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Maternal risk factors for gastroschisis in canada

Maternal Risk Factors for Gastroschisis in Canada Erik D. Skarsgard*1, Christopher Meaney2, Kate Bassil3, Mary Brindle4, Laura Arbour5,Rahim Moineddin2, and the Canadian Pediatric Surgery Network (CAPSNet) Background: Gastroschisis is a congenital abdominal wall defect that occurs confidence interval, 0.83–0.87; p < 0.0001), smoking (odds ratio, 2.86; 95% in one per 2200 pregnancies. Birth defect surveillance in Canada has shown confidence interval, 2.22–3.66; p < 0.0001), a history of pregestational or that the prevalence of gastroschisis has increased threefold over the past 10 gestational diabetes (odds ratio, 2.81; 95% confidence interval, 1.42–5.5; years. The purpose of this study was to compare maternal exposures data p 5 0.0031), and use of medication to treat depression (odds ratio, 4.4; 95% from a national gastroschisis registry with pregnancy exposures from vital confidence interval, 1.38–11.8; p 5 0.011) emerged as significant statistics to understand maternal risk factor associations with the occurrence associations with gastroschisis pregnancies. Conclusion: Gastroschisis in of gastroschisis. Methods: Using common definitions, pregnancy cohorts were Canada is associated with maternal risk factors, some of which are developed from two databases. The Canadian Pediatric Surgery Network modifiable. Further studies into sociodemographic birth defect risk are database, a population-based dataset was used to record maternal exposures necessary to allow targeted improvements in perinatal health service delivery for women who experienced a gastroschisis pregnancy, while a and health policy.
contemporaneous, geographically cross-sectional "control" cohort of pregnant women and their exposures was developed from Canadian Community Health Birth Defects Research (Part A) 103:111–118, 2015.
Survey data. Groups comparison of maternal risk factors was performed using C 2015 Wiley Periodicals, Inc.
univariate and multivariate logistic generalized estimating equation techniques.
Results: A total of 692 gastroschisis pregnancies (from Canadian Pediatric Key words: gastroschisis; population-based registry; maternal risk factors; Surgery Network) and 4708 pregnancies from Canadian Community Health maternal age; teratogenesis Survey were compared. Younger maternal age (odds ratio, 0.85; 95% The Public Health Agency of Canada has documented a Gastroschisis (GS) is a congenital abdominal wall defect threefold rise in prevalence of GS over the last 10 years, which results in the extrusion of the developing fetal intes- to approximately 1 per 2200 births (Moore et al., 2013). A tines into the amniotic space. It is usually detected prena- similarly observed increase in GS prevalence has been tally by maternal serum screening and ultrasound, and made in many other countries, including the United States tends to occur as an isolated congenital anomaly. When a and several European nations (Laughon et al., 2003; Inter-national Clearinghouse for Birth Defects Surveillance and prenatal diagnosis of GS is made, arrangements are made Research, 2009; Langlois et al., 2011), prompting referen- for delivery at an obstetrical center that is functionally ces to a "Gastroschisis Epidemic" (Kilby, 2006; Mastroia- linked to a specialty pediatric hospital with the capability covo et al., 2006; Keys et al., 2008). Epidemiologic studies of providing surgical treatment after birth as well as essen- of causation of GS have emerged from single state/region/ tial neonatal intensive care. Survival following birth of an country birth defect registries, to pooled data from a net- infant with GS exceeds 90%, however, survivors may work of population-based congenital anomaly reporting require prolonged hospitalization in high intensity nurs- registries, all with an intent to better understand modifi- eries, which makes them among the most expensive of con- able risk factors for GS.
genital anomalies to treat (Sydorak et al., 2002; Skarsgard Since 2006, the Canadian Pediatric Surgery Network et al., 2008). The specific cause of GS remains unknown, (CAPSNet) has collected standardized pre and postnatal although the available evidence suggests interactions of data on all cases of GS admitted to each of the 17 hospi- multiple maternal risk factors lead to occurrence.
