The rate of obesity in adult women in the United States is 35.3%.1 In addition to the decrement in overall health and well-being caused by obesity, a multitude of adverse pregnancy outcomes have been consistently associated with maternal obesity. Maternal obesity increases the risk for gestational diabetes, preeclampsia, fetal death, macrosomia, infection, cesarean delivery, thromboembolic events, surgical complications, early neonatal death, and birth trauma.2–7 Whether maternal obesity is associated with an increased risk of fetal malformations remains controversial, with case–control and cohort studies often yielding contrary results.8–17
We undertook the present investigation to estimate whether the increase in the prevalence of obesity in our obstetric population was associated with a corresponding increase in the prevalence of major congenital anomalies and, if so, to evaluate whether other factors, particularly diabetes, could be contributory.
MATERIALS AND METHODS
This study was approved by the University of Alabama Institutional Review Board. We used a computerized perinatal database to identify women who received prenatal care within the University of Alabama maternity care system from 1991 to 2004. We defined three time epochs—1991–1994, 1995–1999, and 2000–2004—to compare patient cohorts in a serial, cross-sectional fashion. In addition to data routinely available in our perinatal database, computerized records of prenatal ultrasound examinations on each patient were linked to the perinatal database to enhance the identification of infants with congenital anomalies. Our perinatal database has been in operation since 1979 and contains almost 1,000 coded antepartum, intrapartum, and postpartum items per patient.18 Immediately after delivery, physicians record the intrapartum and postpartum data on standardized forms. All antepartum data from the patient's clinical chart are entered by dedicated personnel, and these data are subjected to scheduled audit. Neonatal outcome data are derived directly from the infant discharge summary and diagnoses and incorporated into the database. Our current ultrasound database has been in operation since 1991 and includes fields for sonographic findings and diagnoses. This database can be reliably linked to the perinatal database using a medical record number, a unique perinatal care number, and date of birth.
Major congenital anomalies were defined as defects requiring medical or surgical intervention in the neonatal period as well as defects with the potential for significant physical or neurologic morbidity. The analysis was limited to patients delivering after 20 weeks to avoid potential failed ascertainment of anomalies in early second-trimester pregnancy losses or terminations. Women who terminated pregnancies because of prenatally diagnosed major congenital anomalies after 20 weeks of gestation were included in this cohort. All anomalies on terminated fetuses were confirmed after delivery either by gross examination of the abortus or by autopsy. All neonates diagnosed with a major congenital anomaly prenatally or in whom a major defect was diagnosed by the examining pediatrician or neonatologist before discharge or death were considered to have a major anomaly.
We investigated an association between obesity and the presence of any anomaly involving single organ systems (central nervous, cardiovascular, pulmonary, genitourinary, and musculoskeletal) and ventral wall defects. This analysis was limited to singleton gestations to minimize the effect of any temporal changes in multiple gestations and their effect on anomaly rates. Women who delivered at or beyond 20 weeks of gestation and received primary prenatal care in our system were eligible for inclusion in this analysis regardless of the time of antenatal care initiation.
Body mass index (BMI) was calculated from the maternal weight at the first visit and the maternal height from self-report. In the early time periods, up to 30% of patients did not have a height recorded. We therefore used a first prenatal visit weight in excess of 200 lb as our primary definition of obesity so as to include patients without a recorded height. Among women with a weight of at least 200 lb, only those with a height of at least 5 ft 9 in would have a BMI less than 29 kg/m2. As previously reported by our group, in our patient population, this height represents the 99th percentile, so our 200-lb threshold perforce includes few women with a BMI less than 29 kg/m2.19 In secondary analyses, we used Institute of Medicine criteria for obesity: BMI of more than 29.0 kg/m2.20 Women were considered to have pregestational diabetes if they had a diagnosis of medically treated diabetes predating pregnancy, or if they demonstrated evidence of glucose intolerance and were treated medically before 20 weeks of gestation. Because variation in practice patterns during the time studied made it difficult to accurately ascertain whether a woman had insulin-dependent or non–insulin-dependent diabetes mellitus, we collected data on the White classification and the proportion of women diagnosed with diabetes after the initiation of prenatal care but before 20 weeks of gestation. Throughout the time course of this study, our standard management policy was to place women with pregestational diabetes on split-mix regular and intermediate-acting insulin injections once pregnancy was recognized. Women were instructed to check pattern blood sugars with glucose goals of less than 105 mg/dL fasting and less than 120 mg/dL preprandial.
Comparisons between time epochs were made using analysis of variance for continuous variables and the χ2 test for proportions. Multiple logistic regression was performed to examine the independent effect of maternal obesity, hypertension, pregestational diabetes, maternal age, parity, and race on the prevalence of congenital anomalies. A relative risk and 95% confidence interval (CI) for major congenital anomalies in obese women was calculated for each time epoch. Data were analyzed with SAS v9.1 (SAS Institute, Cary, NC). Statistical significance was defined at the α=.05 level.
