More on NTDs in Texas.
Neural tube defects (NTDs) are a group of birth defects presumed to have a common origin in failure of the neural tube to develop properly during the embryonic stage. NTDs are comprised mainly of anencephaly (including craniorachischisis), spina bifida (including meningomyelocele, meningocele, and myelocele), and encephalocele. Anencephaly involves absence of the skull, with the cerebral hemispheres completely missing or reduced to small masses attached to the base of the skull. Spina bifida (which includes myelomeningocele and meningomyelocele) is defective closure of the bony encasement of the spinal cord, through which the cord and meninges may or may not protrude. Encephalocele is protrusion of some or all of the brain through a defect in the skull.
Approximately 10% or less of NTDs are associated with chromosomal abnormalities (O'Reilly and Shields, 2000). The most common types of chromosomal abnormalities include trisomy 18, trisomy 13, trisomy 21, triploidy, and Turner syndrome.
Over the last several decades, women carrying a fetus with an open NTD have been found to have elevated maternal serum levels of alpha-fetoprotein and reduced levels of human chorionic gonadotropin and unconjugated estriol (Canick and Saller, 1993). Prenatal screening of these substances, along with ultrasonography (Vintzileos et al., 1987), have allowed neural tube defects (NTDs) 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 NTDs, with the reduction being greater for anencephaly than for spina bifida (Boyd et al., 2000; Owen et al., 2000; Whiteman et al., 2000; Hendricks et al., 1999; Forrester and Merz, 2000a; Riley et al., 1998; Alembik et al., 1997; Velie and Shaw, 1996; Alembik et al., 1995; CDC, 1995; Roberts et al., 1995; Stoll and EUROCAT Working Group, 1995; Stoll et al., 1995; Julian-Reynier et al., 1994; Bower et al., 1993; Stoll et al., 1992; EUROCAT Working Group, 1991).
IMPACT OF RISK FACTORS
Some studies suggest that certain risk factors appear to have greater impact among populations with higher background rates for NTDs than among populations with lower background rates (Little and Elwood, 1991). Also, the etiology of NTDs is very heterogeneic, with the impact of a given risk factor varying by the types of NTD and the presence or absence of other defects (Holmes et al., 1976; Khoury et al., 1982; Sever, 1995). The neural tube closes by approximately the 28th day of gestation (Campbell et al., 1986; Lemire, 1988), so any potential exposures suspected to have caused an NTD would have to have occurred within the first month of gestation.
DEMOGRAPHIC AND REPRODUCTIVE
There are racial/ethnic differences in risk for NTDs. In the United States, NTD prevalence has been reported to be highest among Hispanics, followed in descending order by non-Hispanic whites, Native Americans, African-Americans, and Asians (Owen et al., 2000; Hendricks et al., 1999; Canfield et al., 1996a; Shaw et al., 1994; CDC, 1992; Chavez et al., 1988). One investigation observed no significant difference in risk of anencephaly and spina bifida in infants born to Vietnamese women compared with infants born to non-Hispanic white women in California (Shaw et al., 2002a). Another study reported no significant difference in NTD rates among whites, Far East Asians, Pacific Islanders, and Filipinos (Forrester and Merz, 2000b). Differences in racial/ethnic rates may be due to differences in genetic susceptibility to NTDs, cultural behaviors, diet, or other factors.
Secular trends have been observed in NTD prevalence since the 1970s. Overall, rates for anencephaly and spina bifida have declined in North America, Europe, Australia, and New Zealand (McDonnell et al., 1999; CDC, 1992; Yen et al., 1992; Little and Elwood, 1991; Campbell et al., 1986), although one study reported an increase in NTD rates in the 1980's-1990's (Forrester and Merz, 2000b). The proportion of NTDs that were electively terminated increased with time in some regions studied (Whiteman et al., 2000; CDC, 1995; Bower et al., 1993; EUROCAT Working Group, 1991). Thus, some of this decline in NTD prevalence may be attributable to increased prenatal diagnosis and elective termination of NTD-affected pregnancies. However, this trend was observed prior to the widespread use of prenatal diagnosis and has occurred in areas where elective termination is not allowed.
Prevalence of NTDs shows wide variation by geographic location, both within and between countries. Also, the distribution of the types of NTDs can vary between regions (Forrester and Merz, 2000b). Berry et al., 1999; Hendricks et al., 1999; Moore et al., 1997; Little and Elwood, 1991). NTD rates in the United States and Canada have shown a decrease from east to west (Little and Elwood, 1991; Campbell et al., 1986). Anencephaly prevalence is generally lower in continental Europe than in the British Isles, and shows a decrease from west to east. NTD rates in Australia and New Zealand are similar to those reported for North America and continental Europe (Little and Elwood, 1991). Rates of anencephaly in Asia have been reported to be comparable to those of other regions outside the British Isles, while spina bifida prevalence was lower in Asia than elsewhere (Little and Elwood, 1991). However, NTD prevalence in northern China has been reported to be among the highest in the world (Moore et al., 1997). Some of these reported differences in geographical location prevalence may be due to differences in racial/ethnic compositions of the populations.