tals in Canada that provide specialty pediatric care forbirth defects. The collected data include maternal demo-graphic (age, home postal code) and exposures (e.g., smok- 1Department of Surgery, University of British Columbia, Vancouver, Canada ing, alcohol, recreational drug use) data for all GS 2Department of Family and Community Medicine, University of Toronto, pregnancies. The purpose of this study was to explore the association between maternal factors and GS in Canada by Dalla Lana School of Public Health, University of Toronto, Toronto, Canada 4Department of Surgery, University of Calgary, Calgary, Canada comparing maternal exposures data for GS cases identified 5Department of Medical Genetics, University of British Columbia, Vancouver, in CAPSNet with household exposures data for a geograph- ically "cross-sectional" group of pregnant women from aCanadian Vital Statistics database.
This work was Supported by the Canadian Institutes of Health Research(CIHR) Funding Reference # Sec 117139.
*Correspondence to: Erik D. Skarsgard, K0–110 ACB, 4480 Oak Street, Van- Materials and Methods couver, BC, V6H 3V4 Canada. E-mail: [email protected] The two primary data sources for this study consisted ofthe CAPSNet registry, and the Canadian Community Health Published online 12 February 2015 in Wiley Online Library (wileyonlinelibrary.
com). Doi: 10.1002/bdra.23349 Survey (CCHS, which is administered by Statistics Canada), C 2015 Wiley Periodicals, Inc.
RISK FACTORS FOR GASTROSCHISIS IN CANADA a cross-sectional survey which collects information related survey was conducted in alternate years). The CCHS sur- to health status and health determinants of Canadians at vey of 65,000 Canadians per year, targets persons aged 12 the household level, across all geographic regions (dissem- years or older who are living in private dwellings in the ination areas) in Canada (Canadian Community Health Sur- ten provinces and the three territories. Persons living on vey [CCHS], 2014). Through integration of data from these Indian Reserves or Crown lands, clientele of institutions, two sources, we were able to develop health and maternal full-time members of the Canadian Armed Forces, and res- exposure risk profiles of mothers who gave birth to infants idents of certain remote regions are excluded from this with GS (from CAPSNet), to pregnant women sampled survey. The sampling method ensures that all provinces' from the CCHS. The variables that were consistently col- health regions (provincially designated health service lected across the two data sources include: history of alco- areas) are sampled in proportion to the size of their hol, tobacco, marijuana, cocaine, methamphetamine and heroin use during pregnancy, history of diabetes (type 1, The CCHS covers approximately 98% of the Canadian type 2, or gestational), use of depression medication dur- population aged 12 or older, and collects information ing pregnancy, and use of folic acid during pregnancy.
related to health status, health care usage, and healthdeterminants. These data can then be used to estimate, on a health regional basis, potential relationships between The CAPSNet consists of the 17 perinatal/surgical centers health outcomes and economic, demographic, occupational, that provide population-based pre- and postnatal care for and environmental factors. Ultimately, the data are meant GS in Canada (The Canadian Pediatric Surgery Network to provide a better understanding of the health of Cana- [CAPSNet], 2014). The CAPSNet registry was designed spe- dians and inform public policy, through health surveillance cifically for outcomes research and contains rigorously and the facilitation of population health research.
