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Article gastrointestinal disorders
Gastroschisis: Embryology, Pathogenesis,
Epidemiology
Shilpi Chabra, MD,*
Objectives After completing this article, readers should be able to:
1. Describe normal embryology and various theories contributing to derangements in
development leading to gastroschisis.
2. Delineate several theories regarding the pathogenesis of gastroschisis.
3. Explain the environmental and other risk factors linked to gastroschisis.
4. Describe the prevalence of gastroschisis in developed countries and various theories
explaining it.
Introduction
Gastroschisis is a congenital anterior abdominal wall defect, adjacent and usually to the
right of the umbilical cord insertion. It occurs as a small, full-thickness periumbilical cleft
either immediately adjacent to the umbilicus or separated from it by a strip of skin. This
results in herniation of the abdominal contents into the amniotic sac, usually just the small
intestine, but sometimes also the stomach, colon, and ovaries (Figure). The abdominal
wall defect is relatively small compared with the size of the eviscerated bowel, which often
develops walls that are matted and thickened with a fibrous peel. Gastroschisis has no
covering sac and no associated syndromes. This differentiates it from an omphalocele,
which usually is covered by a membranous sac and more frequently is associated with other
structural and chromosomal anomalies (Table 1). In addition, although gastroschisis may
be associated with gastrointestinal anomalies such as intestinal atresia, stenosis, and
malrotation, it has a much better prognosis than omphalocele.
Historical Perspective
The term gastroschisis is derived from the Greek word laproschisis, meaning “bellycleft.” It
was used in the 19th and early 20th centuries by teratologists to designate all abdominal
wall defects. No clear distinctions were made between abdominal wall defects until 1953,
when Moore and Stokes classified them based on their appearance at birth. They suggested
that the term gastroschisis be reserved for those cases in which the defect is adjacent to the
normally inserted umbilical cord and there is no evidence of a sac covering the extruded
viscera. Although the first report of a case of gastroschisis was in 1733, the first report of
successful closure of a small abdominal wall defect was not until 1943 by Watkins, a
surgeon from Virginia.
Embryology
The pathogenesis of gastroschisis remains controversial. To
understand various theories regarding this defect, it is essen-
Abbreviations
The gastrointestinal tract develops from the primitive International Clearinghouse of Birth Defects digestive tube derived from the yolk sac. Early in gestation, a portion of the gut opens ventrally into the yolk sac—the International Classification of Diseases, midgut. At 31⁄2 weeks’ gestation, the gut becomes distinct from the yolk sac. The embryonic disk is folded into cephalic, ICD-9-CM: International Classification of Diseases,
caudal, and lateral folds, each of which converges at the umbilicus to obliterate the coelom, which forms the future *Assistant Professor of Pediatrics, University of Washington, Seattle, Wash.
†Division Head and Professor of Pediatrics, Department of Pediatrics, University of Washington, Seattle, Wash.
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gastrointestinal disorders gastroschisis
that subsequently ruptures, resulting in visceral hernia-tion. The left omphalomesenteric artery also involutes,and the right one develops into the superior mesentericartery. Similarly, disruption of this process may causeischemia and the development of gastroschisis. Othertheories speculating on the embryologic origins of gas-troschisis are summarized in Table 2. These includerupture of an omphalocele and various intrauterine in-sults. Infarction due to a vascular insult and strangulationof the eviscerated bowel by the contracting umbilical ringor midgut volvulus are proposed in the pathogenesis ofintestinal atresia and other gastroschisis variants, whichare summarized in Table 3. However, the vascular theoryis supported by the association of gastroschisis with ma-ternal smoking and other anomalies also known to have a Figure. Gastroschisis, resulting in herniation of the abdominal
contents into the amniotic sac.
Animal models have been developed in chicks, rab- bits, lambs, and mice and may hold the key to the origin peritoneal cavity. At the beginning of the 6th week, the of gastroschisis. Most of these models have used terato- midgut elongates at a rate faster than that of the elonga- gens that affect fetal vasculature (Table 4).
tion of the embryonic body. This results in physiologicdevelopment of an umbilical hernia. At 10 weeks, themidgut returns rapidly to the embryonic abdominal cav- Pathogenesis
ity, and the layers of the cephalic, caudal, and lateral folds Gastroschisis is an isolated structural anomaly, and no join to close the defect in the abdominal wall. This single definitive genetic or environmental cause has been normal reduction of the physiologic midgut herniation identified. However, numerous theories have been pro- followed by abdominal wall closure is key to normal development. Various theories have been developed toexplain how or why this does not happen.
