Omphalocele, a rare congenital abdominal wall defect, has an estimated U.S. prevalence of 1.86 (95% confidence interval [CI] 1.73–1.99) per 10,000 live births.1 It has a high co-occurrence (27–88%) with other musculoskeletal, digestive, genitourinary, and cardiovascular system-related birth defects, chromosomal anomalies, and nonchromosomal syndromes.2–7 Perinatal and neonatal mortality rates of omphalocele range from 15.6% to 52.4%2,8; and survival of neonates born with omphalocele varies depending on the presence or absence of associated anomalies. Other adverse outcomes associated with omphalocele include fetal growth restriction,9 low birth weight,2 and preterm birth.10 The economic burden of omphalocele in the first year of life can be considerable; in 2003, the mean length of hospital stay for newborns undergoing surgical repair of omphalocele was 32.5 days with an estimated mean hospital charge of $141,724 for services rendered.11
Risk factors for omphalocele include young or advanced maternal age,12–14 multiparity,15 prenatal alcohol exposure,16 maternal smoking,16,17 prepregnancy overweight or obese status,18 maternal asthma medication use,19 and maternal intake of selective serotonin reuptake inhibitors,20 male neonates,21 and multiple births.10,16 Our study examined the: 1) prevalence of omphalocele in the United States over 11 years, 2) sociodemographic and perinatal characteristics of isolated compared with nonisolated cases of omphalocele, 3) common co-occurring birth defects among nonisolated cases of omphalocele, 4) survival patterns among liveborn neonates with omphalocele with and without co-occurring defects, and 5) sociodemographic and clinical factors associated with 1-year survival. We used 1995–2005 data from the National Birth Defects Prevention Network to obtain a large, population-based sample of omphalocele cases from 12 U.S. states.
MATERIALS AND METHODS
We conducted a multistate retrospective cohort study to investigate the prevalence, correlates, and outcomes of omphalocele from 1995 to 2005 using data on ventral wall defects submitted by states with population-based birth defects registries.22 Participating registries were required to 1) provide access to annual, deidentified, individual-level case data from 2005 backward to whatever full calendar year was the earliest they could contribute (6 of 12 states had complete annual data from 1995 to 2005, and all states contributed data for at least 7 of the 11 years); and 2) verify that all suspected cases of omphalocele were confirmed through medical chart review. The 12 participating states that met all inclusion criteria included Arizona, Arkansas, California (select counties), Colorado, Georgia (select counties), Iowa, New York, Oklahoma, North Carolina, Rhode Island, Texas, and Utah.
All states operated population-based birth defects surveillance programs on a wide range of birth defects and included ventral wall defects as part of their case definition. In Georgia and California, surveillance activities were not statewide but did cover large catchment areas of contiguous counties. Although states used various case ascertainment strategies that ranged from “passive” (linkage of administrative data sets) to “active” (direct review of primary data sources including medical records, hospital logs, autopsy reports),23 all incorporated clinical chart review by trained medical personnel to confirm each ventral wall defect and differentiate between cases of omphalocele, gastroschisis, and other abdominal wall defects. These data were used recently to identify trends in the prevalence and epidemiologic correlates of gastroschisis from 1995 to 2005.22
Cases included liveborn, stillborn, and prenatally terminated fetuses, although not all states were able to provide data on all three outcomes. For all neonates with omphalocele, we collected demographic and perinatal data including maternal age, maternal race and ethnicity, plurality, gestational age, birth weight, and neonatal sex. Maternal age was categorized in years as younger than 20, 20–24, 25–29, 30–34, and 35 years or older. Maternal race and ethnicity were based on self-report and first classified based on ethnicity (Hispanic compared with non-Hispanic) and the non-Hispanic group subdivided by race (white, black, and other). Plurality was grouped into singleton and multiple gestation (twins and higher order) categories. The clinical estimate of gestational age was classified in completed weeks as less than 33, 33–36, and 37 or greater. Birth weight categories included very low (less than 1,500 g), low (1,500–2,499 g), and normal (2,500 g or greater). States also provided data on up to 20 co-occurring birth defects through the use of International Classification of Diseases, 9th Edition, Clinical Modification or modified British Paediatric Association diagnosis codes indicative of each defect. Omphalocele cases were subsequently classified as isolated (no additional birth defects), nonisolated with chromosomal defects (eg, trisomy 18), nonisolated with congenital heart defects (eg, atrial septal defect), nonisolated with central nervous system defects (eg, spina bifida), or nonisolated with other birth defects. The nonisolated categories were made mutually exclusive through hierarchical assignment to categories (eg, presence of a chromosomal defect results in assignment to the chromosomal category regardless of presence of heart or other defects). For liveborn neonates, we also requested either the date of death or the age at death in days for any death that occurred during the study period. Because states provided death information for varying periods of follow-up but at least through age 1 year, we restricted ascertainment of death information through the first year of life.