defined fields that allow discrimination of risk variablesand treatment, as well as relevant clinical outcomes fromthe birth hospitalization to death or discharge. Data are collected from maternal and infant charts by trained This study used a cross-sectional design. In this design, abstractors using a customized data entry program with the GS (case) sample consisted of all mothers identified built-in error checking and a standard manual of opera- from the CAPSNet database between 2006 and 2012, who tions and definitions. Abstracted prenatal information had a GS pregnancy resulting in a live birth, stillbirth or details maternal risk variables including demographics termination of pregnancy, while the non-GS (control) sam- (postal code of residence), prenatal exposures including ple consisted of all pregnant mothers responding to the smoking, alcohol, and a variety of nonprescription drugs; CCHS surveys (Cycle 1.1 [2001], Cycle 2.1 [2003], Cycle medical comorbidities, quantitative ultrasound and other 3.1 [2005], CCHS 2007, and CCHS 2010). Although CCHS prenatal diagnostic data, and information on all pregnancy data do not differentiate women whose pregnancy was or All data collection was not complicated by GS (or any other birth defect), it "observational" and is not used to influence the care of is assumed that the CCHS cohort represents a reasonable any individual patient.
control group because the sample is large and the overall Data from each CAPSNet center are de-identified and birth defect rate is known to be rare, and because controls transmitted electronically to a centralized repository for misclassification causes bias toward the null for the risk cleaning, quality assurance and storage. Thereafter, the aggregate dataset is overseen by a research coordinator The comparison variables of interest between cases and controls are summarized in Table 1. Definitions of steering committee comprised of pediatric surgeons, neo- "exposure" in both databases included any use, on at least natologists, maternal-fetal medicine specialists, and an epi- one occasion of the listed substances, during a time when demiologist. Aggregate data use for research purposes is the woman was pregnant, whether known or unknown enabled by inter-institutional data sharing agreements, (Canadian Pediatric Surgery Network, 2013). A coincident and requires that each CAPSNet center maintain institu- history of diabetes, could mean that the woman had pre- tional review board approval for data collection. Aggregate existing diabetes (type 1 or 2) diagnosed by a health pro- data release requires project-specific institutional review fessional or had gestational diabetes requiring medication board approval from the principal investigator's institu- or dietary modification. A history of depression requiring tion, and complies with Health Information Portability and medication meant that the woman had a mood disorder Accountability Act (HIPPA) requirements.
diagnosed by a health professional and received anti-depressive medication at any time in CAPSNet, (or within past month for CCHS), for any duration during her preg- CCHS is a cross-sectional household survey administered nancy. Folic acid use meant that the woman used a multi- by Statistics Canada on an annual basis (before 2007 the vitamin containing folic acid before or upon realization of BIRTH DEFECTS RESEARCH (PART A) 103:111–118 (2015) TABLE 1. CCHS and CAPSNet Variables Definitions CAPSNet data definitionsa Did you drink any alcohol during your last Record if any alcohol use during pregnancy Cigarette smoking Did you smoke during your last pregnancy?b Record if cigarettes were smoked during this preg- nancy. If unknown or if no cigarettes were During your last pregnancy, did you smoke daily, smoked during pregnancy, leave the box occasionally or not at all?c 1 Daily 2 Occasionally 3 Not at all Have you used marijuana in the past 12 months? Record whether or not the mother used any of the following during this pregnancy.
Have you used cocaine or crack in the past 12 Methamphetamine or crystal meth Have you used speed (amphetamines) in the past 12 Heroin: includes methadone Have you used heroin in the past 12 months? Do you have diabetes? Record the mother's status as a diabetic during this Pre-existing DM diagnosed prior to conception Gestational diabetes In the past month, did you take anti-depressants Record use of antidepressants during this preg- such as Prozac, Paxil or Effexor?: nancy: includes selective-serotonin reuptake inhibitors (SSRI) (i.e. Zoloft, Paxil or Prozac) Did you take a vitamin supplement containing folic Record whether the mother has been taking regular acid before your pregnancy, that is, before you found prenatal vitamins during this pregnancy.
out that you were pregnant? None: no folic acid nor prenatal vitamins taken before the start of the second trimester.
Folic acid: initiated prior to pregnancy or within the first trimester.
