birthweight was 97 g higher (95% CI = 92, 102 g). This estimate was similar across different BMI values, and adjustment for confounders had little impact.
Small- and Large-for-gestational-age Birth
Similar findings were observed when we examined the risks of small- and large-for-gestational-age birth (Figures 3 and 4, eAppendix 2; http://links.lww.com/EDE/B447). For small-for-gestational-age birth, the simple sibling comparison models yielded null effects at all BMI values except 18.5 kg/m2. After adjustment for time-varying factors, point estimates across the BMI categories suggested risk ratios for small-for-gestational-age birth of 0.80 (95% CI = 0.75, 0.86) to 0.85 (95% CI = 0.74, 0.95) per 1 z-score change in pregnancy weight gain. The conventional between-pregnancies analysis estimated that for every 1 z-score difference in pregnancy weight gain, the risk ratio for small-for-gestational-age birth was approximately 0.70 across all BMI categories, in both simple and adjusted models (e.g., adjusted risk ratio at BMI of 25 of 0.70 [95% CI = 0.67, 0.73]).
The adjusted sibling comparison model found a positive association between pregnancy weight gain and large-for-gestational-age birth, but the strength of association varied by early pregnancy BMI. The effect of pregnancy weight gain became weaker with increasing early pregnancy BMI, with an estimated 1.58-fold (95% CI = 1.45, 1.71) increase in risk at a BMI of 18.5 compared with an estimated 1.32-fold (95% CI = 1.23, 1.41) increase in risk at a BMI of 35. A similar trend was seen in the adjusted between-pregnancies analysis, with an estimated 1.76-fold (95% CI = 1.66, 1.87) increase in risk of large-for-gestational-age birth per 1 z-score difference in weight gain at a BMI of 18.5, decreasing to a 1.43-fold (95% CI = 1.34, 1.52) increase in risk at a BMI of 35.
Our sensitivity analyses supported the validity of our sibling comparison models. As shown in eAppendix 3; http://links.lww.com/EDE/B447, the associations between pregnancy weight gain and fetal size estimated in our sibling cohort were similar to those estimated using the total population of Stockholm–Gotland births. This reduces the potential for selection bias introduced by systematic differences between women who do versus do not have more than one offspring.
Additionally, in our model assessing the potential for carryover effects, the coefficient for the interaction term between birth order and weight gain was not clinically meaningful in magnitude (7.2 g [95% CI = −0.4, 14.7]).
In this population-based sibling comparison study of 44,457 infants, we found positive, clinically meaningful associations between pregnancy weight gain and fetal size. This suggests that previously observed associations between pregnancy weight gain and fetal size are not primarily attributable to confounding by unmeasured genetic, environmental, or lifestyle factors that remain constant between a woman’s pregnancies.
Comparison with the Literature
Available studies using a sibling comparison design for causal inference on pregnancy weight gain and birthweight have produced conflicting results.4,5 A small study of 90 women with at least two pregnancies complicated by gestational diabetes found that an association between pregnancy weight gain and infant birthweight from the conventional population analysis (24.8 g per 1 kg pregnancy weight gain [95% CI = 7.6, 42.0]) was attenuated in the sibling comparison analysis (13.7 g [95% CI = −0.6, 27.9]). This suggested that the apparent effect of pregnancy weight gain on birthweight may be primarily due to shared environmental or genetic factors rather than causal, at least in the setting of gestational diabetes.4 In contrast, a large study of birth certificate data from 513,501 term sibling groups in New Jersey and Michigan (1989–2003) found a linear association between maternal weight gain and infant birthweight (7.35 g per 1 kg maternal weight gain [95% CI = 7.10, 7.59]). However, data on prepregnancy BMI were unavailable in this study. As prepregnancy BMI is a known determinant of pregnancy weight gain and birthweight,1 and can vary between a woman’s pregnancies (especially given high weight gain in an earlier pregnancy), the study estimates were likely biased by some degree of confounding.
