American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:162– 179 (2008) A R T I C L E Gastroschisis: International Epidemiology and Public Health Perspectives EDUARDO E. CASTILLA,* PIERPAOLO MASTROIACOVO, AND IÊDA M. ORIOLI Gastroschisis offers the intriguing epidemiological situation of a pandemic, strongly associated with very low maternal age. Identifying gastroschisis, and distinguishing it from the other abdominal wall defects, is theoretically easy but difficult in practice. The baseline birth prevalence of gastroschisis before the pandemic was approximately 1 in 50,000 births and has increased since between 10- and 20-fold. In many populations worldwide, it is still increasing. Such increasing prevalence and the association with very low maternal age are well proven, but the interaction between these two findings remains unknown. Geographic gradients (decreasing prevalence from North to South) are clear in Continental Europe and suggestive in Britain and Ireland. Gastroschisis seems more frequent in Caucasians compared to African Blacks and Orientals, and in Northern compared to Southern Europeans. These observations indicate the need for investigating gene–environment interactions. Since the global human situation is marked by inequalities among as well as within countries, the medical care and public health impact of gastroschisis varies widely among regions and social strata. The postnatal benefits of prenatal diagnosis of gastroschisis include family awareness; adequate planning of delivery with alerted obstetrical, pediatric, and surgical staff; optimal risk categorization, and personalized protocol for action. The increasing prevalence of gastroschisis combined with improved medical techniques to reduce morbidity and mortality are also increasing the burden and costs of this anomaly on health systems. ß 2008 Wiley-Liss, Inc. KEY WORDS: gastroschisis; omphalocele; body wall defects; birth prevalence; increasing trend; low maternal age; teenage; pandemic How to cite this article: Castilla EE, Mastroiacovo P, Orioli IM. 2008. Gastroschisis: International epidemiology and public health perspectives. Am J Med Genet Part C Semin Med Genet 148C:162–179. INTRODUCTION For the last three decades, gastroschisis has offered the intriguing epidemiological situation of a pandemic [Last, 1995], strongly associated with very low maternal age. Nevertheless, the working hypotheses advanced until now have been scarce, and none have yet been substantiated with convincing data and replicated. Therefore, in the absence of a working hypothesis to test, many publications are mainly ‘‘fishing expeditions,’’ typically adding very little to the knowledge of the etiology and pathogenesis of gastroschisis. The present state of affairs for gastroschisis is comparable to that of Down syndrome in the 1930s. At that time, P.J. Waardenburg first [Allen, Eduardo E. Castilla, Director of ECLAMC; Scientist at the National Research Councils of Argentina (CONICET), and Brazil (CNPq); Chief of the Laboratory of Congenital Malformations at the Instituto Oswaldo Cruz, Rio de Janeiro, Brazil; Full Professor of Medical Genetics at the Instituto Universitario CEMIC, Buenos Aires, Argentina. Pierpaolo Mastroiacovo, Professor of Pediatrics, Director of the Centre of the International Clearinghouse for Birth Defects Surveillance and Research, Rome, Italy. He is a pediatrician, and his main interests are clinical genetics, birth defect epidemiology, and evidence based pediatrics. Iêda M. Orioli, ECLAMC Deputy Director; Full Professor of Genetics, Federal University of Rio de Janeiro, Brazil. Grant sponsor: CNPq/MS/DECIT, Brazil; Grant numbers: 40.3444/2004-7, 40.1467/2004-0; Grant sponsor: CNPq, Brazil; Grant numbers: 472086/2004–9, 30.8885/2006-6, 501279/20032; Grant sponsor: FAPERJ, Brazil; Grant numbers: E-26/152.831/2006, E-26/152831; Grant sponsor: Agencia Nacional de Promoción Cientı́fica y Tecnológica (ANPCyT), Argentina; Grant number: PICTO-CRUP 2005 # 31101; Grant sponsor: Consejo Nacional de Investigaciones Cientı́ficas y Técnicas (CONICET), Argentina; Grant sponsor: Centre of the Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities; Grant number: U50/CCU207141; Grant sponsor: Edital MCT-CNPq/MS-SCTIE-DECIT—N8 21/2006, Genética Clı́nica; Grant number: 40.8863/2006-4; Grant sponsor: Edital MCT-FAPERJ/MS-SCTIEDECIT, Brazil; Grant number: E-26/152.831/2006. *Correspondence to: Eduardo E. Castilla, ECLAMC/GENETICA/FIOCRUZ, Av. Brasil 4365, Pav. 26, sala 617, 21045-900 Rio de Janeiro, Brazil. E-mail: firstname.lastname@example.org DOI 10.1002/ajmg.c.30181 ß 2008 Wiley-Liss, Inc. 1974], and L.S. Penrose [Penrose, 1954] next, suggested the possibility of an underlying chromosome aneuploidy in Down syndrome, given that chromosome non-disjunction in Drosophila was known to be associated with advanced age (as was already recognized for Down syndrome in humans). However, at the time the chromosome hypothesis was just one among many under consideration. Its confirmation came many years later with the report by Lejeune et al.  of a ‘‘petit te´locentrique surnume´raire’’ chromosome found in nine cases of Down syndrome. This review summarizes the available essential data in the literature, addressing etiologic, pathogenic, clinical, and epidemiological issues relevant to the understanding of gastroschisis. GASTROSCHISIS AMONG BODY WALL DEFECTS Identifying gastroschisis and separating it from the other abdominal wall defects is theoretically easy but difficult practically. ARTICLE Gastroschisis is a well-defined and precisely delineated congenital anomaly of the abdominal wall. Nevertheless, in practical terms it is frequently confused with other body wall defects. This confusion affects the morphological homogeneity of most, if not all, series of cases reported until now. Differences in definition and delineation hamper any attempt to compare published prevalence rate, time trends, and reported associations with maternal age or other potential risk factors. The differential diagnosis of gastroschisis includes the other types of defect (hole, discontinuity) of the anterior body wall. Among 2,633 newborn infants with an abdominal wall defect born between 1982 and 2006 in South America (ECLAMC, unpublished data), the type of defects were distributed as follows: 2.7% ill-defined, 49.6% omphalocele, 35.2% gastroschisis, 5.2% complete or extended abdominal wall defect, 4.0% infraumbilical or caudal celosomias (excluding bladder/cloacal exstrophy), 1.6% supraumbilical or cephalic celosomias (including ectopia cordis), and 1.8% with other types. A total of 1,128 cases (42.8%) had additional unrelated anomalies, but only 102 (11.0%) among the cases of gastroschisis. This classification of body wall defects in ECLAMC was possible because the program receives verbatim descriptions from voluntarily participating pediatricians, who follow specific descriptive norms given in the program’s Procedures Manual [Castilla and Orioli, 2004] and summarized in six characteristics of the abdominal wall defect that must be specified: (1) relationship with the umbilical cord: periumbilical, paraumbilical, supraumbilical, infraumbilical, other (describe); (2) side: right, left, bilateral, midline; (3) extension of the defect (hole) in cm; (4) covering membranes: yes or not; (5) eviscerated organs; (6) presence of associated independent malformations. The simple enunciation of ‘‘gastroschisis’’ is not