Association between prepregnancy body mass index and risk of congenital heart defects in offspring: an ambispective observational study in China

Congenital heart defects (CHDs) are the most common birth defect, with an estimated prevalence of approximately 9.0 per 1000 live births around the world [1]. CHDs contribute to excess morbidity, premature death, and health-care costs [2, 3]. Genetic factors, infection, phenylketonuria and other factors are known to cause many CHDs [4], but at least 85% of CHDs cannot obviously be attributed to these factors [5]. Therefore, identifying modifiable risk factors of CHDs is important for prevention, and such factors may include drinking, smoking, folic acid intake and prepregnancy body mass index (BMI) [6‐8].

Overweight and obesity have been a growing public health concern in developed and developing countries [9]. Prepregnancy obesity in women has been associated with elevated risk of CHDs in offspring [10‐13]. More generally, however, there is conflicting evidence about the association of CHD risk in offspring and prepregnancy overweight [10‐14] or prepregnancy underweight [13‐16].

One reason for this controversy may be related to the different distribution of BMI between women in Western countries and women in Asia, which may reflect differences in genetic, lifestyle, environment, and nutrition diet [17‐20]. For example, obesity (BMI ≥ 30) occurs in 30–40% of adult women in developed countries but in only approximately 12.4% of adult women in China [21]. Approximately 20% of women in Southwest Asia and 12.6% of women in China are underweight (BMI<18.5) [21]. A study of 20,321 pregnant women in the Chinese provinces of Sichuan, Yunnan and Guizhou showed prevalence of 18.7% for prepregnancy underweight (BMI<18.5), 67.0% for normal weight (18.5 ≤ BMI<24.0), 12.4% for overweight (24.0 ≤ BMI<28.0), and 1.9% for obesity (BMI ≥ 28.0) [22]. These results suggest the importance of examining potential associations of maternal prepregnancy over- and underweight with offspring CHDs in specific ethnic groups.

To gain insights into these potential associations in Chinese, we undertook a multi-site ambispective observational study involving more than 2300 pregnant women. We examined associations of maternal prepregnancy BMI with risk of single and multiple CHDs in offspring, as well as with risk of specific CHD types.

A total of 2318 women were evaluated for potential inclusion in our study and 431 were excluded (Fig. 1). Cases and controls differed significantly in type of residence, maternal age, education level, maternal smoking, paternal smoking, maternal drinking, parity and folic acid supplementation (Table 1).

Based on the reference group of pregnant women with high average BMI before pregnancy, women who were underweight before pregnancy were more likely to have fetuses with CHDs (multilevel logistic regression OR (mOR) 1.53, 95%CI 1.13, 2.08; Table 2). Similarly, mothers with low average BMI showed higher risk of fetuses with CHDs (mOR 1.44, 95%CI 1.10, 1.89; Table 2).

Of the 1206 babies with CHDs in our study, 715 (59.3%) had a single CHD while 491 (40.7%) had multiple CHDs (Table 2). Subgroup analysis showed that prepregnancy underweight significantly increased risk of a single CHD (mOR 1.61, 95%CI 1.12, 2.31) and multiple CHDs (mOR 1.46, 95%CI 0.98, 2.16; P<0.1), which was a marginally significant effect. Low average BMI was associated with significantly higher risk of a single CHD (mOR 1.63, 95%CI 1.18, 2.26).

We observed a tendency for prepregnancy overweight to increase the risk of CHDs, but the effect did not achieve significance (Table 2). Similar results were obtained when the reference group was set to women with BMI of 19.9 or 22.6, corresponding to the 25th and 75th percentiles of Chinese women in our study with average BMI (18.5 ≤ BMI<24.0; Additional files 1 and 2).

Subgroup analysis by type of CHD indicated that prepregnancy underweight was associated with greater risk of septal defect (SPD) (mOR 1.90, 95% CI 1.11, 3.26), as was low average BMI (mOR 1.63, 95% CI 0.99, 2.67, P<0.10), which was a marginally significant effect. Among the SPD subtypes, risk of prepregnancy underweight was associated with significantly higher risk of VSD (mOR 2.03, 95% CI 1.06, 3.88). Low average BMI was associated with greater risk of conotruncal defect (mOR 1.60, 95% CI 1.01, 2.53) (Table 3).