Sibling comparison studies of pregnancy weight gain and longer term offspring size have likewise produced conflicting findings.13–15 A study of 2,758 sibling groups in the Collaborative Perinatal Project found a positive association between gestational weight gain and child BMI at 4 years using the conventional between-women analyses (0.07 z-score increase per 1 kg increase in total pregnancy weight gain [95% CI = 0.04, 0.11]), which was attenuated in the sibling comparison design (0.03 [95% CI = −0.02, 0.08]). This led the authors to conclude that the association between pregnancy weight gain and child size may be explained by shared family characteristics rather than a causal effect of the intrauterine environment.15 In contrast, a study of administrative data from 42,133 women in Arkansas found that an association remained between pregnancy weight gain and childhood obesity using a sibling analysis, suggesting that maternal weight gain in pregnancy has a causal influence on child anthropometry.14 Finally, a sibling analysis using the Swedish Medical Birth Register was used to examine pregnancy weight gain and offspring adiposity at the time of conscription at age 18 in 46,066 male sibling groups.13 The study found that the effect of pregnancy weight gain and offspring adiposity observed in conventional population analyses disappeared in the sibling analyses among normal weight women, but remained in overweight and obese women. However, pregnancy weight gain data were missing in more than 60% of the original cohort, as the Swedish Medical Birth Register is based on information from the delivery admission, and women in Sweden are not routinely weighed at delivery (whereas our cohort included weight measurements from antenatal care).16 As a result, the generalizability of the study findings is unclear.
Our study overcame the concerns of small sample size, selection bias, or confounding of previous sibling comparison studies by using a large, population-based obstetrical cohort with detailed clinical data including early pregnancy BMI. We also accounted for effect modification by early pregnancy BMI, which makes our findings easier to interpret in the context of BMI-specific pregnancy weight gain recommendations. Our results provide robust evidence that pregnancy weight gain has an effect on fetal growth, when shared genetic and time-invariant environmental factors between siblings are taken into account. For Swedish women of normal early pregnancy BMI, one pregnancy weight gain z-score corresponds to approximately 5.2 kg at 40 weeks.7 Thus, our findings suggest that each 1 kg increase in weight gain would correspond to a 17.2 g increase in birthweight (=5.2 kg/89.51 g per 1 z-score of weight gain at BMI = 25 kg/m2). Potential biologic mechanisms linking gestational weight gain and fetal size could include altered availability of metabolites that cross the placenta such as fatty acids, glucose, and lactate in the maternal blood stream used for fetal fat deposition, or increases in adipokines released by maternal adipose tissues crossing the placenta and altering fetal metabolism.17 Translating these findings into public health pregnancy weight gain recommendations will require identifying the weight gain range that best balances the risks of small- and large-for-gestational-age birth, while simultaneously considering other important maternal and child health outcomes that also differ in the direction of their association with pregnancy weight gain. These include maternal and child obesity, cesarean delivery, preterm birth, and infant death.1
Alternative strategies exist for estimating the causal effects of pregnancy exposures. In the Mendelian randomization design, genome-wide association studies are used to identify genotypes that are robustly associated with an exposure of interest. The genes can then be used as an instrumental variable to establish the effects of the exposure on a health outcome of interest.18 A Mendelian randomization design was recently used to demonstrate that prepregnancy obesity has a causal effect on birthweight,19 but we are unaware of a Mendelian randomization study examining weight gain in pregnancy. This research would provide valuable insights to confirm or refute the findings from sibling comparison studies.
Randomized trials of interventions aiming to influence pregnancy weight gain through diet or physical activity can also provide high-quality evidence on the effect of weight gain on infant birthweight. Two systematic reviews with meta-analyses have summarized the effects of such interventions.20,21 Both found that dietary or lifestyle interventions can modify pregnancy weight gain, but neither found differences between groups in birthweight, small- or large-for-gestational-age birth. However, the mean differences in weight gain between intervention and control arms were generally very modest (1.42 kg [95% CI = 0.95, 1.89] in the meta-analysis that reported a summary of the average weight gain difference between groups20). This could explain the lack of differences in fetal size.