accepted. Incomplete descriptions are returned to the source for completion. Incomplete cases remain coded as abdominal wall defect of unspecified type. AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) Because knowledge of body wall defects has changed in the past 50 years, birth defect registries that began operations in the 1960s or earlier would have heterogeneous data for many defect categories. Through the decades, nomenclature, clinical criteria, coding, and classification have changed substantially. Consequently, some registries recently reviewed their coding, based, when available, on the original reporting forms [Källén and Winberg, 1968; Kazaura et al., 2004; Williams et al., 2005b]. The ECLAMC data for body wall defects were reviewed by one of the authors (EEC) in the mid 1990s. Up through version 9, the International Classification of Diseases (ICD) lumped the two most common body wall defect types (omphalocele and gastroschisis) under one code (7567). Only recently, in version 10, these two main defects have separate codes: Q79.2 for omphalocele, Q79.3 for gastroschisis. Before version 10, only the extension of the ICD to a fifth digit, as in the modification by the British Up through version 9, the International Classification of Diseases (ICD) lumped the two most common body wall defect types (omphalocele and gastroschisis) under one code (7567). Only recently, in version 10, these two main defects have separate codes: Q79.2 for omphalocele, Q79.3 for gastroschisis. Paediatric Association, allowed for the individualized consideration of omphalocele (Code 75670) and gastroschisis (Code 75671). Some investigations used the less known code 54.71 from the ICD-9-CM (ICD-9-Clinical Modification for Surgical Procedures Code) to identify gastroschisis repair in hospital discharge records [Williams et al., 2005a; Arnold et al., 2007a]. 163 As established by use, gastroschisis is an inaccurate term, seriously hampering the validity of reported observations. The Clearinghouse  (International Clearinghouse for Birth Defects Research and Surveillance) defines gastroschisis as: ‘‘a congenital malformation characterized by visceral herniation through a right side abdominal wall defect to an intact umbilical cord and not covered by a membrane. The definition excludes aplasia or hypoplasia of abdominal muscles, skin-covered umbilical hernia, and omphalocele (herniation of abdominal contents through the umbilical insertion and covered by a membrane which may or may not be intact).’’ This definition agrees with those used by other institutions such as EUROCAT [Calzolari et al., 1995] and ECLAMC [Rittler et al., 2007], as well as with working definitions used in other studies [Rickett, 1979; Stoll et al., 2001]. However, many times precise definitions constitute a good intention and do not translate into a real characterization of the data. Coding at registry headquarters comes too late in the data handling process, since the actual use of the term gastroschisis at the reporting centers, the maternity hospitals, is frequently different from the definitions applied at the central level. With the increasing use of prenatal ultrasonography since the early 1980s, more or less concurrently with the awareness of the increasing frequency of gastroschisis, obstetricians, and pediatricians learned about gastroschisis, including its definition and nomenclature, mainly from ultrasonographers. Well-known books for ultrasonography of congenital anomalies do not define gastroschisis [Bianchi et al., 2000], or define it too succinctly: ‘‘intrauterine evisceration of fetal intestine through a paraumbilical wall defect’’ [Sanders, 2002]. This results in a generalized misconception that congenital abdominal evisceration is a proxy for gastroschisis. Giant omphaloceles can be prenatally misdiagnosed as gastroschisis if the ultrasonographer does not search carefully for a faint covering membrane. Even when the prenatal ruptured 164 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) membrane of an omphalocele is believed to be rare [Bianchi et al., 2000; Chen, 2007], the abdominal contents will also be floating in the amniotic cavity, as in gastroschisis. Finally, in 15% of the cases the sac breaks during or immediately after delivery [Densler, 1982; Wilson and Johnson, 2004], and for the examining surgeon or pediatricians they become broken omphaloceles, which can also be easily misdiagnosed as gastroschisis [Aizenfisz et al., 2006]. Obviously, these perinatal complications are expected to occur more frequently in low resource areas of the world. Therefore, while broken omphalocele could be a rare event prenatally, it may be less rare for the pediatric surgeon, whose diagnosis will most probably be the one reported to databases for further analysis. Considering the ECLAMC data just described, that 13% of all abdominal wall defects were neither omphalocele nor gastroschisis, lacked a covering sac, included intrauterine evisceration, and are likely to be mistaken with gastroschisis; and that an additional 7% (15% of 49.6% ¼ 7.4%) were misdiagnosed broken omphaloceles, perhaps as many as 20% of all abdominal wall defects could be erroneously considered gastroschisis cases because of an existing evisceration. This error can be avoided if a detailed anatomical description of the anomaly is systematically provided (e.g., by a pathologist or a surgeon), but this is very seldom evident from published series. The abdominal wall defect in gastroschisis is nearly always small enough to avoid the evisceration of solid organs such as spleen, kidneys, or liver. It is organs such as the small intestine— hollow organs with positive intraluminal pressure and well lubricated surface— that can be eviscerated. Rarely, this general rule is violated such as when the Fallopian tubes are pulled by the intestines to the outside of the body, or, exceptionally, the small hole is enlarged by the ripping effect of a solid organ such as the spleen [Wilson and Johnson, 2004]. Gastroschisis is seldom associated to other non-gastrointestinal tract malformations [Mastroiacovo et al., 2007]. Published epidemiological series vary in their working definition of gastro- schisis. Some reports provide a complete and correct definition [Stoll et al., 2001; Williams et al., 2005b]; in some, working definitions are incomplete, generally omitting the very small size of the defect and the absence of eviscerated solid organs [Calzolari et al., 1995; Rankin et al., 1999; Reid et al., 2003; Salihu et al., 2003; Wilson and Johnson, 2004], or even lacking a covering membrane [Kazaura et al., 2004; Kunz et al., 2005; Lam and Torfs, 2006; Kilby, 2006]. Finally, some reports do not provide a working definition at all [Hemminki et al., 1982; Stone et al., 1998]. Omphalocele does not mimic gastroschisis, but other body wall defects do. In trying to explain the increasing secular trend of the birth prevalence of gastroschisis, several authors suspected a misdiagnosis of omphalocele for gastroschisis, possibly related to changing registration patterns. However, most reports were unable to show the rise of one together with the drop of the other [Lindham, 1981; Egenæs and Bjerkedal, 1982; Hemminki et al., 1982; Martı́nez-Frı́as et al., 1984; In trying to explain the increasing secular trend of the birth prevalence of gastroschisis, several authors suspected a misdiagnosis of omphalocele for gastroschisis, possibly related to