Vitamins: initiated prior to pregnancy or within the aFrom CAPSNet Abstractors' Manual vol 5.1.0, April 2013.
bQuestion from CCHS 1.1.
cQuestion from CCHS 2.1, 3.1, 2007, 2010.
her pregnancy. Age was estimated from maternal date of residence was assigned using dissemination area (DA), a birth, as reported through both datasets, and was analyzed small, relatively stable geographic unit composed of one or as a continuous variable. Geographic location of home more adjacent dissemination blocks. It is the smallest

RISK FACTORS FOR GASTROSCHISIS IN CANADA FIGURE 1. Inclusion/exclusion flow diagram of patients analyzed in this study.Patients were collected from five cycles of the CCHS (1.1, 2.1, 3.1, 2007 and 2010). Patients who were pregnant during the time of the survey were included. The CAPSNet registry was used to identify women who had gastroschisis preg- nancies between 2006 and 2012, and those with complete data were included.
standard geographic area for which all census data are cies (from CAPSNet) and 4708 "control" pregnancies from disseminated within Canada, and can be assigned using the Postal Code Conversion File software (Wilkins and The 692 GS mothers came from a total of 465 DAs and Khan, 2010).
the 4708 control mothers came from a total of 1285 DAs.
Initially, we intended to perform a 1:1 matched case The mean age of the GS mothers was significantly lower control study where mothers were matched on age (a than that of the controls (23.64 years; SD 5 4.79 years vs.
known GS risk factor) and DA, which would have allowed 28.84 years; SD 5 6.11 years; p < 0.0001). When maternal us to control for some predisposing environmental factors.
age was interrogated as a predictive variable using bivari- When analysis was completed under the proposed design ate and multivariate generalized estimating equation mod- many associations between categorical risk factors and independently predictive outcome of a GS pregnancy had low counts in some cells occurrence of a GS pregnancy (odds ratio [OR], 0.85; 95% of the contingency tables. As a result, these data could not confidence interval [CI], 0.83–0.87; p < 0.0001).
be released from Statistics Canada due to anonymity con- The relationships between maternal risk factors during cerns and an alternative design was necessary.
pregnancy and the occurrence of GS are summarized inTables 2 and 3. Table 2 displays 2x2 tables, estimated STATISTICAL ANALYSIS odds ratios, 95% confidence intervals and p-values associ- To avoid issues related to low cell counts, we chose not to ated with a variety of maternal substance exposures dur- match based on any demographic variables a priori. Rather ing pregnancy, folic acid use, depression medication use or we treated GS mothers and CCHS controls as being a history of diabetes. Due to low cell counts, exposures "clustered" within DAs and used logistic generalized esti- data for cocaine, heroin, and methamphetamine were sup- mating equation methods to account for this design fea- pressed, and so an aggregate variable (any illicit drug use ture. Moreover, we treated maternal age, (a known risk inclusive of marijuana) was created. Table 2 suggests that factor for GS occurrence) as a covariate in each model and exposure to alcohol, tobacco, marijuana, illicit drugs or estimated the adjusted odds of a GS birth, as a function of medication for depression during pregnancy, as well as a other hypothesized maternal risk factors after controlling history of diabetes increases the likelihood of a GS preg- for age. Where sample size allows we have summarized nancy. Conversely, the use of folic acid appears to be pro- the association between maternal factors (all categorical tective against a GS pregnancy.
variables) and GS occurrence using contingency tables.
