Obesity-related diseases in pregnancy were identified in the National Discharge Register. Preeclampsia included eclampsia and was defined from the presence of the diagnoses O14 or O15 (International Classification of Diseases, 10th Revision). The codes I10 through I15 and O10, O11, and O13 were used to identify chronic and gestational hypertension. Diabetes included both pregestational and gestational diabetes and was identified by the codes E10 before or in pregnancy and O24 in pregnancy. We suspected underreporting of type 2 diabetes in the National Discharge Register, so we also relied on self-reported information on diabetes from the telephone interviews. The study was approved by the Scientific Ethics Committee of the Cities of Copenhagen and Frederiksberg on behalf of all the committees in Denmark. The study was also approved by the Danish Data Protection Board.
The main outcome in the study was fetal death, defined as either a spontaneous abortion (< 28 completed weeks of gestation) or a stillbirth (28+ completed weeks of gestation). Intrapartum events were not considered a fetal death because the etiology may be different and highly dependent on the quality of clinical care during labor.4,21 Multiple pregnancies (n = 1,174) were coded as live births if both (n = 1,151) or just one (n = 10) baby was liveborn.
The relative risk of fetal death according to prepregnancy BMI was estimated as a hazard ratio (HR) by using a Cox regression with gestational days as the underlying time scale and the day of the first pregnancy interview as entry time.22 To improve comparability we stratified the analysis by gestational week of the first pregnancy interview. Follow-up ended at the time of fetal death, live birth, intrapartum event, induced abortion, hydatidiform mole, or emigration. We used a 2-sided significance level of .05 in all statistical tests.
In the Cox regression analyses, a number of potential confounders was used to adjust the effect of BMI on fetal death. These confounders were chosen a priori and included age, parity, height, socio-occupational status, smoking, coffee consumption, and alcohol consumption, because these covariates have been considered in previous studies of stillbirth.3,4,6,23,24 Finally, physical exercise was included because it has been suggested that the association between obesity and stillbirth may be confounded by this variable.6
In a separate analysis of stillbirth, the relative risk according to prepregnancy BMI was estimated as an odds ratio (OR) using multiple logistic regression. Only ongoing singleton pregnancies at 28 completed weeks of gestation and with a completed first interview before this point were included in these analyses. The effect of BMI on the risk of stillbirth was estimated with adjustments for the same variables as in the Cox regression. This analysis was repeated after exclusion of women with obesity-related diseases in pregnancy, including preeclampsia, other hypertensive disorders, and diabetes. Finally, the effect of weight gain, included in the model as a continuous variable, was assessed in this subsample. A likelihood ratio test of the hypothesis of no interaction was used to assess whether the effect of BMI on fetal death/stillbirth was modified by categories of height, parity, smoking, or weight gain.
Because 1,436 women contributed more than one pregnancy to the study, we used robust methods to obtain standard errors of the estimates that allowed for within-cluster correlation.25 This methodology is implemented in STATA 8.0 Special Edition (Stata Corporation, College Station, TX), which was used for all statistical analyses.
The study population consisted of 54,505 pregnancies and 679 fetal deaths. Eight percent of the women was categorized as obese, 19% as overweight, 68% as normal weight, and 5% as underweight. The overall crude risk of stillbirth was 2.8/1,000 (n = 155, 13 intrapartum events excluded) and of spontaneous abortions during follow-up was 9.6/1,000 (n = 524). Compared with normal-weight women, obese and overweight women were slightly younger, smoked more, drank less alcohol, exercised less, and had lower socio-occupational status (Table 1). Preeclampsia, other hypertensive disorders, and gestational diabetes were more common among overweight and obese women. Moreover, overweight and obese women reported longer waiting times to pregnancy and had more frequently received infertility treatment.
The models used to describe the association between BMI and fetal death included an interaction term between BMI group and gestational age, which was categorized into 6 periods as shown in Table 2. This approach was used because an initial assessment of the assumption of proportional hazards across levels of BMI showed a statistically significant increase of the relative risk of fetal death with gestational age for both overweight and obese women (P = .02 and P = .001, respectively).
