BIRTH DEFECT RISK FACTOR SERIES: Omphalocele

Omphalocele is an abdominal wall defect involving herniation of the bowel and liver into the umbilical cord.  The defect is always covered by a membrane, although sometimes this membrane may have ruptured, in which case the defect may be mistaken for gastroschisis. Infants with omphalocele tend to have more additional birth defects (30-94%), including chromosomal abnormalities (11-31%) (most often trisomy 13, trisomy 18, and trisomy 21), and a lower survival rate than gastroschisis (Garne, 2002; Hsu, 2002; Barisic, 2001; Stoll, 2001a; Rankin, 1999; Forrester and Merz, 1999a; Byron-Scott, 1998; Kallen, 1996; Tan, 1996; Calzoleri, 1995; Calzolari, 1993; Morrow, 1993; Castilla and Lopez-Camelo, 1990; Torfs, 1990; Carpenter, 1984; Mann, 1984; Baird and MacDonald, 1981).  The defect is found in association with numerous syndromes and other conditions, such as otopalatodigital syndrome type II; Melnick–Needles syndrome; Rieger syndrome; neural tube defects; Meckel syndrome; Shprintzen–Goldberg omphalocele syndrome; lethal omphalocele-cleft palate syndrome; cerebro-costo-mandibular syndrome; fetal valproate syndrome; Marshall–Smith syndrome; fibrochondrogenesis; hydrolethalus syndrome; Fryns syndrome; omphalocele, diaphragmatic defects, radial anomalies and various internal malformations; diaphragmatic defects, limb deficiencies and ossification defects of skull; Donnai–Barrow syndrome; CHARGE syndrome; Goltz syndrome; Carpenter syndrome; Toriello–Carey syndrome; familial omphalocele; Cornelia de Lange syndrome; C syndrome; Elejalde syndrome; Malpuech syndrome; cervical ribs, Sprengel anomaly, anal atresia and urethral obstruction; hydrocephalus with associated malformations; Kennerknecht syndrome; lymphedema, atrial septal defect and facial changes; and craniosynostosismental retardation syndrome of Lin and Gettig (Chen 2007).

Over the past several decades, women carrying a fetus with omphalocele have been found to have elevated maternal serum levels of alpha-fetoprotein (Canick and Saller, 1993). Prenatal screening of this substance, along with ultrasonography (Vintzileos, 1987), have allowed omphalocele to be identified in utero.  Studies from various birth defects surveillance systems have found that, in regions where elective termination is allowed, prenatal diagnosis and elective termination reduce the birth prevalence of omphalocele (Stoll, 2001a; Barisic, 2001; Rankin, 1999; Forrester and Merz, 1999b; Byron-Scott, 1998; Riley, 1998; Heydanus, 1996; Calzolari, 1995; Chi, 1995; Stoll, 1995; Morrow, 1993; Stoll, 1992).

Prior to the 10^th week of gestation, the intestine of the fetus is herniated into the umbilical stalk.  At 10-12 weeks’ gestation, the intestine retracts into the abdomen.  If this retraction fails to occur, omphalocele may result.

Several studies have investigated the relationship of race/ethnicity in risk for omphalocele and failed to find any effect (Canfield 2006; Leck and Lancashire 1995; Yang 1994; Yang 1992; Roeper 1987), but one study in New York did find higher rates among infants born to black mothers (Salihu 2003). The same study found much higher rates among the offspring of women grouped in “Other” ethnicity (not black, white or Hispanic). One study in Hawaii found the omphalocele prevalence to be lower in Pacific Islanders than in whites, Far East Asians, and Filipinos; however, this difference disappeared when the rates were adjusted for maternal age (Forrester and Merz, 1999a).  Another investigation observed no significant difference in risk of abdominal wall defects in infants born to Vietnamese women compared to infants born to non-Hispanic white women in California (Shaw, 2002).

Most studies have reported no secular trends for omphalocele (Bugge and Holm, 2002; Yang, 1994; Roeper, 1987; Carpenter, 1984; Martinez-Frias, 1984; Hemminki, 1982; Baird and MacDonald, 1981).  However, several studies has found an increase in omphalocele rates over time (Rankin, 1999; Forrester and Merz, 1999a).  One investigation reported no seasonal variation in omphalocele rates (Bound, 1989).

Prevalence of omphalocele demonstrates wide variation by geographic location, both within and between countries (Forrester and Merz, 1999a; Tan, 1996; Goldbaum, 1990; Roeper, 1987; Hemminki, 1982).  One investigation failed to identify any association between omphalocele and altitude (Castilla, 1999).

A number of studies that have examined maternal age risk for omphalocele have found various patterns, including U-shaped (highest rates for both youngest and oldest maternal age groups) (Byron-Scott, 1998; Tan, 1996; Roeper, 1987; Martinez-Frias, 1984), increasing with younger maternal age (Reefhuis 2004), or with greater maternal age (Rankin, 1999; Forrester and Merz, 1999a; Torfs, 1990; Hemminki, 1982).  However, other investigations reported no clear association between omphalocele risk and maternal age (Bugge and Holm, 2002; Stoll, 2001a; Calzolari, 1993). Part of the increased risk among older mothers is related to omphalocele’s association with chromosomal abnormalities, which occur more frequently with advanced maternal age. There does not appear to eb an association with paternal age (Materna-Kiryluk 2009).