changing registration patterns. However, most reports were unable to show the rise of one together with the drop of the other or to convincingly explain in this way the geographic variations of birth prevalence. Calzolari et al., 1993, 1995; Salihu et al., 2003], or to convincingly explain in this way the geographic variations of birth prevalence [Stone et al., 1998]. This is ARTICLE not surprising since, as discussed above, the confusion of gastroschisis exists, albeit not with omphalocele, exception made for the abovementioned 7% of broken omphaloceles, but with other types of abdominal wall defects with evisceration. Williams et al. [2005a] underscored the need to access the original medical records to validate the diagnosis of abdominal wall defects, and highlighted the advantages of using a surgical code system. These authors retrieved 142 cases with ICD-9 code 756.7 for abdominal wall defects born in the State of Florida in the year 2000, and registered at the State of Florida Hospital Discharge Database. Cases were then linked to the Florida Birth Defect Registry by the ICD-9-Clinical Modification for Surgical Procedures Code, finding 93 cases with code 54.71. By reviewing medical records manually, the authors confirmed the diagnosis of gastroschisis in 92 cases and identified 4 cases missed by the birth defect registry. GEOGRAPHICAL VARIATION Most reported data are not comparable. It is difficult to interpret the observed geographic and temporal variations of birth prevalence because different factors interfere in the observed rates of gastroschisis. The following factors are just the most outstanding factors. All vary widely among registries and surveillance systems, as well as within each registry when long periods are considered, as it is the case when evaluating secular trends. (1) Sample size: Sample size relates both to the population and the time period under study. Sample size is crucial for rare events such as gastroschisis. For instance, detecting an increase from 1 to 2 cases per 10,000 births during a 10-year period will require monitoring at least 185,477 births yearly (with P < 0.01; beta error of 20%, and power of 80%). Therefore, in many ARTICLE European countries, even with countrywide data, it will be necessary to group yearly figures to reach testable sample sizes. (2) Population or hospital-based: Hospital-based systems are not suitable to study prevalence of a prenatally conspicuous anomaly as gastroschisis. The solution, in a review like this one, is very simple: discard these data if necessary. However, the main problem resides with the term population-based system because it is often used loosely. The extent to which a population-based system is truly ‘‘population-based’’ is seldom known. Many systems call themselves population-based, but provide no grounds for the statement. Most of the self-denominated populationbased programs are not exactly that, because, for instance, they often do not cover births from area residents that occur outside that area. This can be a serious problem in areas with high population density such as in most of Europe. EUROCAT defines three different levels of population-based registries: (I) All mothers who reside in defined geographic area (14 registries); (II) All mothers who deliver within a defined geographic area, irrespective of place of residence (7 registries); (III) All mothers who deliver in a defined geographic area excluding non-residents of that area (7 registries). There are also four hospitalbased registries, defined as all mothers delivering in selected hospitals irrespective of place of residence (EUROCAT Member Registries. 2006 http://www.eurocat.ulster.c. uk/memberreg/memberreg.html). Therefore, in many situations the so-called population-based type III would be very similar to hospitalbased systems and subject to similar ascertainment biases. (3) Diagnostic certainty: As discussed above (Gastroschisis Among Other Body Wall Defects), this is a crucial issue for gastroschisis. (4) Data handling: Important issues are access to original medical reports for diagnosis validation and the use of AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) appropriate coding system. The problem with coding systems has been discussed. (5) Terminations of pregnancy (ToP): The registration of cases undergoing termination of pregnancy after a prenatal diagnosis of gastroschisis varies considerably among populations, to the point that comparing most datasets becomes very difficult. Criteria that vary widely across systems include legislation for ToPs, the registration of cases that are ToP, certainty of prenatal diagnosis, and medical indication for ToP in that case of gastroschisis. Data from collaborative multicentric studies are more comparable than single studies collected from the literature. Because all reporting registries have to follow a common explicit protocol (at least in theory), regional or worldwide studies are supposed to be more homogeneous with respect to case definition, exclusion criteria, time period, ascertainment rate, and other elements that can influence the observed prevalence rates. Table I presents the birth prevalence rates for gastroschisis published in 6 different multicentric studies, based on 54 registries, during different periods covering a 30 years period (1974–2003). These registries cover different geographic areas, from a single country such as Italy to a worldwide area including four continents. Prevalence rates from single-center studies are not considered here because of lack of comparability. The data from the Clearinghouse  are shown only for the 11 registries with 10 or more years of data. To simplify data display, only the median birth prevalence rates are shown in Table I, and confidence limits from the original papers have been omitted. Three publications from the Clearinghouse included data from registries in different areas in the world. They covered the time period starting in 1974–1988 (14 years) [Clearinghouse, 1991], through 1998 (24 years) [Di Tanna et al., 2002], and through 2003 (29 years) [Mastroiacovo et al., 2006]. 165 Prevalence rates from 29 of the 54 registries included in more than one of the 6 studies were quite similar, indicating reporting consistency. Some differences are not unexpected due to small sample sizes in some registries and, in others, possibly due to time trends. Low prevalence populations are concentrated in Southern Europe and Middle East, and particularly in Italy. The 54 registries in Table I are distributed in 7 world regions: Great Britain, Northern Europe, Central Europe, Southern Europe, Middle East, Far East, Oceania, North America, and South America. Data on low prevalence populations, here defined as having 1 case in 10,000 births or less, were reported for recent years (until 2002 or 2003) from 12 registries. Four of these registries are in Italy (North-East, Tuscany, Emilia-Romagna, Campania), another 3 are also in southern Europe (Malta, S-Portugal, Basque Country), 3 are from Northern and Central Europe (N-Netherlands, Antwerp-Belgium, Hungary), and 3 are from the Middle East (Israel, United Arab Emirates). The publication including five Italian registries during 5 years was included in Table II because the unique situation of this country in which prevalence rates for gastroschisis is neither high nor increasing [Calzolari et al., 1993]. The North to South decreasing gradient of birth prevalence, described