Based on the reference group of mothers with prepregnancy BMI of 21.25, which was the median among women with BMI between 18.5 and 24.0, prepregnancy BMI showed an L-shaped relationship with risk of CHDs (Fig. 2). These results are consistent with Table 2. We also found a non-linear relationship of prepregnancy BMI with risk of single or multiple CHDs (Additional files 3 and 4).

We found that prepregnancy BMI showed an L-shaped relationship with risk of CHDs in offspring. Risk of CHDs was significantly higher among mothers with prepregnancy underweight and low average BMI. We failed to observe any significant relationships between prepregnancy overweight or obesity and risk of CHDs in offspring, even after using different cut-off values to define reference groups. This lack of significant association probably reflects the relatively small numbers of mothers in these BMI categories.

Our results are consistent with studies in southeastern and eastern of China, which found that prepregnancy underweight can elevate risk of CHDs in offspring [16, 29]. Similarly to the study in Fujian [29], we divided BMI into groups of BMI < 18.5, 18.5 ≤ BMI < 21.25, 21.25 ≤ BMI < 24.0, and BMI > 24.0, and we found the effect of low average BMI to be associated with higher risk of CHDs in general. The L-shaped relationship that we observed between prepregnancy BMI and risk of general or single CHDs changed to a U-shaped curve when we examined specifically the risk of multiple CHDs. This contrasts with previous work in China showing a U-shaped relationship between prepregnancy BMI and fetal CHDs [16, 29].

For prepregnancy overweight or obesity, some previous studies have found it was associated with a higher risk of offspring CHDs [11, 12]. While, we could not found a statistically significant effect of BMI ≥ 24.0, and it may be due to the relatively small number of overweight women in our study. We did observe a weakly U-shaped correlation between maternal prepregnancy BMI and risk of multiple CHDs in offspring.

How prepregnancy underweight may increase risk of CHDs is unclear. One possibility is malnutrition or nutritional imbalance [31, 32], which can harm embryonic and placental development [33]. Malnutrition or nutritional imbalance can also delay development of the fetal trunk and viscera [31], and cause maternal endocrine abnormalities [29]. In fact, maternal malnutrition or nutritional imbalance can harm fetal organ function even after the organs have fully formed [31]. Some researches have indicated maternal malnutrition or malnutrition imbalance is related with fetal organ dysplasia or malformation, such as: bronchopulmonary dysplasia or neural tube defects [34, 35], while the research of fetal CHDs is few. Future work should examine whether women with different prepregnancy BMI are at risk of malnutrition or micronutrient intake, and whether this in turn affects risk of fetal cardiac anomalies.

Several limitations of the study should be noted. One is that despite the large sample, relatively few subjects were overweight or obese, which may have prevented us from detecting the significant association of such high BMI with CHD risk in offspring that has been reported in studies from the US and Europe [11]. Besides, the very local population in our study may limit the extrapolation of our findings and make direct comparisons to other studies difficult. Therefore we caution against drawing any firm conclusions about these associations from the present study. Another limitation is the design based on retrospective, self-reported data on prepregnancy BMI, which introduces recall bias. We tried to reduce risk of such bias by enrolling women during pregnancy rather than much later. Future work could reduce this bias even more by recording BMI at the first prenatal visit in the first trimester. We were unable to assess whether weight gain during pregnancy influenced risk of CHDs in offspring, since the necessary data were missing for most of our subjects and the gestational weeks for measuring weight were inconsistent, owing that pregnant women do not have regular prenatal examination in the hospitals. Similarly, we did not analyze diet or intake of specific nutrients, which may affect CHD risk. Future work should include these variables. Indeed, our results as a whole should be verified and extended in a prospective cohort study.

Our analysis of a relatively large sample of women from multiple regions in China suggests that prepregnancy underweight is a risk factor of CHDs in offspring. Our data do not allow firm conclusions about whether prepregnancy overweight or obesity significantly influences CHD risk. Our results should be verified in larger studies, preferably with a prospective cohort. If our findings can be validated, they imply that women planning to get pregnant should maintain or even gain weight in order to maintain an adequate, balanced diet and thereby reduce the risk of CHDs in their offspring.