With the increase in the rate of obesity over the past two decades, we suspected that there might be a concomitant escalation in the rate of pregestational diabetes. Given the association between poorly controlled maternal diabetes and fetal anomalies, we examined the magnitude of the effect of diabetes on anomaly rates in the face of increasing prevalence of obesity by considering the etiologic fraction and the population-attributable risk for obesity and pregestational diabetes. The etiologic fraction, also known as the proportion of the attributable risk among the exposed, was calculated to estimate the proportion of anomalies due to obesity or pregestational diabetes. It is derived by dividing the difference in the incidence rates between exposed and unexposed groups by the incidence rate of the exposed group. The population-attributable risk estimates the proportion of all cases in the population that arise because of the exposure and is calculated by dividing the difference between the incidence in the total population and the incidence in the nonexposed by the incidence in the total population. It serves as a measure of the impact of the exposure on the population as a whole and represents the proportion of outcomes that could be eliminated in the population if it were possible to eliminate the exposure.21
A total of 41,902 singleton gestations were included in this analysis. Over the three 5-year epochs of this study, there was an increase in the proportion of patients receiving care in our health system who were Hispanic (1.3%, 4.2%, and 17.0%, respectively; P<.001). Because these patients were underrepresented during the earlier epochs, we limited our analysis to whites and African Americans. Key demographic data are displayed in Table 1. In each subsequent time epoch, there was an increase in the mean maternal weight, the mean BMI, the proportion of women weighing in excess of 200 lb, the proportion with a BMI greater than 29, and the prevalence of pregestational diabetes (P<.001). In univariable analysis, the rate of major anomalies increased at each time period with the greatest relative increases in the cardiac and pulmonary systems (Table 2).
During each time period, there was no significant independent association between maternal obesity by either definition and the presence of a major congenital anomaly (Table 2). Moreover, even considering the entire time course of the study as one unit, obesity was not independently associated with an increase in the risk of major congenital anomalies. The adjusted odds ratio (OR) (95% CI) for major anomalies using the 200-lb threshold was 0.9 (0.6–1.3), and for BMI greater than 29, it was 1.3 (0.3–5.1).
In both obese and normal-weight women, the prevalence of pregestational diabetes increased across time periods (Table 3). In a multivariable logistic model, the major factor contributing to the increasing rate of congenital anomalies was the prevalence of pregestational diabetes (OR 3.8, CI 2.1–6.6; Table 4).
Although there was no direct association between maternal obesity and major congenital anomalies, the proportion of anomalies in obese women related to obesity increased from 0 to 23% during the time course of our study (Table 3). Among women with diabetes, the fraction of anomalies attributable to diabetes ranged from 58% to 76% during the time periods studied. In women with obesity and diabetes, the proportion of anomalies related to diabetes increased dramatically from 48% in 1991–1994 to 74% in 2000–2004. For our obstetric population as a whole, the population-attributable risk of anomalies related to obesity increased from essentially 0% in 1991–1994 to 6.1% in 2000–2004, whereas that related to diabetes increased from 3.3% to 9.2% during the same time periods (Table 3).
From 1991 to 2004, in our obstetric population there was a nearly 15-lb increase in mean maternal weight at the first prenatal visit and greater than a 30% increase in the proportion of women with a BMI greater than 29 kg/m2. During this time, we also noted a nearly twofold increase in the rate of major congenital anomalies. There was not, however, an independent association between maternal obesity and major congenital anomalies. Interestingly, we saw a 250% increase in the prevalence of pregestational diabetes during this time period, and its presence, either with or without associated obesity, seems to be a major contributor to the increasing rate of anomalies in our population.
Our results, derived from an inner-city population receiving primary obstetric care in our facilities, differ from many other reports in the literature. Naeye11 was the first to report an increase in the prevalence of congenital malformations from 4.0% in thin patients to 5.5% in obese patients. Although the rate of congenital anomalies was 4.5% in women of normal weight, this group was not compared with the obese women. Furthermore, those data were derived from a cohort followed up from 1959–1966; the rates and management of diabetes have changed dramatically since that time, and the contribution of diabetes to the occurrence of congenital anomalies was not considered. Cedergren and Källén8 reported a 30% increase in orofacial clefts in the offspring of obese Swedish women; however, diabetic status was not considered in their analysis. Waller et al13 were the first to report an association between maternal weight and neural tube defects. In this case–control study, they reported an OR of 1.8 for a neural tube defect, and several other groups have reported a similar magnitude of risk.12,13,16,17 An increased risk of cardiac defects in obese women without diabetes has also been reported in several case–control studies, but varying definitions of obesity have been used.9,14,22 Excluding women with known preexisting diabetes, Watkins et al15 reported an increased risk of not only neural tube defects and heart defects, but also omphalocele and multiple anomalies in the Atlanta Birth Defects Risk Factor Surveillance Study. Although the point estimates are similar, analyses were based on maternal interview after delivery and were therefore susceptible to selection and recall bias. Two recent meta-analyses demonstrated small obesity-associated increases in the risk of neural tube defects, some cardiac defects, and cleft lip; however, many of the primary sources evaluated in these systematic reviews either excluded people with diabetes or based the classification only on maternal recall. Furthermore, several lumped people with pregestational and gestational diabetes together for the purpose of analysis. No assessment of the magnitude of the contribution of diabetes to the occurrence of fetal anomalies in the setting of obesity was provided.23,24
In one of the few prospective, population-based cohort studies examining this issue, Moore et al10 examined risk factors and outcomes of nearly 23,000 women undergoing midtrimester maternal serum screening. These investigators interviewed women during the second trimester of pregnancy regarding medical history and risk factor exposure. Infant outcomes were obtained from physician and patient questionnaires. In the absence of diabetes, obese women had no higher risk of having offspring with a major defect, but women who had diabetes and obesity had a threefold risk compared with women who had neither. These findings parallel ours in that the risk in obese women is concentrated in those with diabetes. More recently, a case–control study by Shaw and Carmichael25 of more than 650 cases of neural tube defects and heart defects failed to demonstrate an association with obesity.