in continental Europe and Britain and Ireland, is still unproven. A North-to-South decreasing gradient in the birth prevalence rate of gastroschisis has been reported for Britain and Ireland [Chalmers et al., 1997] and Continental Europe [Calzolari et al., 1995]. Conversely, gastroschisis is more frequent in Southern than in Northern Finland, and could reflect variations in factors such as the proportion of urban population or time periods [Hemminki et al., 1982]. However, North-to-South trends are not evident in the data shown in Table I, neither for continental Europe, nor for the UK. Furthermore, on closer scrutiny, rates decreased significantly in Sweden from 1974 to 1988, 166 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE TABLE I. Prevalence Per 10,000 of Gastroschisis in 6 Multicentric Studies Population Britain and Ireland England-Wales UK-Glasgow UK-Trent UK-Wales UK Wessex UK-Liverpool UK-Belfast Ireland-Dublin Ireland-Galway Ireland-Cork & Kerry North and Central Europe Sweden Norway Finland Denmark Denmark-Odense Belgium-Antwerp Belgium-Hainaut Netherlands-Northern Hungary Czech Republic Austria-Styria Prevalence per 10,000 Median year* Period 2.3 1.5 2.1 0.6 1.8 3.9 4.3 2.7 1.6 0.8 0.0 0.1 0.3 1.1 1.6 2.1 1.0 1.3 1983 1996 2002 1985 1989 2000 2000 1998 1984 1985 1980 1981 1985 1991 1998 2002 1985 1998 1979–1988 1995–1997 2001–2003 1981–1990 1980–1999 1998–2002 1998–2002 1994–2002 1980–1988 1980–1990 0.7 1.0 1.3 1.2 3.1 2.7 0.9 0.6 1.7 2.3 1.9 3.7 1.0 1.1 1.3 0.2 1.0 2.1 1.0 1.1 0.9 0.8 0.5 0.5 0.4 0.3 1.0 0.7 2.8 1980 1974 1975 1980 1998 2002 1984 1986 1994 1997 1998 2002 1985 1985 1991 1985 1999 1985 1983 1985 1991 1992 1996 1983 1992 1996 1976 1996 1995 1974–1988 1980–1982 1980–1990 1980–2002 2001–2003 1981–1990 1996–2001 1974–1976 1974–1988 2001–2003 1984–1988 1993–1995 1993–2002 2001–2003 1983–1988 1980–1990 1980–2002 1980–1990 1997–2002 1980–1990 1981–1984 1981–1990 1981–2002 1981–2003 1995–1998 1982–1984 1982–2003 1995–1998 1974–1979 1995–1998 1990–2001 Source a c c e f f f f e e b c e f b c e f a b c a b c b a c f b c a e f e f e b1 e f c b1 b1 c b1 b1 b1 f ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 167 TABLE I. (Continued ) Population Slovak Republic Germany-Mainz Germany-Saxony-Anhalt Switzerland-Vaud Luxemburg France-Strasburg France-Paris France-Central-East France-Marseille South Europe Croatia-Zagreb Italy-IPIMC Italy-North-East Italy-Emilia Romagna Italy-Umbria Italy-Tuscany Italy-Campania Prevalence per 10,000 Median year* 0.6 1.1 4.5 1.5 2.5 1.2 1.6 0.4 0.8 1.5 1.2 1.3 1.9 0.0 0.2 1.1 1.1 1.6 2.7 3.4 0.2 0.4 0.8 0.9 1.5 1.6 1.0 1996 2002 1996 1995 1996 1999 1995 1984 1983 1985 1986 1991 1996 1981 1982 1984 1985 1991 1998 2002 1978 1979 1982 1987 1998 2002 1987 Period 2001–2003 1985–1990 2.0 1.6 0.4 0.5 0.7 0.6 0.5 0.8 1.0 0.9 0.8 0.8 0.9 0.5 0.6 0.3 0.4 0.4 0.3 0.4 0.6 0.7 1986 1992 1982 1986 1985 1986 1992 1982 1983 1985 1986 1990 1991 1996 1983 1986 1985 1986 1991 1997 1997 1997 1983–1990 1983–2002 1978–1988 1984–1989 1981–1990 1984–1989 1981–2003 1978–1988 1980–1984 1980–1990 1984–1989 1978–2003 1981–2002 1995–1998 1980–1986 1984–1989 1980–1990 1984–1989 1980–2002 1992–2003 1991–2003 1996–1999 1995–1997 2001–2003 1990–2002 1987–2003 1991–2002 1988–1990 1989–2002 1980–1989 1982–1984 1982–1988 1982–1990 1982–2001 1995–1998 1981–1983 1981–1988 1981–1990 1981–2002 2001–2003 1978–1980 1976–1988 1985–1990 Source c c f c f e f e b1 a e f b1 b c a e f b c b c a e b c e e f a d e d c a b1 e d c f b1 e d e d f c c f (Continued ) 168 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE TABLE I. (Continued ) Population Portugal-S Spain-ECEMC** Spain-Asturias Spain-Barcelona Spain-Bilbao Malta Middle East Israel-IBDMS United Arab Emirates Far East China-Sichuan Japan-Tokio Japan-JAOG Oceania Australia-Victoria Australia-W Australia New-Zealand North America USA-Atlanta** USA-Texas Canada-Alberta Central and South America Mexico-RYVEMCE Prevalence per 10,000 Median year* 0.7 0.2 0.6 0.4 1.5 1.1 1.2 0.8 0.7 1.0 1.0 1996 1998 1982 1996 1996 1997 1990 1996 1988 1994 1998 Period 1980–1984 1995–1998 1990–2002 1992–2002 1990 1990–2002 1986–1990 1986–2002 1993–2003 f b1 b1 b1 f f e f e f c 0.4 0.5 0.3 0.1 0.8 1982 1983 1990 1996 1999 1980–1984 1978–1988 1978–2003 1995–1998 1996–2003 b1 a c b1 c 1.7 0.7 1.0 1.0 1.1 2.3 2.6 1986 1984 1974 1975 1983 1998 2002 1985–1988 1980–1988 a a b c a b c 0.7 2.4 1.5 4.3 0.9 1.0 2.7 0.6 1984 2002 1981 2002 1981 1984 1997 1984 1983–1985 2001–2003 1980–1983 2001–2003 1981–1988 c c c c b a b a 0.7 1.7 1.9 1.7 2.5 3.9 1.6 1.5 2.5 3.5 1980 1976 1980 1996 2002 1999 1981 1982 1996 2002 1974–1998 1974–1979 1974–1988 1995–1998 2001–2003 1996–2002 1980–1983 1980–1984 1995–1998 2001–2003 b1 b1 a b1 c c c b1 b1 c 1.4 1.2 1.4 4.9 5.1 1975 1980 1984 1998 2002 1974–1976 c b a b c 1990–2002 1974–1976 1979–1988 2001–2003 1981–1988 1980–1988 1980–1998 2001–2003 Source ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 169 TABLE I. (Continued ) Population Prevalence per 10,000 Median year* 0.1 0.0 0.5 2.9 2.9 1974 1975 1980 1998 2002 S-America-ECLAMC Period 1974–1976 1974–1988 2001–2003 Source b c a b c Prevalence unless otherwise stated is mean birth prevalence per 10,000. a, Clearinghouse ; b, Di Tanna et al. ; b1, Di Tanna et al. : data quoted but not published, available on Clearinghouse ; c, Mastroiacovo et al. ; d, Calzolari et al. ; e, Calzolari et al. ; f, Loane et al. . *Median year of the period of observation. **Terminations of pregnancy are not included. and in England and Wales from 1979 to 1988 [Clearinghouse, 1991]. Gastroschisis seems to be more frequent in Caucasians compared to African Blacks and Orientals, and in Northern compared to Southern Europeans. Since the biological and cultural concept of ethnicity includes the genetic concept of race, ethnic differences could shed light in the understanding on the role of gene–environment interaction in the etiology of gastroschisis. However, in societies where ethnic groups are stratified, there is a close association with variations in socio-economic status (SES) and, as discussed below, in public health impact. Since geographic variations may be confounded by ethnic background (in addition to differences in definitions and ascertainment), it is helpful to stratify findings by race or ethnicity, even within the same study. In the US, reported rates of gastroschisis were higher in Caucasians compared to African-Americans [Salihu et al., 2004; Williams et al., 2005b; In the US, reported rates of gastroschisis were higher in Caucasians compared to African-Americans and Orientals. Genetic susceptibility to specific environmental (e.g., lifestyle) factors may play a role in the reported geographic variation of gastroschisis. Canfield et al., 2006; Abdullah et al., 2007], and Orientals [Forrester and Merz, 1999]. Genetic susceptibility to specific environmental (e.g., lifestyle) factors may play a role in the reported geographic variation of gastroschisis. Nevertheless, the role of race and ethnicity in the time trends observed worldwide remains unclear. SECULAR TRENDS Increasing birth prevalence rates of gastroschisis were reported for the early 1970s in Sweden by Källén and Lindham , followed shortly by similar findings from Norway [Egenæs and Bjerkedal, 1982]. In both instances, the increase was sudden. To explain these findings, Källén and Lindham  proposed a cohort hypothesis, whereby mothers born between 1953 and 1955 would have