When stratified by gestational age in this manner, the crude rates of fetal death before 14 completed gestational weeks were comparable among the different groups of BMI (Table 2; Fig. 1). Subsequent to week 14, the expected decline in the absolute rate of fetal death across gestation was more pronounced in normal-weight women than in either overweight or obese women. This pattern of divergence resulted in an adjusted relative risk among obese women, which steadily increased with gestational age and ended with a 360% higher risk of stillbirth in pregnancies exceeding 280 days (Table 2). The higher relative risks were statistically significant from week 14 and onwards. A similar, but less pronounced, trend from early to late pregnancy was observed among overweight women, ending with nearly a 190% higher risk of stillbirth in the last gestational age category. The adjustment for a variety of maternal characteristics and life style factors had virtually no effect on the crude estimates (Table 2). Moreover, the effect of BMI on fetal death was not modified by height (P = .83), parity (P = .92), or smoking (P = .24).
A number of additional analyses were performed to assess the robustness of these results to changes in specific aspects of the analytic approach (data available on request). We repeated the analyses after including intrapartum events as fetal deaths. This resulted in a less pronounced trend with gestation in both overweight and obese women. To evaluate the impact of the method for calculation of gestational age, we repeated the analyses with gestational age based on the last menstrual period. A slightly lower excess risk of fetal death in obese women was observed, but results remained otherwise unchanged. We also explored whether the association reflected factors related to subfertility among overweight and obese women by restricting the analysis to primi gravidae with a waiting time to pregnancy of 6 months or less and no reported infertility treatment. This restriction led to an even higher excess risk among obese women compared with women of normal weight.
Next, we focused on the overall risk of stillbirth in 51,655 singleton pregnancies (151 stillbirths), using the same adjustments as in the analysis of fetal death (Table 3). To evaluate whether obesity-related diseases mediated the risk of stillbirth, we excluded women with diabetes (n = 735), preeclampsia (n = 1,122), and other hypertensive disorders (n = 790) from the sample (some had several of these diseases). This resulted in only minimal changes of the adjusted risk estimates. Compared with women of normal weight, overweight women still faced twice the risk of stillbirth, whereas obese women had a 240% increase in risk. Also, the effect of BMI on stillbirth was not modified by height (P = .09), parity (P = .57), or smoking (P = .96).
Within the subset of women without obesity-related diseases, and with weight gain data, we examined the possible effect of maternal weight gain on the risk of stillbirth (n = 39,187). The adjusted odds ratio related to an increased weight of 100 g per week was estimated to be 0.94 (95% CI 0.87–1.03), and those related to overweight and obesity were only slightly reduced. Interaction between BMI and weight gain was not found (P = .37).
Finally, we considered recorded causes of stillbirth. The distribution of causes according to BMI in women without obesity-related diseases is displayed in Table 4. Intrapartum events are included as a separate category. The crude odds ratios showed that unexplained intrauterine deaths and, especially, deaths due to outcomes categorized as placental dysfunction were increased among overweight and obese women. Adjustment for confounders did not change the results, but the limited number of cases may not justify such detailed analysis.
The risk of fetal death was elevated among obese women and, to a lesser degree, also among overweight women. A temporal trend of the risk appeared after 14 weeks of gestation and continued to increase across gestation, with the highest risk of stillbirth after week 40. Weight gain in pregnancy was not significantly associated with the risk of stillbirth for any of the BMI groups.
Hypertensive disorders, diabetes, systemic lupus erythematosus, chronic renal disease, thyroid disorders, and cholestasis in pregnancy have been associated with stillbirth.26 A review of the medical records of all stillbirths in the study showed that these women were without medical diseases, except those 11 women who suffered from obesity-related diseases and had already been excluded from the analysis. We therefore believe that the presence of these medical diseases cannot account for the observed association between obesity and stillbirth.
We found that obesity was associated with a 5-fold increase in risk of stillbirth with placental dysfunction, but the confidence interval was wide. Biologic mechanisms behind this excess risk remain unknown. Obese pregnant women without clinical disease may present with metabolic and vascular abnormalities similar to those seen in preeclamptic women,9,10,27 where failure of normal placentation may lead to both infarction and abruptio of the placenta in later pregnancy.28–30 A recent study suggested that placental dysfunction causing stillbirth may be an endpoint for impaired placental function in the first 10 weeks of pregnancy.31 One may speculate that endothelial dysfunction in obese women is associated with such impaired early placental function.