The vascular disruption theory is held most com- Gastroschisis is primarily an isolated defect occurring monly. The embryo begins with two umbilical veins and sporadically and having a multifactorial etiology. How- two omphalomesenteric arteries. Between 28 and ever, familial clusters and occurrence in twins suggest a 32 days after conception, the right umbilical vein invo- role of heredity and an autosomal inheritance pattern lutes. One gastroschisis theory is that premature involu- with variable expression. Sibling recurrence rates range tion can lead to ischemia, which results in a weak spot from 3% to 5%, which emphasizes the need for appropri- Table 1. Differences Between Gastroschisis and Omphalocele
Gastroschisis
Omphalocele
Incidence
1 in 10,000 (now increasing)
1 in 5,000
Defect Location
Right paraumbilical
Covering Sac
Present (unless sac ruptured)
Description
Free intestinal loops
Firm mass including bowel, liver, etc
Associated With Prematurity
50% to 60%
10% to 20%
Necrotizing Enterocolitis
Common (18%)
Uncommon
Common Associated Anomalies
Gastrointestinal (10% to 25%)
Trisomy syndromes (30%)
● Intestinal atresia
Cardiac defects (20%)
● Malrotation
Beckwith-Weidemann syndrome
Cryptorchidism (31%)
Bladder extrophy
Prognosis
Excellent for small defect
Varies with associated anomalies
Mortality
Varies with associated anomalies
(80% with cardiac defect)
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Table 2. Theories Regarding Embryogenesis of
Gastroschisis
Duhamel (1963)
Teratogenic insult resulting in defective
differentiation of the somatopleural
mesenchyme
Shaw (1975)
Rupture of a hernia of the umbilical cord at the
site of involution of the right umbilical vein
DeVries (1980)
Abnormal right umbilical vein atrophy resulting in
weakness and defect of abdominal wall, with
failure of epidermal differentiation
Van Allen (1981, 1987)
Vascular disruption theory
Hoyme (1981, 1983)
Omphalomesenteric artery insult with disruption of
umbilical ring
the risk of fetal gastroschisis 3.6-fold and the risk of small intestinalatresia 4.2-fold.
ate counseling for recurrence in a family that has a history Young maternal age and primigravida status have of gastroschisis. Experimental studies have attempted to been associated with increasing prevalence of gastroschi- identify a gene responsible for gastroschisis. In 1998, a sis. However, young paternal age has not been identified study in mice implicated the region of mouse chromosome as a significant risk factor. The association of gastroschisis 7 in the pathogenesis of radiation-induced gastroschisis. In with younger women who could have increased use of another study, induction of mutation in the bone morpho- illicit drugs, alcohol, and smoking may point to a poten- genic protein-1 gene in mice resulted in a condition similar tial factor associated with their lifestyle. Other factors to gastroschisis; unfortunately, no mutation of this gene has associated with increased risk are low pregnancy body been found in affected human infants. This lack of evidence mass index and maternal diet. The teenage diet may have for genetic predisposition further emphasizes the need to low levels of alpha-carotene and total glutathione and identify possible environmental factors.
high levels of nitrosamines, which may suggest a patho-genetic role for a nutrient deficiency.