Although one of the goals of our study was to examine temporal changes in the incidence of anomalies and obesity, standard medical practice also changed over the time period of investigation. In the early time periods, BMI was not routinely recorded; therefore, this parameter could not be reliably used or calculated. We relied instead on an alternative definition of obesity for our primary analysis. However, results were similar when only women with available BMI were included; thus, we believe that our definition allows for reasonable representation of this group of women.
Changes also occurred in the reliability with which congenital anomalies are diagnosed prenatally. Ultrasound technology improved dramatically from 1991 to 2004, so it is possible that even major congenital anomalies could have been missed more in the early time periods. However, a recent study by Dashe et al26 showed a persistently lower detection rate for fetal anomalies in obese women even during the past 6 years. To minimize a potential for ascertainment bias, we limited our investigation to congenital anomalies that would be significant enough to necessitate treatment in the neonatal period or would be recognized in the neonatal period. Furthermore, we included all neonates who had defects diagnosed in the neonatal period and did not limit inclusion to only infants with prenatally diagnosed anomalies. With prenatal ultrasound findings and an examination of each child by a pediatrician, neonatologist, or both before discharge, it is unlikely that major congenital malformations would go undetected. Prenatal ultrasound findings were particularly important in ascertainment of visceral malformations, such as cystic adenomatoid malformations of the lung, which might otherwise be undetected during a neonatal examination. The prevalence of the anomalies we report was similar to the prevalence reported in the EUROCAT survey, a European congenital anomaly surveillance program, for live births and fetal deaths.27 The relatively low prevalence of anomalies in our study is likely a reflection of limiting our analysis to patients delivered beyond 20 weeks of gestation. Despite the low prevalence of some types of anomalies, given our sample size, a post hoc power analysis demonstrated that we had greater than 90% power to detect a doubling in the prevalence of anomalies in obese women compared with the rates seen in nonobese women.
Among the strengths of our clinical database study are the size of the study group and the availability of individual patient clinical data that are not subject to recall bias. One of the weaknesses of this type of study, however, is the limitation of investigation to data points that were collected during the course of clinical care. In our case, detailed data regarding individual patient glycemic control are not available in the database, and therefore we cannot comment on the association between glycemic control and anomaly rates.
Our findings are noteworthy for a number of reasons. First, although much attention has been given to population-based, epidemiologic data linking maternal obesity with all birth defects, including some organ-specific defects, the pathophysiologic basis and underlying cause of the association has been poorly investigated because of limited data. Lower levels of folic acid, increased serum insulin, chronic hypoxia, and increased inflammatory mediators have all been postulated to contribute to the occurrence of malformations.5,13,15–17 Our study provides evidence that the defects may not be due solely to the maternal obesity per se but may be due to undiagnosed diabetes. Second, from a public health standpoint, these findings highlight the need to consider refocusing attention on interventions that can best decrease the rate of adverse pregnancy outcomes. Although obesity alone has been associated with myriad poor outcomes, the coexistence of diabetes further increases the risk. Interventions to decrease the prevalence of maternal obesity require high levels of patient motivation, and goal attainment is often delayed. In contrast, diagnosis and treatment of diabetes can readily achieve desired aims as long as a patient is reasonably compliant. In our population, during the 2000–2004 period, more than 9% of all major congenital anomalies and 71% of those in obese women were attributable to diabetes. If euglycemia could be achieved before pregnancy, or at least embryogenesis and organogenesis, the majority of these anomalies could potentially be avoided. This suggests a role not only for weight-reduction strategies, but also consideration of screening for diabetes in obese women contemplating pregnancy and at presentation for antenatal care in those already pregnant. Moreover, given the lack of an independent effect of obesity, it may be that even women who are not overtly obese, but have other risk factors for diabetes, may be at increased risk for fetal anomalies and could benefit from attention to glycemic control.
We conclude that the association between obesity and fetal anomalies may be due to underlying diabetes, which if uncontrolled can lead to hyperglycemia. Because hyperglycemia is a major contributor to developmental malformations, interventions to address obesity and identify women at risk for diabetes and hyperglycemia should be considered in efforts to reduce the occurrence of congenital anomalies.
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© 2010 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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