We calculated birth prevalence of omphalocele for each year, state, and category of maternal age, race, ethnicity, plurality, and neonatal sex. The numerator consisted of all birth outcomes affected by omphalocele, including live births, fetal deaths, and elective terminations. The denominator was based exclusively on the total number of live births and data were obtained primarily from the National Center on Health Statistics. For two states, we obtained population data from the state's Office of Vital Statistics (California, 1995–2005; Texas, 1996–1998). We calculated birth prevalence as the number of neonates with omphalocele of any birth outcome divided by the total number of live births. Live births are used as the denominator because the true number of spontaneous fetal deaths and pregnancy terminations are difficult to estimate with accuracy because many occur before a woman knows she is pregnant and are highly underascertained. Fetal demise is also relatively rare in comparison with all live births.24 The absence of fetal deaths and pregnancy terminations in the denominator had little effect on the reported prevalence estimate. We used Poisson regression to generate 95% CIs for each birth prevalence estimate and to calculate crude and adjusted prevalence ratios across levels of maternal age, race, ethnicity, plurality, and neonatal sex.
We compared sociodemographic and perinatal characteristics of isolated cases of omphalocele to those of neonates born with omphalocele plus additional birth defects using χ2 tests of statistical independence to assess statistically significant differences. We also investigated, within each nonisolated defect category, the most common co-occurring birth defects among omphalocele cases. We used Kaplan-Meier survival curves to describe the pattern of survival among liveborn neonates with omphalocele with and without co-occurring defects and Cox proportional hazards regression to calculate crude and adjusted hazard ratios that represent the association between sociodemographic and clinical correlates and 1-year survival. All statistical analyses were performed using SAS 9.3. Hypothesis tests were two-sided and declared significant at P<.05. This study was reviewed by the University of South Florida Human Research Protection Program institutional review board and found to be exempt because the project involved secondary data analysis with deidentified data.
During the 11-year study period, there were 12,006,912 live births and 2,308 clinically confirmed omphalocele cases among the 12 reporting states, a birth prevalence of 1.92 per 10,000 live births (95% CI 1.85–2.00). Although the prevalence of omphalocele decreased during the study period, from 1.90 in 1995 to 1.71 in 2005, no consistent trend was observed over time (Table 1). Omphalocele rates for each participating state are reported in Table 2. As expected, the two states that include as cases only liveborn neonates had the lowest omphalocele rates (Rhode Island: 0.79; New York: 1.23), whereas states including all pregnancy outcomes in their case ascertainment protocol had rates between 1.57 (Arizona) and 3.02 (Arkansas).
The distribution of all live births and of cases by maternal and neonatal characteristics is presented in Table 3. The highest crude prevalence rates of omphalocele were observed among multiple births (3.59), more than twice as high as singletons (1.54). A J-shaped association was observed by maternal age with women 35 years and older and those younger than 20 years having the highest crude rates (2.73 and 2.02, respectively). Although Hispanic mothers had the lowest rates of omphalocele in offspring (1.54), the rates among non-Hispanic subgroups were similar at approximately two cases per 10,000 live births. After multivariable analyses that adjusted for all covariates as well as state of residence and year of birth, there were no significant racial or ethnic disparities in the risk of omphalocele. Compared with women 25–29 years old, those 35 years and older and those younger than 20 years had 1.77 (95% CI 1.54–2.04) and 1.34 (95% CI 1.14–1.56) higher odds of having an omphalocele-affected pregnancy, respectively. Multiple gestations were more than twice as likely as singletons to have omphalocele (prevalence ratio 2.22, 95% CI 1.85–2.66) and there was a slight (22%) increased odds for males compared with females.
In our study population, omphalocele rarely occurred in isolation with less than 22% of cases occurring without any other birth defects (Table 4; Fig. 1). Nearly 17% of neonates with omphalocele also had chromosomal anomalies, 32% had congenital heart defects, 8% had central nervous system defects, and the remaining 22% had defects that spanned every body system (Fig. 1). Chromosomal anomalies were significantly more common in offspring of women 35 years and older and among male neonates, neonates with central nervous system defects were more likely to be electively aborted, and neonates with chromosomal anomalies and central nervous system defects were significantly more likely to be of earlier gestational age and lower birth weight if carried to term (Table 4). The sociodemographic and clinical characteristics of neonates with congenital heart defects or with other birth defects tended to be more similar to that of isolated neonates with omphalocele. Of the neonates with chromosomal anomalies (n=385), the most common were trisomy 18 (n=193 [50.1%]), trisomy 13 (n=111 [28.8%]), and trisomy 21 (n=32 [8.3%]). The most common of all co-occurring congenital heart defects (n=732) were atrial septal defects (n=374 [51.1%]), patent ductus arteriosus (n=255 [34.8%]), and ventricular septal defects (n=181 [24.7%]). Spina bifida (n=86 [45.3%]) and anencephaly (n=36 [19.0%]) were the most common of the 190 central nervous system defects. Other common defects diagnosed among neonates with omphalocele included anomalies of the genitourinary system (n=199), anomalies of the digestive system (eg, Hirschsprung's disease, biliary atresia, pyloric stenosis [orofacial clefts excluded]) (n=197), musculoskeletal or limb deformities (n=176), and anomalies of the eyes, ears, face, and neck (n=96; Fig. 1).