Environmental
The trend of increasing birth prevalence of gastroschisis Epidemiology
in different populations at different time periods over a The prevalence of gastroschisis has increased internation- wide geographic distribution suggests possible exposure ally (Table 7). This increased prevalence of gastroschisis to environmental teratogens (Table 5). Current research (but not of omphalocele) was first observed in Finland in has focused on vasoactive drugs. Epidemiologic studies the 1970s. In the 1980s, increases were observed in have shown an increased risk of gastroschisis in mothers Strasbourg, Paris, Israel, and Atlanta, as reported by the who have reported taking vasoactive over-the-counter International Clearinghouse of Birth Defects Monitor- medications, including pseudoephedrine, phenylpropa- ing Systems (ICBDMS). Reports of increased prevalence nolamine, aspirin, ibuprofen, and acetaminophen. Aspi-rin has been shown to increase the risk for gastroschisis in Table 3. Gastroschisis Variants
both animal and human studies. In one mouse study,gastroschisis developed after aspirin administration on Proposed Pathogenesis
day 9 of gestation (corresponds to the 4th week of Left-sided Gastroschisis
Regression of left umbilical
human gestation), but not when aspirin was adminis- tered on days 10 and 12, implicating a window of devel- Vanishing Gut
Midgut volvulus and bowel
opmental vulnerability. Use of these types of medications infarction
during upper respiratory tract infections suggests the Closed Gastroschisis
Tightening of abdominal
possibility of an underlying infectious agent as another fascial defect around the
bowel, causing ischemia,
potential etiologic factor. Various risk factors associated resorption, and
with gastroschisis are summarized in Table 6. These spontaneous closure
factors cover a wide spectrum, including parental occu- NeoReviews Vol.6 No.11 November 2005 e495
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Table 4. Animal Models of Gastroschisis
Investigator (Year)
10,000 total births, and there wasno significant overall linear trend Kimmel (1971)
Salicylates
Nielsen (1986)
Hyperthermia
Randell (1994)
Hillebrandt (1998)
Irradiation during preimplantation
Singh (2003)
Protein and zinc deficiency with carbon
monoxide exposure
periods, with a low, stable rate ofgastroschisis from 1968 through1975 (0.8 per 10,000 births) and a of gastroschisis continued into the 1990s, along with higher, stable rate from 1976 through 2000 (2.3 per geographic variations attributed to maternal age. Around 10,000 births), and no temporal trend observed since the same time period, reports of an increased prevalence of gastroschisis in England showed geographic variationwithin the country. Several of these epidemiologic stud- Maternal Age
ies have demonstrated an increased prevalence of gastros- Maternal age of less than 20 years has been identified as a significant risk factor for gastroschisis, especially in devel- In the United States, a similarly increased prevalence oped countries. The reasons for this association remain of gastroschisis has been reported in several states, which unclear, although speculations of an unidentified terato- varies widely geographically (Table 8). In the past, the gen related to modern lifestyle factors, including hob- ratio of the number of cases of omphalocele to gastro- bies, occupation, and diet, have been made. An associa- schisis has been reported to be 3:2. However, some have tion with nulliparity and the use of oral contraceptives suggested that the prevalence of gastroschisis has been during conception could point toward teratogenic increasing in contrast to a stable or decreasing prevalence of omphalocele, thus altering the ratio. In Florida, forexample, a study analyzing cases of abdominal wall de- Maternal Race
fects between 1982 and 1999 reported the ratio of Gastroschisis has been reported with increased frequency number of cases of omphalocele to gastroschisis to be in Hispanics. In a study from Utah, 23% of the gastros- chisis cohort was Hispanic. A retrospective study from This increased prevalence occurs in phases over differ- Mexico reported one of the highest prevalence rates of ent time periods. For example, a study in Denmark that gastroschisis of 4.93 per 10,000 in 1998 among persons evaluated abdominal wall defects data from 20 birthcohorts in three nationwide registries showed an initialphase of increase in gastroschisis until 1976, followed by Table 6. Risk Factors Associated
a decrease to the initial 1970s value in 1983, and asubsequent new increase. The average point prevalence With Gastroschisis
● Parental occupation (eg, printer/computer
manufacturing factories)
Table 5. Potential Teratogens
● Young maternal age
● Hispanic race
Associated with Gastroschisis
● Poor maternal education
● Low socioeconomic status
● Organic chemicals/solvents
● Lack of prenatal care
● Cyclooxygenase inhibitors (aspirin, ibuprofen)
● Nulliparity
● Decongestants
● More than one elective abortion
● Acetaminophen
● Short interval between menarche and first pregnancy
● Oral contraceptives
● Chorionic villus sampling
● Maternal smoking
● Residence surrounding landfill sites
● Alcohol
● Maternal diet (low alpha-carotene, low total