Given the awareness of young maternal age as a risk factor for GS, age adjustment was performed in the logisticgeneralized estimating equation risk modeling, as summar- ized in Table 3. After adjustment for maternal age, the The process of deriving the case (GS pregnancies from association between maternal exposures to cocaine and CAPSNet) and control (non-GS pregnancies from CCHS) marijuana individually, (and illicit drugs collectively) and maternal cohorts is illustrated in Figure 1. After exclusions the occurrence of GS persists. In the multivariate model, for incomplete data there were a total of 692 GS pregnan- BIRTH DEFECTS RESEARCH (PART A) 103:111–118 (2015) (OR, 3.54; 95% CI, 2.22–5.63; p < 0.0001), and use of med- TABLE 2. 2 x 2 Contingency Tables with Odds Ratios, 95% Confidence Inter- ication to treat depression (OR, 4.4; 95% CI, 1.38–11.8; vals, and p-Values Describing the Relationship between the Association between Maternal Risk Factors and the Occurrence of a Gastroschisis DiscussionGastroschisis is among the most common structural birth defects, and its cause remains unknown. The phenomenon of increased prevalence has been observed in several juris- 583 (92.98) 4454 (95.64) dictions, and continues to be a stimulus for epidemiologic evaluation of risk factors, both maternal (physiological,teratogens, socioeconomic) and environmental (Torfs et al., 231 (33.38) 610 (13.06) 3.34 2.79, 3.99 <0.0001 1994; Reefhuis and Honein, 2004; Rittler et al., 2007; Cas- 461 (66.62) 4061 (86.94) tilla et al., 2008; Salemi et al., 2009; Waller et al., 2010; Agopian et al., 2013).
8.03 5.63, 11.46 <0.0001 The most widely observed association in GS pregnancy 614 (88.73) 3477 (98.44) occurrence is its inverse relationship with maternal age.
The risk seems to be highest in the teenage cohort. Aggre- gate data from EUROCAT (a consortium of birth defect registries which combines registry data from 23 countries) report a relative risk of 7.0 in the under 20 age cohort, and a RR of 2.4 in the 20 to 24 age cohort, compared withthe age 25 to 29 reference group (Reefhuis and Honein, 2004). While a strong association with maternal age is certain, what is less clear is whether the increased preva- lence of GS is due exclusively to an increased prevalence within the teenage mother population, or to a GS preva- lence increase across all maternal age strata (Kazauraet al., 2004; Loane et al., 2007). Regardless of the exact nature of this association, the relationship between mater- 9.35 6.64, 13.15 <0.0001 nal age and GS should be factored in to all studies of GS 600 (86.71) 3475 (98.39) epidemiology, with analyses of all putative risk factors being subject to age-adjustment.
Several epidemiologic studies of causation suggest a moderate risk of GS associated with smoking during preg- 672 (97.25) 4651 (98.81) nancy (Haddow et al., 1993; Draper et al., 2008; Feldkamp et al., 2008), and data from Canada identify a higher rate 4.65 2.61, 8.30 <0.0001 of smoking during pregnancy in mothers with GS (Wein- 670 (96.82) 3544 (99.30) sheimer et al., 2008). Not only is there a maternal smokingassociation with GS prevalence, there is also an association with clinical outcome, with GS infants of smoking mothers 134 (19.36) 1289 (27.83) 0.62 0.51, 0.76 <0.0001 having more severe bowel injury at birth (Weinsheimer 558 (80.64) 3342 (72.17) et al., 2008; Brindle et al., 2012). In addition to smoking, Empty cells, suppressed due to low counts.
illicit drug use is another purported risk factor for GS,with cocaine, marijuana, and methamphetamine observed significant predictor of GS occurrence. Similarly, although to have a significant age-adjusted association with GS alcohol exposure remained predictive after age adjustment, occurrence (Draper et al., 2008; Weinsheimer et al., 2008; its predictive association with GS occurrence disappeared Brindle et al., 2012).
with multivariate analysis. The other significant variable The current study provides further insight into GS epi- change associated with age-adjustment was the loss of the demiology through integration of a contemporary, Cana- apparent protection associated with folic acid use.
dian population-based GS dataset with Vital Statistics data Younger maternal age, smoking (OR, 2.86; 95% CI, from a cross-sectional, representative cohort of pregnant 2.22–3.66; p < 0.0001), a history of diabetes (OR, 2.81; mothers from the Canadian Community Health Survey.
