Gastroschisis is an abdominal defect that results in either a separation of the amnio-ectodermal junction or split in the base of the umbilical cord permitting the midgut to prolapse into the amniotic cavity (Bargy & Beaudoin, 2014; Beaudoin, 2018; Rittler et al., 2013). Based on the human evidence, this midgut prolapse occurs on the thin upper-right side (pars flaccida) of the umbilical ring during the normal physiologic hernia in the first trimester (Bargy & Beaudoin, 2014; Beaudoin, 2018; Rittler et al., 2013; Shaw, 1975), whereas the abdominal wall per se (comprised of skin, muscle, etc.) remains essentially intact. What factor(s) negatively impact the connection at the amnio-ectodermal junction is unknown. At birth, gastroschisis presents with the midgut prolapsed outside the abdomen through an aperture, most often to the right of the umbilicus (the umbilicus remains attached only on the left side). The prolapsed organs are not covered by a membrane. However, at times the defect’s presentation requires careful differentiation from a ruptured omphalocele, another birth defect with a different origin, risk factors, and epidemiologic patterns. Distinctive features of omphalocele are an enlarged umbilical ring with the umbilical cord centrally inserted into the covering membrane of the prolapsed organs, or rarely rupture (Khan et al., 2019).

Unlike other major birth defects, gastroschisis prevalence has increased over the past several decades (Jones et al., 2016), and this pattern has raised questions and concerns. During the 1960s and 1970s, the baseline prevalence of gastroschisis was estimated at approximately 1 in every 50,000 births. Lindham (1981) first reported a 30% increase in gastroschisis prevalence between 1965 and 1976 in Sweden. This increase in prevalence was then noted by others (Barboza-Argüello & Benavides-Lara, 2018; Calzolari et al., 1993; Goldbaum et al., 1990; Hemminki et al., 1982; Kirby et al., 2013; Loane et al., 2007; Martinez-Frias et al., 1984; Roeper et al., 1987; Tan et al., 1996), including by Castilla et al. (2008) who reported a 10 to 20-fold increase in the prevalence of gastroschisis in several countries over time since the 1960s.

A second unusual finding in gastroschisis is the maternal age pattern, namely, the consistent finding that regardless of overall prevalence, the highest prevalence of gastroschisis within a population is observed among women <20 years of age (Castilla et al., 2008; Kirby et al., 2013; Salinas-Torres et al., 2018).

These two findings, time trends and maternal age risk, raise the question of whether the increasing prevalence is present in all age groups or only those at highest risk (i.e., women <20 years of age). In general, the observed increase in prevalence was reported primarily among women <20 years (Barboza-Argüello & Benavides-Lara, 2018; Bermejo et al., 2006; Kilby, 2006; Kirby et al., 2013; Laughon et al., 2003; Reid et al., 2003) whereas others have reported a decrease in this age group (Calderon et al., 2019; Loane et al., 2007). Some investigators have reported an increase in prevalence in all maternal age categories (Jones et al., 2016; Kazaura et al., 2004; Salinas-Torres et al., 2018; Vo & Langlois, 2015). The increase in prevalence during the past several decades and the highest prevalence among women under 20 years of age are unique to gastroschisis (Bhat et al., 2020; Stallings et al., 2019).

A third finding relates to striking differences in prevalence in different regions and countries (Castilla et al., 2008). Cluster investigations have been conducted on gastroschisis without identifying specific new risk factors (Materna-Kiryluk et al., 2016; Yazdy et al., 2015). Loane et al. (2007) reported gastroschisis prevalence among 25 registries from 15 European countries during 1980–2002 ranging between 0.31 (Italy-Tuscany) and 4.48 (Germany-Mainz) per 10,000 births. Mastroiacovo et al. (2006) analyzed data from 25 registries included in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) and reported a statistically significant increasing trend of gastroschisis prior to 2004 in 14 (56%) registries compared to no increasing trend for 36 other types of birth defects. Though not a focus of this study, the reasons for such disparities in prevalence are not known but perhaps behaviors and exposures to environmental factors differ in different areas of the world.

This study updates previously published data on gastroschisis prevalence among multiple countries (Loane et al., 2007; Mastroiacovo et al., 2006) with three main objectives: (1) evaluate the multinational prevalence and trends of gastroschisis between 1980 and 2017 among participating ICBDSR member programs; (2) compare prevalence in three geographic regions, by surveillance program and maternal-age groups; and (3) evaluate population changes in the proportion of births by maternal age groups during the study period.

The ICBDSR is an international voluntary and non-profit organization in official relations with the World Health Organization (WHO) whose members conduct birth defect surveillance in their country, region, or at the state-level (Mastroiacovo et al., 2007). Created in 1974, its mission is to use the power of international public health monitoring to track, study, and ultimately prevent and improve outcomes related to birth defects (Botto et al., 2006).

Programs were eligible to participate if they could provide relevant data on gastroschisis cases among all pregnancy outcomes (live births, stillbirths, and elective terminations of pregnancy for fetal anomaly [ETOPFA] if legally permitted) as well as population births (live births, stillbirths) by birth year and maternal age at delivery/termination.