● Illicit drugs (eg, cocaine, amphetamine)
glutathione, high nitrosamines)
● X-ray irradiation in early pregnancy
● Low pregnancy body mass index
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Geographic Distribution
Table 7. Increased Prevalence of
An association of gastroschisis with a behavioral or envi- Gastroschisis in Developed
ronmental exposure has been postulated due to its asso-ciation with geographic variations in different parts of the Countries
world. The prevalence of gastroschisis may vary between Incidence per
rural and urban regions, although information in the 10,000 Births
literature is insufficient. In a Finnish study, an apparent 1970 to 1974
increase in prevalence of gastroschisis was noted in 1975 to 1979
northern Finland only, and urban residence was a corre- England and Wales
late of the increased gastroschisis risk. In the United States, there have been reports of disparity in distribution Southwestern England
of gastroschisis, such as preponderance in the rural part Northern England
of New York. A retrospective study of a cluster of gas- troschisis from Kentucky found no evidence of temporal or spatial clustering in the cases, and there was no asso- 1996 to 1997
ciation with county of maternal residence. Anomalies of Western Australia
1980 to 1990
the central nervous system, orofacial clefts, and limb 1985 to 1990
reduction defects have been associated with parental 1996 to 2000
exposure to pesticides. The risk of gastroschisis in rural areas, especially with farming communities, could be increased due to use of pesticides or fertilizers, but no 1967 to 1974
definitive studies have confirmed this hypothesis.
1995 to 1998
Seasonal Association
Conflicting reports have suggested an association of gas- *International Clearinghouse for Birth Defects Monitoring Systems troschisis with month of birth, raising the question of aninfectious cause. One such study reported that 37% ofgastroschisis conceptions occurred during the first quar- of Mexican origin. A study from Hawaii found a de- ter of the year. In another study, infants born during creased prevalence in Far East Asians. In New York, there January, February, or March were at greater risk. How- was a higher mortality rate for black infants who had ever, yet another study found that month of birth was not gastroschisis compared with whites, and a recent study in associated with gastroschisis. Due to the seasonal varia- Atlanta found that the infants who had gastroschisis born tions reported and association with medications used for to teenage mothers and mothers 20 to 24 years of age respiratory illnesses, a viral cause is still speculated.
were less likely to be born to black mothers than to whitemothers.
Other Factors
Although the recent rapid increases in the rate of gastros-chisis have been linked primarily to environmental fac- Table 8. Increased Prevalence of
tors, several other theories have been offered. For exam-ple, lack of differentiation between the clinical forms of Gastroschisis in the United States
abdominal wall defects either due to selection bias, pre-vious underreporting of the defect, or misclassification of Incidence per
10,000 Births
gastroschisis as omphalocele could be a factor. In aSwedish study, 8% of cases of abdominal wall defects were “unclassifiable,” and in a Danish study, 20% of cases of gastroschisis were misclassified. In British Columbia, there were no reports of gastroschisis before 1969 be- North Carolina
cause the condition was unknown, and previous cases were diagnosed as omphalocele. Another theory regard- Atlanta, Georgia
1968 to 1975
ing the increased prevalence of gastroschisis suggests that 1976 to 2000
shifts in maternal age distribution and selected termina- NeoReviews Vol.6 No.11 November 2005 e497
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tion in fetuses have occurred due to improvements in smoking, leading to speculations of a teratogen related to prenatal diagnosis. A study from the ICBDMS postu- modern lifestyle that remains to be identified. Also, it is lated underreporting of cases in countries such as France possible that gastroschisis may be related to a combina- and Netherlands, where there is a high proportion of tion of factors working synergistically, rather than an selective terminations. This also was suggested in a Dan- isolated single event or exposure. This rising prevalence ish study after induced abortions were legalized in Den- of gastroschisis has been described as an epidemic, em- mark in 1973. One study reported the incidence of phasizing the importance of continued monitoring and abdominal wall defects in stillborn infants to be 20 times evaluation of pathogenetic factors. The potential associ- ation of gastroschisis with medications, diet, and other One of the disadvantages of the epidemiologic studies maternal factors could have implications for pregnancy evaluating changes in prevalence is the reliance on vari- planning similar to neural tube defects. Thus, it is an able reporting of data to birth defects surveillance pro- important public health issue, highlighting the need for a grams. For example, some studies include elective termi- more complete multicenter epidemiologic study.