Infant sex influences the risk for omphalocele.  The risk for omphalocele is higher for males than females (Hsu, 2002; Barisic, 2001; Riley, 1998; Tan, 1996; Calzoleri, 1995; Calzolari, 1993; Carpenter, 1984; Hemminki, 1982), although not all studied have reported this difference (Stoll, 2001a; Forrester and Merz, 1999a; Yang, 1994). No association has been found between omphalocele risk and parity  in some studies (Byron-Scott, 1998; Hemminki, 1982) , but Salihu did observe a higher risk for multiparous mothers(Salihu 2006). Omphalocele is also associated with multiple gestation pregnancy, lower birth weight, prematurity, and intrauterine growth retardation (Rasmussen, 2001; Stoll, 2001a; Mastroiacovo, 1999; Riley, 1998; Calzolari, 1993; Doyle, 1991; Mili, 1991; Khoury, 1988), although one study reported no association between omphalocele/diaphragmatic hernia and plurality (Kallen, 1986).  One investigation reported no statistically significant association between omphalocele and macrosomia (Waller, 2001).  Omphalocele risk is increased with lower gestational age (Calzolari, 1993).

There is no apparent relationship between parental consanguinity and omphalocele (Rittler, 2001).

One study reported an increased risk of abdominal wall defects with socioeconomic deprivation, although the difference was not statistically significant (Vrijheid, 2000).

An examination of maternal occupation found mothers in service work slightly overrepresented among omphalocele cases while housewives and farmers’ wives were underrepresented (Hemminki, 1982).  Living in proximity to hazardous waste sites or various industries has not been found to affect risk of omphalocele (Castilla, 2000; Dolk, 1998), although residence in proximity to landfill sites has been associated with a slightly increased risk of abdominal wall defects (Elliott, 2001).  Water chlorination does not appear related to abdominal wall hernia (Kallen and Robert, 2000).

One study reported an increased rate of abdominal wall defects among infants born to women with obesity but who were not diabetic (Moore, 2000) and others have found increased risk of omphalocele with maternal obesity (Waller 2007, Watkins, 2001, Watkins 2003).  However, another investigation reported no increased risk of abdominal wall defects among African-American women who were obese (Mikhail, 2002).  Maternal hyperthyroidism and hypothyroidism do not appear to increase risk of omphalocele (Khoury, 1989).  One study found no relationship between maternal diabetes and risk of abdominal wall defects (Moore, 2000).

Maternal smoking has not been associated with omphalocele (Van Den Eeden, 1990; Shiono, 1986), although one investigation noted increased risk of omphalocele/gastroschisis with maternal smoking (Honein, 2001).  One investigation found no association between maternal use of the antibiotic oxytetracycline during pregnancy and omphalocele/gastroschisis (Czeizel and Rockenbauer, 2000).  Case reports have suggested increased risk of omphalocele with misoprostol, a synthetic prostaglandin used for elective termination; however, a case-control study failed to verify this association (Orioli and Castilla, 2000).  Recent  investigations found no relationship between cephalosporin antibiotics, nalidixic acid, ampicillin, or the benzodiazepines nitrazepam, medazepam, tofisopam, alprazolum, and clonazepam and omphalocele or gastroschisis (Eros, 2002; Czeizel, 2001a; Czeizel, 2001b; Czeizel, 2001c). Research that examined co-trimoxazole, a combination of trimethoprim and sulfamethoxazole t, failed to find any association between the medication and abdominal wall defects (Czeizel, 1990).

Maternal periconceptional consumption of multivitamins may reduce risk of omphalocele (Botto, 2002a; Mulinare, 1995).  Moreover, another investigation reported increased risk of omphalocele with maternal fever and no multivitamin use; however, risk was reduced with when women who had febrile illness also took multivitamins (Botto, 2002b). While one investigation found no association between maternal folic acid use and abdominal wall defects (Czeizel, 1996), there is evidence that certain mutations of a folate-related gene (MTHFR) in infants increases their likelihood of having omphalocele (Mills 2005). A three-fold increase of odds of having a child with omphalocele was observed among mothers who reported taking selective serotonin reuptake inhibitors (SSRI antidepressants) (Alwan 2007), but Kallen did not find any higher risk for abdominal wall defects (Kallen 2007).

Birth prevalence for omphalocele in Texas among 1999-2003 deliveries was 2.17 cases per 10,000 live births (Texas Department of State Health Services 2006). Birth prevalence in the United States is 2.09 per 10,000 live births (Canfield 2006).

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Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations.  It summarizes literature about risk factors associated with this defect.  The strengths and limitations of each reference were not critically examined prior to inclusion in this report.  Consumers and professionals using this information are advised to consult the references given for more in-depth information. This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health.  Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.