been exposed to a teratogen, along the lines of what was proposed (and confirmed) for adenocarcinoma of the vagina in females exposed ‘‘in utero’’ to diethyl-stilboestrol [Davis et al., 1981]. However, for gastroschisis time did not confirm this hypothesis, since maternal age did not return to expected values, as the secular trend reached a plateau in the following years as expected [Hemminki et al., 1982]. Data on the secular trends of prevalence reported from 4 multicentric studies are summarized in Table II, and those from 29 single-center publications are summarized in Table III. Data reported by Calzolari et al. , and Loane et al.  are not included in Table II because no data on temporal trends were reported. Increasing temporal trends were reported by 16 of the 33 multicentric in Table II, while stable trends were reported in 17. Six of the 17 registries with stable trend are in Italy, 5 of which are included in Calzolari et al.  publication. The consistency of the findings from Italy suggests that the low observed prevalence in Italy is real. According to comparable data from the mid 1970s to the late 1980s (Table II), reported to the Clearinghouse  by 11 congenital anomalies monitoring systems in three continents, only ECLAMC-South America showed increasing secular trends, with a birth prevalence of 0.1 per 10,000 births in 1974 increasing to 0.6 in 1988. Other eight programs reported stable rates during the same period, and two programs reported decreasing rates (Sweden and England and Wales). In Sweden, after the initial increase, rates appeared to decrease from about 1979. A later Clearinghouse study, with data through the late 1990s [Di Tanna et al., 2002] showed evidence for significant rising secular trends in 9 of 19 reporting programs (Table II). Increasing time trends were reported by 27 of the 36 single-center studies shown in Table III. No one program had stable rates: three in Europe (Italy [Calzolari et al., 1993], Denmark 170 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE TABLE II. Time Trends in the Birth Prevalence of Gastroschisis in 4 Multicentric Studies Population Britain and Ireland England and Wales Ireland-Dublin N-Europe Sweden Norway Finland Trend Period Source ! ~ ~ ~ 1979–1988 1995–2003 1981–1998 1980–2003 a c b c ! 1974–1988 1974–1988 1974–1998 1974–2003 1984–1998 1993–2003 1983–1998 1981–2003 a a b c b c b c 1982–1998 1982–2003 1974–1998 1987–2003 1995–2003 1983–1998 1981–1998 1981–2003 1976–1988 1984–1998 1978–2003 b c b c c b b c a b c 1978–1988 1984–1989 1982–1998 1981–2003 1984–1989 1978–1988 1978–1998 1978–2003 1984–1989 1984–1989 1992–2003 1984–1989 1991–2003 1976–1988 1980–1998 1993–2003 a d b c d a b c d d c d c a b c 1974–1998 1978–2003 1996–2003 b 1979–1988 a ~ ~ ~ ~ North Netherlands Central Europe Hungary Czech Republic Germany-Saxony Slovak Republic France-Strasbourg France-Paris ~ ~ ~ France-Central East ~ ~ S-Europe Italy-Multicentric National IPIMC Italy-North East Italy-Emilia Romagna Italy-Umbria Italy-Tuscany Italy-Campania Spain-ECEMC ~ ns Malta Middle East Israel United Arab Emirates Far East Japan National ~ ns c ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 171 TABLE II. (Continued ) Population Trend Period Source ~ ~ 1978–1988 1974–1998 1974–2003 a b c ~ ~ ~ 1981–1997 1980–2003 1983–2003 b c c ~ 1978–1988 1974–1988 1974–2003 1996–2002 1980–1998 1974–2003 a b c c b c ~ ~ ~ ~ ~ 1980–1998 1980–2003 1974–1988 1974–1998 1974–2003 b c a b c Japan JAOG Oceania Australia Western Australia Australia-Victoria N-America Atlanta-USA ~ Texas-USA Canada-Alberta S-America Mexico-RYVEMCE South America-ECLAMC ns ¼ not statistically significant. a, Clearinghouse ; b, Di Tanna et al. ; c, Mastroiacovo et al. ; d, Calzolari et al. . [Bugge and Holm, 2002] and Strasburg [Stoll et al., 2001]), three in North America: Florida [Williams et al., 2005a], New York State [Salihu et al., 2003], and Canada-British Columbia [Baird and McDonald, 1981]), two in Oceania (South Australia and Western Australia [Byron-Scott et al., 1998], and one in Asia (China-National) [Zhou et al., 2005]. A global picture of the prevalence data from the literature data summarized in Tables I–III is illustrated in Figure 1. This figure clearly shows the increased prevalence over the last decades, and particularly in the last 15 years (Fig. 1). The baseline birth prevalence rate of gastroschisis before the pandemic may have been approximately 1 in 50,000 births, has increased worldwide 10- to 20-fold as of now, and may still be increasing in many areas. The baseline birth prevalence rate of gastroschisis before the pandemic may have been approximately 1 in 50,000 births, has increased worldwide 10- to 20-fold as of now, and may still be increasing in many areas. Gastroschisis used to be a very rare congenital anomaly, under the standard definition of a birth prevalence rate less than 1 in 10,000. In the late 1950s, Simpson and Caylor  described in the surgical literature cases 15 and 16 of this rare body wall defect type. Before then, gastroschisis was rarely distinguished clearly from omphalocele in the clinical literature [Moore and Stokes, 1953]. Birth defect monitoring started in the mid 1960s, with seven registries in Europe, North America, and South America. The Czechoslovakian Registry started in 1961 [Kucera, 1961]; in 1964 the British Columbia Health Surveillance Registry [Lowry et al., 1975; Baird and McDonald, 1981], the Congenital Malformation Monitoring Program of England and Wales [Weatherall and Haskey, 1976], and the Swedish Registry of Congenital Malformations [Källén and Winberg, 1968]; and in 1967 the Medical Birth Registry of Norway [Irgens, 2000], the Metropolitan Atlanta Congenital Defects Program-USA [Williams et al., 2005a], and ECLAMC in South America [Castilla and Orioli, 2004]. The first registered cases of gastroschisis are known for four of those seven programs. In British Columbia, no cases were reported for the first 5 years (1964– 1968) among 168,654 monitored births, one case was reported in 1969, and 28 cases were reported among 322,129 births (0.87/10,000) during the 1970s [Baird and McDonald, 1981]. In Sweden, the Register of Congenital Malformations started in 1965 with nationwide coverage 8 years later, and monitored yearly between 80,000 and 100,000 births. Diagnoses of gastroschisis were validated by medical record review. No cases were registered until 1970, 3 cases in 1971, none in 1972, and Ireland-E England-N England-Wales England-SW England-5 regions England-Wales Sweden Sweden Norway Norway Finland Denmark France-Strasbourg Spain-ECEMC Spain-ECEMC c Italy-5 registries BC-Canada California Atlanta Utah Saskatchewan-Canada Hawaii Hawaii Tennessee New York State Florida N Carolina ECLAMC Britain and Ireland Period 1981–2000 1986–1996 1987–1991 1987–1995 1991–1999 1994–2004 1965/1968–1973/1976 1965–1980 1967/1974–1995/1998 1966/1967–1978/1979 1970/1974–1975/1979 1970–1989 1979–1998 1976–1981 1980/1985–2000/2004 1984–1989 1964–1978 1968–1977 1968–1998 1971–2002 1985/1990–1996/2000 1986/1990–1997/2002 1986–1997 1989–2001 1992–1999 1997–2001 1997–2000 1982–2006 Trend ~ ~* ~** ~** ~a ~ ~* ~ ~** ~* ~** — — ~**,b ~a — — ~** ~a ~** ~* ~** ~* ~ns — — ~** ~ 10 11 5 9 10 11 12 16 22 13 10 20 20 6 15 6 15 10 33 32 6 17 12 13 8 5 4 25 0.06 0.76 0.36 1.85 2.19 2.52 2.00 1.32 3.80 1.96 0.42 0.00 1.57 1.00 1.48 0.65 1.60 2.10 2.50 0.31 0.40 0.48 0.15 0.77 Rate per 10,000 earliest year(s) 0.57 0.81 1.33 1.76 0.89 2.00 3.92 4.06 4.03 3.85 5.60 1.65 2.90 4.50 5.79 1.20 2.99 4.94 5.29 1.35 4.90 3.10 4.40 1.20 0.80 2.91 1.25 1.42 Rate per 10,000 latest year(s) 14.83 2.63 10.89 2.19 1.84 1.53 2.80 1.25 0.76 2.30 13.79 NC 1.90 4.94 3.57 2.08 3.06 1.48 1.76 3.87 2.00 6.06 8.33 1.84 Rate ratio latest/ earliest McDonnell et al.  