Of the 1,727 liveborn neonates with omphalocele, 496 (28.7%) died within the first year of life and 75% of all deaths occurred in the first 28 days of life (Table 5). One-year survival varied markedly among isolated and nonisolated cases (Fig. 2). Isolated infants experienced the best 1-year survival (approximately 90%), whereas infants with congenital heart defects and central nervous system defects were 2.4 and 4.9 times more likely to die, even after adjusting for potential confounders including birth weight. Neonates born with chromosomal defects in addition to omphalocele experienced the worst survival and were more than seven times as likely as isolated infants to die in the first year of life (hazard ratio 7.75, 95% CI 5.40–11.10). Birth weight was also a statistically significant predictor of neonate survival with very-low-birth-weight neonates experiencing the worst survival. There was an improvement in survival throughout the study period; neonates born 2001–2005 had a 22% improved survival compared with those born 1995–2000 even after adjusting for differences in sociodemographic and clinical characteristics (Table 5). Improvement in survival over time was observed in both isolated and nonisolated cases (data not shown).
The prevalence of omphalocele in our population-based, multistate, 11-year retrospective cohort study was 1.92 per 10,000 live births. No temporal or seasonal trends were observed. As in previous studies, the prevalence rate of omphalocele was higher among multiples,10,16 male neonates,16,21 and in mothers older than 35 years and younger than 20 years.12–14 Although we did not observe a yearly trend in the overall prevalence of omphalocele, an increasing trend among mothers older than 35 years of age was noted (data not shown).
The proportion of neonate with co-occurring anomalies in our study (78%) was in range with other studies (27–88%).4,7 Among neonates with chromosomal anomalies, the majority (87%) had trisomy 13, 18, or 21, commensurate with previous studies.4,6,12 Our finding that atrial septal defects, ventricular septal defects, and patent ductus arteriosus were the most common congenital heart defects associated with omphalocele is also consistent with others.4,12,25 However, in this study we found higher co-occurrence with anomalies of the genitourinary tract, ear, face, and neck compared with the existing literature.7,26 Neonates with chromosomal anomalies were more likely to be male (61.8%), born preterm (54.0%), and of low birth weight (62.1%). In a 2005–2011 study from the British Isles Network of Congenital Anomaly Registers, 75% of neonates with omphalocele with chromosomal defects were born preterm and 62% were male.27
The infant mortality rate in our study was 28.7%, with 75% occurring in the first 28 days of life. Mortality was substantially higher in neonates born with co-occurring birth defects, especially those associated with chromosomal anomalies. An Australian study reported a slightly lower neonatal mortality rate of 15.6% compared with our observed rate of 21.5%.2 The 92.2% neonatal survival rate in isolated cases is similar to a 2005–2011 study in England and Wales,27 whereas the survival rate of 38.8% in neonates with chromosomal anomalies is higher than both the 27% rate found in the same study27 and the 30% rate reported in a 1992–1999 New York study.13 Consistent with previous research,28 our study found the worst 1-month survival in neonates born under 1,500 g (33.9%) followed by other low-birth-weight neonates (68.9%) and normal-weight neonates (91.2%). This dose–response relationship between birth weight and survival is of prognostic importance. Early identification and thorough evaluation using the best available genetic technologies may help ensure the best possible clinical management of omphalocele during and after pregnancy. Interventions to prolong gestation and increase birth weight may improve outcomes for fetuses affected by omphalocele. The health care team can prepare and support families with neonates born at higher risk for neonatal mortality, and awareness of common co-occurring conditions and comorbidities can facilitate care planning for children who survive beyond the first month. Our study showed a 22% decrease in risk of death from 2001–2005 compared with 1995–2000, a likely reflection of increasing prenatal diagnoses or improved treatment for neonates born with omphalocele.
A primary strength of this study is the sample size, which includes a source population of more than 12 million live births, nearly one fourth of the U.S. births over the study period. The data were obtained from population-based surveillance programs in 12 states with diverse representation from racial and ethnic groups in the United States.
In interpreting our findings, we recognize that the use of only live births in the denominator for the calculation of prevalence could be a potential source of bias. The burden of morbidity resulting from associated chromosomal aberrations or multiple malformations will lead to premature in utero demise of affected fetuses. Furthermore, information regarding poor survival and the health and economic burden of current and future morbidities may lead to the decision to electively terminate omphalocele-affected pregnancies. Without complete identification and ascertainment of all pregnancies, the true incidence of omphalocele cannot be estimated.29 Fewer states participated before 1999, and in some states (California and Georgia), surveillance catchment areas were not statewide, leading to possible over- or underestimation of prevalence rates. As a result of differences in case-finding methodologies, some states were able to provide case and denominator data for all pregnancy outcomes, including stillbirths and terminations, whereas others only included live births. Inconsistencies in data regarding maternal smoking during pregnancy, maternal prepregnancy body mass index, and parity precluded our ability to account for these characteristics in our analyses. Furthermore, information on the size of the omphalocele or the method of delivery was not provided.
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© 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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