95% CI, 1.42–5.5; p 5 0.0031), history of illicit drug use Critical to the accuracy and reliability of this dataset RISK FACTORS FOR GASTROSCHISIS IN CANADA TABLE 3. Bivariate, Age-Adjusted, and Multivariate Logistic Regression Models Evaluating Risk Factor Prediction of a Gastroschisis Pregnancy Bivariate logistic gee model Age-adjusted logistic GEE model Multivariate logistic GEE model —, not used in multivariate model, rather combined in composite "illicit drug" variable.
GEE, general estimating equation.
integration, is the accuracy of case and control ascertain- for maternal age and race (Polen et al., 2013). Conversely, ment, and equivalence of risk factor definitions. One of the two other studies looking at associations between selective limitations of birth defect registry ascertainment (for serotonin-reuptake inhibitors in pregnancy did not demon- example EUROCAT) is the accuracy of discharge diagnosis strate a significantly increased rate of common structural abstraction from hospital charts. The diagnostic code for birth defects among exposed infants (Alwan et al., 2007; GS (International Classification of Disease, ICD-9 756.7) is Louik et al., 2007). It is likely that an association between shared with another congenital defect of the abdominal depression and/or its treatment and the occurrence of GS wall (omphalocele), which differs dramatically from GS has many confounders, and, therefore, caution should be and is frequently associated with genetic patterns of inher- exercised in inferring a direct relationship in the absence itance. The British Pediatric Association modification of of other supportive studies.
ICD-9 is used by some registries, and allows differentiation Our data identify a maternal history of pregestational of gastrochisis from omphalocele, however it is not used type 1 or type 2 or gestational diabetes mellitus as being uniformly. The Canadian Pediatric Surgery Network (CAP- independently predictive of a GS pregnancy. While a rela- SNet) database, on the other hand, is a research database, tionship between pregestational/gestational diabetes and for which cases are ascertained by clinicians who are increased rates of several birth defects (specifically, cardio- directly involved in either prenatal diagnosis or postnatal vascular defects), is well established, no specific associa- treatment of GS, which improves diagnostic accuracy tion with human GS has been reported previously.
Although the concept of abdominal wall malformations Our study reinforces the inverse relationship between associated with a hyperglycemic state is plausible and sup- maternal age and GS occurrence, as well as associations ported by observations of GS in pregnant rats who were with maternal smoking and illicit drug use, which were made diabetic by intraperitoneal streptozotocin (Padma- both independently predictive of occurrence on multivari- nabhan and al-Zuhair, 1987–1988), this relationship is ate logistic regression modeling. Although it was observed intuitively at odds with the observed protective effect of to be protective on univariate analysis, use of folic acid overweight or obese prepregnancy BMI on the risk of hav- lost its predictive effect following adustment for maternal ing a GS pregnancy (Lam et al., 1999; Waller et al., 2007; age. We also observed that treatment of depression with Stothard et al., 2009). A potential explanation for our find- any anti-depressive medication was associated with an ings is an underreporting of gestational diabetes in the increased risk of GS (OR, 4.04; 95% CI, 1.38 5 11.8). A CCHS cohort. A population-based study of rates of bio- recent report from the National Birth Defects Prevention chemically validated gestational diabetes in the province Study using a case control methodology, looked at the of Ontario, showed a doubling of age-adjusted rate from effect of periconceptual use of the anti-depressant venla- 2.7 to 5.6% between 1996 and 2010 (Feig et al., 2014), faxine on the occurrence of birth defects, and observed a which is substantially higher than the rate of 1.2% statistically significant association with GS, after adjusting observed in our CCHS cohort, and suggests the possibility BIRTH DEFECTS RESEARCH (PART A) 103:111–118 (2015) that a diagnosis of gestational diabetes was unknown to many pregnant women at the time they were surveyed.
The authors thank Alison Butler, CAPSNet coordinator, for We are reluctant to ascribe much significance to this her administrative efforts in support of this work observation, other than to note its statistical significance,and suggest that future studies of GS epidemiology should evaluate this potential association further.
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