Rankin et al.  Tan et al.  Penman et al.  Rankin et al.  Kilby  Lindham  Källén and Lindham  Kazaura et al.  Egenæs and Bjerkedal  Hemminki et al.  Bugge and Holm  Stoll et al.  Martı́nez-Frı́as et al.  Bermejo et al.  Calzolari et al.  Baird and McDonald  Roeper et al.  Williams et al. [2005b] Hougland et al.  Baerg et al.  Forrester and Merz  Forrester and Merz  Collins et al.  Salihu et al.  Williams et al. [2005a] Laughon et al.  Unpublished References AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) S-America N-America Central-Europe S-Europe N-Europe Population Area Number of years considered TABLE III. Time Trends of Birth Prevalence of Gastroschisis in Single Center or Single Country Studies 172 ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 2.22 2.00 3.62 1.51 0.00 3.18 2.00 0.47 0.56 Far East ns, not stated; NC, not computable. a No statistically significant difference between rates in earliest year compared with rates in latest year. b Statistically significant temporal trend. c Only under 21 years of maternal age; no increase in over 20 years maternal age. *P < 0.05. **P < 0.001. 1.43 1.00 0.13 0.37 1980/1990–1991/1993 1980–2001 1975/1980–1996/1997 1993/1997–1998–2002 1996–2000 ~* ~** ~ns ~a — Australia-Perth Australia-W Japan Nationwide Singapore China-National 20 22 23 10 5 1980–1990 1980–1990 1980–1993 — — ~ns Oceania Australia-S Australia-W Australia-W 11 11 14 0.48 2.56 2.03 1.50 3.16 0.00 0.00 6.58 Byron-Scott et al.  Byron-Scott et al.  Quoted by Byron-Scott et al.  Nichols et al.  Reid et al.  Suita et al.  Tan et al.  Zhou et al.  ARTICLE 173 1 case in 1973 [Källén B, personal communication; Källén and Lindham, 1982]. In Norway, no cases were registered among 67,288 births in the register first year, 1967, 2 in 1968, 4 in 1969, 0.92/10,000 in the 1970s, rising to 2.9/ 10,000 in the late 1990s [Kazaura et al., 2004]. In Atlanta, no data were reported for 1967, 2 cases registered in 1968, and 2 in 1969, giving a birth prevalence rate of 0.74 in the 1960s, rising up to 1.31 in the 1970s, 2.01 in the PubMed e 1980s, 2.15 in the 1990s, and 4.60 in the 2000s [Williams et al., 2005b]. Also in Spain (1976–1978) and in Emilia Romagna (1978–1980) no gastroschisis cases were detected in the first 3 years of the registries [Clearinghouse, 1991]. ECLAMC did not registered any case of gastroschisis among the 238,655 births covered in its first 6 years, between 1967 and 1972; registering an increasing birth prevalence rate of 0 in the 1960s, 0.08 in the PubMed e 1970s, 0.56 in the 1980s, 1.66 in the PubMed e 1990s, and 3.98 in the 2000s [Castilla and Orioli, 2004]. Gastroschisis was a very rare anomaly until the 1960s, when the prevalence started increasing at somewhat different times around the world. It is difficult to distinguish whether these changes were real or related to changes in ascertainment and registration by surveillance systems that were in the initial years of their operation. However, even if some cases were missed or misdiagnosed, the birth prevalence of gastroschisis in the 1960s was most probably similar to that of very rare anomalies such as sirenomelia, cyclopia, acardio-acephalus, and conjoined twins. It is reasonable to conclude that the birth prevalence of gastroschisis, once very rare, has increased worldwide for about 50 years, from the 1960s until the present time, and it is still increasing in most regions. Even if some reports suggest that the increase in birth prevalence has slowed or stopped, it is still too early to be sure that a plateau has been reached. The initial report of a rising trend from Sweden in the early 1970s [Lind- 174 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE body stalk disruptions, and hemifacial microsomia. Figure 1. Birth prevalence of gastroschisis over time, as reported by the published studies reviewed in Tables I–III of this article. ham, 1981], followed by the decreasing trend reported from the same registry for the 1974–1988 period [Clearinghouse, 1991], suggests that a plateau was reached in that country in the late 1970s or early 1980s. However, no other evidence can be found in the literature of a similar phenomenon, including for the early reporting rise from Norway [Kazaura et al., 2004] where the rising trend persisted until 1998. A stabilization of the trend was reported from the state of Tennessee-USA for recent years in the 21st. century [Collins et al., 2007]. In Denmark there was an increase in prevalence in the 1970s, until 1976, followed by a decrease to its initial baseline value in 1983, and a new rise for the rest of the 1980s [Bugge and Holm, 2002]. In the Atlanta Metropolitan Area, unlike other places, the percentage of gastroschisis born from mothers younger than 20 years, decreased from 50% in the 1968–1975 period, to 35% in 1976–2000, thus indicating a stabilization after the increase in the 1970s [Williams et al., 2005b]. Asynchronies in time trends among populations could be real or artificial. Rates increased first in Scandinavian countries in the 1970s and stabilized in the late 1980s. These asynchronies could be artificial, perhaps due to better diagnosis, registration by system with a real population basis (EUROCAT Type I), and increase use of prenatal diagnosis and elective pregnancy termination. These factors, however, do not exclude that residual asynchrony really exists among populations, as predicted by the cohort hypothesis of Källén and Lindham’s [Källén and Lindham1982], although the cohort hypothesis is not supported by the lack of predicted increase of the average maternal age as the trends in prevalence leveled off. MATERNAL AGE AND RELATED VARIABLES Most congenital anomalies that are associated with maternal age display a direct relation, with risk increasing with increasing maternal age. An inverse An inverse association (increasing risk with lower maternal age) has been described for gastroschisis and very few other structural anomalies such as schizencephaly hydranencephaly, porencephaly, septo-optic dysplasia, early association (increasing risk with lower maternal age) has been described for gastroschisis and very few other structural anomalies such as schizencephaly [Curry et al., 2005], hydranencephaly, porencephaly, septo-optic dysplasia, early body stalk disruptions, and hemifacial microsomia. These anomalies were grouped by Lubinsky  as vascular disruptions. Low maternal age is also associated with an increased risk for pre-eclampsia [Terje Lie et al., 1998]. However, very low maternal age is not strongly associated with birth defects other than gastroschisis, and the rare exceptions [Chen et al., 2007] are likely due to misclassification. The relation between risk and maternal age for omphalocele is reported to be U-shaped [Martı́nez-Frı́as et al., 1984; Roeper et al., 1987; Tan et al., 1996; ByronScott et al., 1998], or simply increasing with age [Hemminki et al., 1982; Torfs et al., 1990]. From published data it is often difficult to know how much of the peak at young age of the risk of gastroschisis reflects the maternal age distribution in the general population maternal age, and how much