nations in their calculations, thereby increasing theirreported occurrence. Several retrospective studies useICD-9 codes to identify patients. However, it is impor-tant to clarify that the code for gastroschisis is the same as Suggested Reading
for omphalocele. In fact, the ICD-9 code includes all Baerg J, Kaban G, Tonita J, Pahwa P, Reid D. Gastroschisis: congenital anomalies of the abdominal wall (756.79 A sixteen-year review. J Pediatr Surg. 2003;38:771–74 Calzolari E, Bianchi F, Dolk H, Milan M. Omphalocele and gas- Anomalies of the abdominal wall, other congenital troschisis in Europe: a survey of 3 million births 1980 –1990.
anomalies of abdominal wall). Currently, individual de- EUROCAT Working Group. Am J Med Genet. 1995;58: fects cannot be separately identified based on ICD-9 codes, and chart review and medical record data are Forrester MB, Merz RD. Epidemiology of abdominal wall defects, needed to separate abdominal wall defects accurately.
Hawaii, 1986 –1997. Teratology. 1999;60:117–123 Perhaps, the time is right to petition for a new ICD-9 Goldbaum G, Daling J, Milham S. Risk factors for gastroschisis.
code or make clinical modifications to it, identified as Hwang PJ, Kousseff BG. Omphalocele and gastroschisis: an 18-year ICD-9-CM, in an attempt to separate these vastly differ- review study. Genet Med. 2004;6:232–236 ent anomalies and improve data collection for future Laughon M, Meyer R, Bose C, et al. Rising birth prevalence of gastroschisis. J Perinatol. 2003;23:291–293 Nichols CR, Dickinson JE, Pemberton PJ. Rising incidence of gastroschisis in teenage pregnancies. J Matern Fetal Med. 1997;6:225–229 Epidemiologic studies from the United States and other Torfs CP, Velie EM, Oechsli FW, Bateson TF, Curry CJ. A popu- developed countries around the globe have reported an lation-based study of gastroschisis: demographic, pregnancy, increased prevalence of gastroschisis over a wide geo- and lifestyle risk factors. Teratology. 1994;50:44 –53 graphic distribution. Although environmental and ma- Werler MM, Sheehan JE, Mitchell AA. Association of vasoconstric- ternal factors have been suspected, the cause of gastros- tive exposures with risks of gastroschisis and small intestinalatresia. Epidemiology. 2003;14:349 –354 chisis remains unclear, and no single cause has yet been Werler MM, Sheehan JE, Mitchell AA. Maternal medication use implicated. Universally, there is a significant association and risks of gastroschisis and small intestinal atresia. Am J of gastroschisis with young maternal age along with e498 NeoReviews Vol.6 No.11 November 2005
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NeoReviews Quiz
1. Gastroschisis is a congenital anterior abdominal wall defect, adjacent and usually to the right of the
umbilical cord insertion. Of the following, the most common anomaly associated with gastroschisis is:
A. Beckwith-Wiedemann syndrome.
B. Congenital heart defect.
C. Cryptorchidism.
D. Trisomy 21.
E. Urinary bladder exstrophy.
2. The pathogenesis of gastroschisis remains controversial, although several theories have been proposed to
explain its development. Of the following, the most commonly held theory of the pathogenesis of
gastroschisis is:
A. Ethanol exposure during early embryogenesis.
B. Irradiation during preimplantation.
C. Protein and zinc deficiency with carbon monoxide exposure.
D. Teratogenic effect on differentiation of somatopleural mesenchyme.
E. Vascular disruption involving omphalomesenteric blood vessels.
3. Gastroschisis is primarily an isolated defect that occurs sporadically. No specific genetic mutations or
environmental factors have been identified as its cause. However, epidemiologic studies have identified a
number of maternal risk factors associated with the development of gastroschisis in the fetus. Of the
following, the most common maternal risk factor associated with fetal gastroschisis is:
A. Advanced age.
B. Hispanic race.
C. Multiparity.
D. Obesity.
E. Urban residence.
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