Strengths and Limitations
The validity of our findings is supported by our use of a large, population-based cohort. The quality-controlled electronic medical record data provided a high degree of clinical detail, including measured early pregnancy weights and day-specific, ultrasound-confirmed estimates of gestational age. Unlike the Swedish Medical Birth Register, the Stockholm–Gotland Obstetrical database contains weight gain measurements for most women because it contains antenatal clinic data in addition to information from the delivery admission. By modeling early pregnancy BMI and pregnancy weight gain as continuous variables (rather than BMI categories of underweight, normal weight, overweight, and obese and/or weight gain adequacy categories), our analyses reduced the potential for residual confounding. By using the continuous measure of birthweight as our primary outcome, we avoided the reduction in effective sample size to discordant pairs only that occurs when a binary outcome is used. This helped maintain the generalizability of our findings.
The sibling comparison design is dependent on several assumptions.22 First, the design assumes that there are no carryover effects between pregnancies; i.e., the conditions of the first pregnancy cannot affect the exposure–outcome association in subsequent pregnancies. The findings from our sensitivity analysis to determine whether the weight gain–fetal size association differed between a woman’s first and second pregnancy were consistent with the conclusion that any carryover effects were likely negligible. Second, the sibling comparison design only controls for confounding that is invariant between siblings and does not control for factors such as differences in child genotype (including change in paternity), or changes in home environmental, lifestyle, or other factors. As a result, we cannot rule out potential confounding due to these additional factors. Nevertheless, we speculate that variation within women in characteristics such as socioeconomic status, lifestyle, or environmental toxins is likely smaller in magnitude compared with the total variation in these risk factors across a population, resulting in greater internal validity in our approach. This speculation is consistent with previously observed differences in BMI and socioeconomic position between a woman’s successive pregnancies versus across populations of pregnant women.23,24
We used early pregnancy BMI as a proxy for prepregnancy BMI. Although weight gain in the first trimester is negligible,1 it is likely that pregnancy weight gain in our cohort was underestimated to a small degree. However, this would have affected both our sibling design and conventional analyses equally, so would be unlikely to have had a meaningful impact on our comparisons of the two approaches. Also, we used a primary outcome of birthweight for sex and gestational age rather than birthweight z-score to increase clinical interpretability of our model estimates. However, this approach could have introduced bias if gestational age at delivery is systematically different according to gestation weight gain (as this would be analogous to use a reference chart derived from birthweights rather than estimated fetal weights at preterm ages). As recent estimates suggest that the association between pregnancy weight gain and preterm birth is modest at best,25 this reduced the likelihood of bias. Our outcomes of small- and large-for-gestational-age birth were not prone to this bias as they were derived using a reference chart derived from intrauterine estimated fetal weights; however, the clinical importance of these outcomes is unclear as a birthweight in the smallest (or largest) 10% of the population may reflect constitutional smallness rather than an underlying pathological process.26
Finally, our conclusion that these findings lend support to a causal effect of pregnancy weight gain on fetal growth assumes that the manner in which a woman achieved her total gestational weight gain does not influence its relation with the outcome (fetal size). There are multiple ways to arrive at the same total weight gain: e.g., through different longitudinal weight gain patterns across pregnancy (e.g., steady weight gain throughout, low weight gain in early pregnancy with later catch-up gain), through different distributions of fat mass, fat-free mass, and water, and following different biological mechanisms (e.g., hyperemesis causing low gain vs. dietary restriction). However, the extent to which these differences in how total weight gain was reached translate into different exposure–outcome associations is unclear. Although pregnancy weight gain is used in clinical practice because it is a reliable, inexpensive, and simple monitoring tool, further research using an exposure definition that more closely mirrors a well-defined intervention would be valuable.
Our results provide evidence consistent with the hypothesis that pregnancy weight gain has an effect on fetal growth, independent of shared genetic, lifestyle, or environmental factors that remain constant across a woman’s pregnancies. The current Institute of Medicine gestational weight gain guidelines were established assuming that fetal size is influenced by pregnancy weight gain, despite the acknowledged absence of clear evidence on causality.1 Our findings lend support to including fetal size as a consequence of inadequate or excess weight gain when establishing optimal pregnancy weight gain ranges.
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Birthweight; Fetal growth; Gestational weight gain; Large-for-gestational-age; Pregnancy; Sibling analysis; Small-for-gestational-age
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