is due to overrepresentation of teenage mothers, probably from misclassified gastroschisis cases. None of the reviewed studies described normal maternal age distribution for the cases with gastroschisis. Temporal increase of teenage mothers were reported only from North Carolina [Laughon et al., 2003], and Norway [Kazaura et al., 2004], whereas other two studied found that the temporal increase in the prevalence of gastroschisis was almost entirely based on cases from teenage mothers Suita et al.  from Japan, and Bermejo et al.  from Spain. All these four studies also found high prevalence (above 1/10,000) and increasing temporal trends in the prevalence of gastroschisis cases with very low maternal ages. ARTICLE The contribution of increasing rates of teenage pregnancy on the rising trends of gastroschisis remains unclear. Few series are sufficiently well described and large enough to contribute meaningful data to this question. The population-based study encompassing all mothers in Norway over 32 years (1967–1998) concluded that the prevalence of gastroschisis increased in all maternal age categories, supporting the notion that time trends and low maternal age are independent [Kazaura et al., 2004]. A similar conclusion was reached by three other studies in England [Penman et al., 1998], Hawaii [Forrester and Merz, 1999], and Japan [Suita et al., 2000]. The only exception was one study of 11 years (1986–1997) in the US state of North Carolina that concluded that the increase was almost entirely due to the increase of teenage mothers [Laughon et al., 2003]. One study in Western Australia analyzed the distribution of maternal age in gastroschisis in three periods, from 1992 to 2001, concluding that the effect of teenage mothers in cases of gastroschisis seems to be diminishing in time, with an increase in the proportion of 20–24 years old mothers [Reid et al., 2003]. It is unclear whether the increased risk associated with young maternal age was already present during the baseline period, before the pandemic started. It is difficult to know the maternal age distribution in gastroschisis cases during the ‘‘baseline period,’’ before the mid 1960s, mainly because of the lack of precise diagnosis, specified maternal age data, and reliable registry data. Bernstein  reported one case of gastroschisis born in New York City in 1939, from a 28-year-old mother. The description seems to fit our present understanding of this defect even if it is left-sided, and it is difficult to understand how one lobe of the liver can herniate through a ‘‘3 cm in diameter circular opening.’’ Bernstein names this patient’s defect as gastroschisis, or epigastroschisis, following Taruffi’s classification of gastroschisis in 1894. As already discussed, the confusion in nomencla- AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ture impedes any interpretation of those early data. Bernstein  carefully reviewed the literature since the 16th century and no mention is made to unusual maternal age. Likewise, Simpson and Caylor  do not provide the ages of the mothers for the two reported cases, alleged to be reported cases number 15th and 16th in the medical literature, and maternal age is not mentioned. On the other hand, since adolescent motherhood was not an unusual event in most world populations before World War II [Carp, 2002], perhaps this was not a noteworthy piece of information in those days. Maternal age and covariates. Kazaura et al.  reported a residual effect of paternal age in gastroschisis, which suggests that low maternal age could not be the only risk factor, but perhaps the most conspicuous factor correlated with an underlying causal factor. Changing paternity, its closely related short pre-pregnancy interval, and short co-habitation were investigated both as part of this type of reasoning, fueled also by the recognition of the post-World War II changes in sexual behavior, values, and practices. An unquestionable worldwide epidemic such as that of gastroschisis calls for a causal investigation of global catastrophes, in its Greek etymological sense of ‘‘overturn.’’ Even when the results are not conclusive yet [Chambers et al., 2007; Rittler et al., 2007], a short cohabitation time could be a primary acting factor, suggesting that antigenic or other factors related to modern lifestyles might be involved in the causation of gastroschisis. Elsewhere in this seminar series others will discuss very young maternal age as an indicator of obstetrical high risk group, possibly correlated to social deprivation, environmental risks including malnutrition, poor health care, unwanted pregnancies, increased consumption of social drugs, and other potential risk factors. In populations with low prevalence and no increasing trend of gastroschisis, the relation between low maternal age and increased risk of gastroschisis still 175 seems to exist, as reported in studies from Italy [Calzolari et al., 1993], California [Roeper et al., 1987], and Spain [Bermejo et al., 2006], among others. Furthermore, as seen before, increasing secular trends in gastroschisis prevalence are not entirely explained by increasing secular trends in the young maternal age group, in spite of two indirect observations about the important, thought partial, role of maternal age on prevalence temporal trends [Suita et al., 2000; Bermejo et al., 2006]. The fact that other body wall defects, as well as gastroschisis associated with other malformations, do now show the association with young maternal age underscores the uniqueness of gastroschisis as a nosological entity. The lack of association with young maternal age for other body wall defects, as well as for gastroschisis cases associated with other unrelated anomalies, is widely proved in the literature [Roeper et al., 1987; Geronimus and Korenman, 1993; Haddow et al., 1993; Nichols et al., 1997; Penman et al., 1998; Terje Lie et al., 1998; Suita et al., 2000; McDonnell et al., 2002; Laughon et al., 2003; Kazaura et al., 2004; Curry et al., 2005; Emusu et al., 2005; Loane et al., 2007; Yang et al., 2007]. This uniqueness of isolated gastroschisis strongly suggests it constitutes a single nosological entity. PUBLIC HEALTH IMPACT The global human situation is marked by inequalities among as well as within countries. Therefore, because obstetrical and neonatal management as well as the public health impact of gastroschisis is expected to vary widely among regions and social strata, only general principles will be mentioned here. A public health evaluation of gastroschisis should consider the increasing occurrence—gastroschisis used to be as rare as sirenomelia, is now as frequent as esophageal atresia, and could come to be much more frequent in the future. Furthermore, this evaluation should consider the strong relation with 176 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) A public health evaluation of gastroschisis should consider the increasing occurrence—gastroschisis used to be as rare as sirenomelia, is now as frequent as esophageal atresia, and could come to be much more frequent in the future. adolescent mothers with all its related social and medical complications. On the other hand, if properly managed, gastroschisis may have a very good prognosis, with low morbidity and mortality [Abdullah et al., 2007], further supporting proactive medical care of the affected infant from the time of fetal diagnosis [Baerg et al., 2003]. Prenatal diagnosis, either