It has been suggested that rapid fetal growth due to fetal hyperglycemia may place the fetus at risk of death by hypoxia if the placenta cannot transfer sufficient oxygen for metabolic requirements.5 We would expect such stillbirths to appear as unexplained intrauterine fetal deaths in late pregnancy, with a particular excess risk among obese women, as found in our study. However, even when gestational age was taken into account, the birth weights of unexplained intrauterine deaths among obese women were typically lower than the median birth weights of all live births (data available on request). This suggests the presence of some intrauterine growth restriction rather than excess fetal growth.
Excess risk of fetal death in obese women may in part be explained by deranged endocrinology and impaired fertility in a subgroup of obese women.32,33 Restricting our analysis to fertile women with their first pregnancy did not support this hypothesis.
We found no association between BMI and fetal death in the gestation period before week 14, and it cannot be ruled out that obesity acts as a pregnancy-preserving factor in very early pregnancy, leading to delayed fetal loss of less viable fetuses. A recent study found a slightly elevated risk of first-trimester abortions in obese women,14 which may suggest that obesity is at least not protective of early fetal loss.
There are potential criticisms of this study. Self-reported weight is likely to be underreported, whereas height is likely to be overreported, resulting in an underestimation of the true BMI.34 We assumed that the large majority of the participants would report prepregnancy weight and height as obtained during routine antenatal care. This would reduce underreporting because all women are weighed in early pregnancy. For women who experienced a stillbirth, the self-reported information on weight and height was consistent with the information obtained from the medical records. All information was collected at the time of entry into the study and misclassification is therefore likely to be nondifferential. Information bias, if present, would most likely lead to an underestimation of the true effect of obesity.
Information about obesity-related diseases in pregnancy was based on the National Discharge Register, and we found relatively low frequencies of these diseases. A validation study of the register has recently been published, and for categorizations of diseases at the level we used, a high validity was found.35
Recruitment to the Danish National Birth Cohort took place in 2 steps, and each of these steps involve a selection.16 We found, however, that the prevalence of prepregnancy obesity in the study population was very close to the national estimates in the general female population aged 25–44 years, where 9.1% were found to be obese and 20.6% to be overweight.36 Also, the absolute risk of stillbirth in singleton births in the study was 0.32% (intrapartum events included) and only slightly lower than the similar national estimate of 0.37% for the years 1999–2001.37 All comparisons are made within the cohort. Selection bias requires selection on both the exposures and outcomes, and the outcome was not known at the time of recruitment. We therefore believe that the comparisons between normal-weight and obese women in our study were not subject to selection bias. The association between obesity and fetal death may, however, be different in other populations with higher overall risks of fetal death.
Three studies have reported an increased risk of stillbirth in both normal-weight and overweight and obese women when compared with lean women with a BMI less than 18.2 or 20, respectively.3,4,6 However, in the most recent study, the results became less consistent when women with obesity-related diseases in pregnancy were excluded.6 In a large British register-based study, a modestly increased risk of stillbirth was found only in obese women relative to women of normal weight (BMI 20–25) after adjustment for obesity-related diseases in pregnancy.5 The interpretation of the findings in these studies is complicated by the choice of reference groups. We found that the temporal pattern of fetal death among underweight women indicates a high risk of late spontaneous abortions, which may explain in part the subsequent, lower risk of stillbirth. Previous studies have relied on retrospectively collected data on exposure, register data, or medical records, and information on some important confounding factors was missing. The present study is based on prospectively collected data on a large number of potential risk factors from more than 54,000 women. The consistency between various sources of information was high, and we were able to obtain complete ascertainment of all pregnancy outcomes. Furthermore, we had a complete and cause-specific ascertainment of all stillbirths. Although the study was large, the number of stillbirths was limited and reduced our ability to investigate more specific etiological hypotheses.
We found that prepregnancy obesity correlates with an increased risk of both late spontaneous abortion and stillbirth. The present evidence cannot preclude the possibility that obesity and stillbirth share common causes, and that the association we see is not causally related to obesity per se. Advocating weight reduction for obese women who want to become pregnant may be advisable, taking into account other benefits of such a weight reduction. Nevertheless, such advice is offered in a context where causal inference is still speculative.
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