The following criteria were used for case inclusion: all pregnancy outcomes (live births, stillbirths, and ETOPFA) were included that listed gastroschisis (International Classification of Diseases, Ninth Revision [ICD-9] code 756.7, British Pediatric Association [BPA] modified code 756.71, and International Classification of Diseases, 10th Revision [ICD-10] code Q79.3) during the program’s surveillance time period. Cases considered or listed with a limb–body wall defect, an abdominal defect due to amniotic bands, omphalocele, or a ruptured omphalocele were excluded.

Of the 43 ICBDSR members, 27 programs participated in this study representing a total of 24 countries. Surveillance programs were divided into three regions based on geography. European⁺ region included programs from the Czech Republic, France (Rhone-Alpes and Paris), Germany Saxony-Anhalt, Hungary, Italy (Lombardy and Tuscany), Malta, Northern Netherlands, Slovak Republic, Spain, Wales, plus (⁺) Iran. The Latin American region included programs from South America (Argentina, Chile, Colombia-Bogota, Colombia-Cali), Central America (Costa Rica) and North America (Mexico Nuevo León, Mexico’s Registry and Epidemiological Surveillance of Congenital Malformations, Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City [RYVEMCE]), and the Latin American Collaborative Study of Congenital Malformations (ECLAMC) a hospital-based program with data from nine countries in South America (Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, and Venezuela). The North American region included programs from Canada (Alberta and nation-wide) and the United States (Arkansas, Atlanta, Texas, and Utah). Surveillance characteristics are shown for each participating program (Table 1). Hospital-based surveillance systems included two European⁺ programs (Spain ECEMC and Iran TRoCA) and all Latin America programs (with the exception of Costa Rica). The remaining programs were population-based. Among the 27 participating programs, 22 were able to provide counts by maternal age and year of birth for cases and the source population. Five programs (Hungary, Iran, Colombia-Bogota, Colombia-Cali, and South America ECLAMC) were either unable to provide complete counts by birth year and maternal age for the denominator-source population or maternal age was missing for many of the case and/or population counts to obtain accurate estimates. Because only four programs were able to submit surveillance data prior to 1980, all analyses for prevalence and maternal-age specific prevalence were calculated for the period between 1980 and 2017. As shown in Table 1, some programs only began monitoring gastroschisis during the 1990’s.

The study population included 14,020 gastroschisis cases (live births, stillbirths, and ETOPFA) among 45,755,137 total births (stillbirths + live births), from 27 surveillance programs representing 24 countries and three regions during birth years 1980–2017 (Table 2).

In this international study from 27 programs in 24 countries, we observed three main findings. First, 14 (61%) programs with sufficient data representing 18 countries (six European⁺, 10 Latin American which includes nine from the ECLAMC program, and two North American) showed a significant increase in gastroschisis prevalence over time, nine of which were based on data from 1980 to 2017. Second, prevalence of gastroschisis among programs in Latin America and North America was more than two times that observed in European⁺ programs. Third, in all programs, with one exception, the prevalence was highest among women under 20 years of age, with progressively lower prevalence as maternal age increased.

Our findings are consistent with prior observations of increasing time trends (Barboza-Argüello & Benavides-Lara, 2018; Calderon et al., 2019; Jones et al., 2016; Kirby et al., 2013; Loane et al., 2007; Salinas-Torres et al., 2018) and an inverse relationship with maternal age (Barboza-Argüello & Benavides-Lara, 2018; Bourque et al., 2021; Jones et al., 2016; Kirby et al., 2013; Loane et al., 2007; Salinas-Torres et al., 2018). Further assessment could inform to what extent these two observations might be related. We also identified changes in the proportion of maternal age-specific births during the study period. The largest decline was observed in the proportion of births among women under 20 years and 20–24 years of age (approximately three-quarters of the programs) compared to women 25–29 years of age (<50% of the programs). Conversely, in most programs (>80%) the proportion of births among women ≥30 years of age increased. One important question is whether the observed increase in prevalence, especially among the youngest women, may be due to the changing population dynamics of women giving birth observed in this study. For example, in the United States, teen pregnancies have declined since 1991 (cCDC.gov/teen pregnancy), which may change maternal age specific prevalence. However, a more detailed investigation is required to assess each program’s specific changes in the maternal age-specific births in the population and the potential influence on prevalence over time. Generally, the increasing trends for gastroschisis appear to be primarily driven by the increasing occurrence among women under 20 years of age (the highest prevalence age group), relative to older maternal age groups. One might postulate that either a common exposure or exposures that induce a similar response (e.g., cell death at the umbilical region of the pars flaccida) among young women may explain this trend. Understanding environmental risk factors that are common in different populations and/or a maternal response periconceptionally or in early pregnancy that results in a gastroschisis is critical to reducing its occurrence, particularly among the youngest women. Improvements in our study methodology will be required to obtain measurable biomarkers either during the first trimester or as close to the first trimester as possible to assess modifiable exposures that are difficult to capture with maternal interviews.