early by alpha-feto-protein determinations, or late by ultrasound, allows the elective termination of pregnancy, if accepted by local culture, allowed by legislation, and desired by the parents. The latter is the most controversial issue, because of the expected good prognosis of gastroschisis given best medical practices. In practice, termination of pregnancy is reported in only 15% of cases of gastroschisis, compared for example to 30% among cases of omphalocele [Forrester et al., 1998]. Prenatal diagnosis is the essential first step for appropriate treatment. Irreversible damage of the eviscerated intestines might be preventable with transabdominal amniotic fluid exchange [Aktug et al., 1998], and reduced by monitoring of intestinal wall thickening to decide timing and way of delivery [Charlesworth et al., 2007; Murphy et al., 2007]. The postnatal benefits of prenatal diagnosis are clear and many, and include earlier family awareness, adequate institution of delivery with alerted obstetrical [Santiago-Muñoz et al., 2007], pediatric, and surgical staff [Aizenfisz et al., 2006], better risk categorization, and personalized protocol for action. A recent study of 4,344 cases with gastroschisis in the USA developed a categorization index for risk of death considering complex and simple classes, according to the presence or absence of associated congenital anomalies, prematurity, low birth weight [Charlesworth et al., 2007], length of necrotized intestines, and other complications [Abdullah et al., 2007; Arnold et al., 2007a,b]. Of these cases, 11% were classified as complex gastroschisis, and significantly differed from the 89% of simple cases in median length of stay (67 vs. 28 days), inpatient mortality (8.7% vs. 2.9%), and median hospital charges ($197,871 vs. $90,788, in 2005 US dollars). Similar findings, also from the US, were reported the Centers for Disease Control and Prevention (CDC) in 2007 [CDC, 2007]. Even if countries and health system would differ from these values in absolute terms, they should be similar in relative terms. Even thought health inequalities are more marked in developing countries, they exist in almost every country. Perhaps the US is one of the countries that has and shares more information on this issue, which does not imply that it is the only country with this problem. In spite of gastroschisis being less frequent in whites than in blacks, black infants with gastroschisis, compared to similarly affected white infants, tend to have a more complicated clinical course [Arnold, 2004; Arnold et al., 2007a,b; Charlesworth et al., 2007] and a higher mortality rate [Salihu et al., 2004]. Gastroschisis hits disproportionately the vulnerable population of very young women, whose socio-economic status may be low and who may not seek or get health care [Geronimus and Korenman, 1993; Emusu et al., 2005; Chen et al., 2007]. Public health intervention should consider these array of Gastroschisis hits disproportionately the vulnerable population of very young women, whose ARTICLE socio-economic status may be low and who may not seek or get health care. factors and their correlates, including smoking [Haddow et al., 1993; Rodrı́guez-Pinilla et al., 1996; Lam and Torfs, 2006], social drug consumption [Torfs et al., 1994], unprescribed medications [Werler et al., 1992a,b, 2003], malnutrition [Torfs et al., 1998; Lam et al., 1999], and obesity [Waller et al., 2007]. The increasing frequency of gastroschisis, as well as improvements of medical techniques to reduce morbidity and mortality, is also increasing the burden and costs of this anomaly on the health systems. The number of surgical repairs in the US doubled between 1996 and 2003 at the National level, averaging 3 procedures for every 10,000 births [Alvarez and Burd, 2007]. This scenario calls for an increase in public health investments aimed at extending and improving surveillance, mainly in the areas of the world where such surveillance does not exist [Mastroiacovo et al., 2006], promoting the use of birth defect registries for etiologic studies, improving surveillance of risk factors, and supporting basic and applied research to test sensible hypothesis for the etiology of gastroschisis. The understanding of the etiology and pathogenesis of gastroschisis, and particularly the characterization of modifiable risk factors, are essential components for effective strategies aimed at the primary prevention of this serious and common congenital anomaly. CONCLUSIONS Gastroschisis offers the intriguing epidemiological situation of a worldwide pandemic with secular trends increasing internationally and a strong association with very low maternal age. We estimate that the birth prevalence rate of gastroschisis before the pandemic was approximately 1 in 50,000 births, that such baseline rate increased between 10- and 20-fold, and that rates are still increasing in many areas worldwide. Even if some ARTICLE reports suggest that prevalence has reached a plateau, it is still too early to know for sure. A significant challenge in interpreting current epidemiologic data is that many of the published data are not comparable, mainly because of differences (or uncertainties) in each study’s case definition of gastroschisis, particularly with respect to what is included and what is excluded. Because most cases of gastroschisis are isolated, and because the diagnosis is commonly made prenatally, timely and appropriate care and treatment is feasible with low morbidity and mortality rates. However, this ideal scenario requires pre-established protocols at all levels of medical care. Since gastroschisis hits disproportionately the vulnerable population of very young women, often with low socio-economic status, public health interventions should address a range of related social factors in this group, including smoking, social drug consumption, use of unprescribed medications, malnutrition, and obesity. The postnatal benefits of a prenatal diagnosis of gastroschisis are many, and includes family awareness, adequate planning of delivery with alerted obstetrical, pediatric, and surgical staff; optimal risk categorization, and personalized protocol for action. Since gastroschisis is more frequent in Caucasians than in African Blacks and Orientals, etiologic studies should address the role of gene–environment interactions. From the perspective of primary prevention, there needs to be a renewed focus on modifiable risk factors. Finally, there is an urgent need for sound and testable working hypotheses that build on biologic considerations and epidemiologic data to guide etiologic studies of gastroschisis—following the steps of Lejeune in the late 1950s whose identification of aneuploidy in Down syndrome connected the epidemiology of Down syndrome and the biology of Drosophila, both well-known decades earlier. REFERENCES Abdullah F, Arnold MA, Nabaweesi R, Fischer AC, Colombani PM, Anderson KD, Lau H, AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) Chang DC. 2007. Gastroschisis in the United States 1988–2003: Analysis and risk categorization of 4344 patients. J Perinatol 27:50–55. Aizenfisz S, Dauger S, Gondon E, Saizou C, De Lagausie P, Luton D, Aigrain Y, Beaufils F. 2006. Gastroschisis and omphalocele: Retrospective study of initial postoperative management in the ICU. Eur J Pediatr Surg 16:84–89. Aktug T, Demir N, Akgur FM, Olguner M. 1998. 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