One investigation found risk of anencephaly and spina bifida, but not encephalocele, to be higher with lower altitude (Castilla et al., 1999).
Seasonal variations in NTD rates have been reported by some studies but not others (Castilla et al., 1990; Bound et al., 1989).
A number of studies have reported maternal age risk for NTDs to be U-shaped, i.e., highest among youngest and oldest women, while other studies have found risk to decrease with increasing age or the reverse (Owen et al., 2000; Hendricks et al., 1999; McDonnell et al., 1999; Little and Elwood, 1991; Campbell et al., 1986), or clear maternal age trend (Forrester and Merz, 2000b). Paternal age has not been clearly linked to NTD risk (Shaw et al., 1994; Little and Elwood, 1991), although one investigation identified increased NTD risk with lowest and highest paternal age groups (McIntosh et al., 1995).
Parity has shown either a U-shaped pattern of NTD risk, i.e., risk being higher for the lowest and highest number of births (Little and Elwood, 1991; Campbell et al., 1986) or increasing risk with increasing parity (Owen et al., 2000; Whiteman et al., 2000).
NTD risk seems to be greater if a woman has had a previous fetal or infant death, even if the previous infant or fetus did not have an NTD (Owen et al., 2000; Whiteman et al., 2000; Canfield et al., 1996b; Little and Elwood, 1991; Myrianthopoulos and Melnick, 1987). However, it is not clear to what extent recall bias or an undiagnosed NTD in the previous fetal death may contribute to this observation (Little and Elwood, 1991). Moreover, not all investigations have reported this association (Todoroff and Shaw, 2000). Studies examining a potential link between the length of time between pregnancies and NTD risk have also found mixed results (Todoroff and Shaw, 2000). NTD risk does not appear to be related to subfertility (Whiteman et al., 2000).
NTD rates may also be higher among multiple births and with lower birth weight (Owen et al., 2000; Whiteman et al., 2000; Mastroiacovo et al., 1999; Riley et al., 1998; Doyle et al., 1991; Mili et al., 1991; Ramos-Arroyo, 1991) and lower gestational age at delivery (Rasmussen et al., 2001; Shaw et al., 2001a). However, one study reported no relationship between NTD risk and plurality (Kalen, 1986). NTDs have also been associated with intrauterine growth retardation (Khoury et al., 1988). One investigation reported increased risk of encephalocele but not anencephaly or spina bifida with macrosomia (Waller et al., 2001), while another found no association between large for gestational age and anencephaly, spina bifida, or encephalocele (Lapunzina et al., 2002).
Infant sex influences the risk for NTDs. Females are more likely than males to have anencephaly and spina bifida, with the difference greater for the latter defect. This preponderance among females appears to be influenced by the presence of additional birth defects, geographical area, and other factors (Lary and Paulozzi, 2001; Forrester and Merz, 2000b; Whiteman et al., 2000; McDonnell et al., 1999; Hendricks et al., 1999; Berry et al., 1999; Riley et al., 1998; Canfield et al., 1996a; Little and Elwood, 1991). Potential explanations for the preponderance among females include differences between the sexes in embryonic development, susceptibility to teratogenic insult, and spontaneous abortion rates (Little and Elwood, 1991).
The recurrence risk for NTDs is approximately 3-4%, with the risk being slightly higher if the prior infant or fetus had anencephaly (Little and Elwood, 1991). However, 95% of infants with NTDs are born to parents with no family history of the defect. With respect to consanguinity, NTD rates have been found to be higher when the parents are related (Little and Elwood, 1991), although not all studies identified this association (Rittler et al., 2001; Stoltenberg et al., 1997).
FACTORS IN LIFESTYLE OR ENVIRONMENT
Various studies have suggested that NTD risk is higher among families of lower socioeconomic status, although other studies failed to support this (Vrijheid et al., 2000; Wasserman et al., 1998; Little and Elwood, 1991).
Hyperthermia, due to fever or use of saunas and hot tubs, has been linked to increased risk of NTDs, particularly spina bifida, although the results are not consistent (Shaw et al., 1998; Lynberg et al., 1994; Milunsky et al., 1992; Little and Elwood, 1991). Several studies (Shaw et al., 1999a; Dlugosz et al., 1992) found that periconceptional use of electric bed-heating devices (electric blankets, bed warmers, and heated waterbeds) did not appear to affect risk for NTDs.
Women with diabetes are at increased risk for having an infant with a birth defect. The results of several studies suggest that this increased risk applies to NTDs in particular (Janssen et al., 1996; Ramos-Arroyo et al., 1992; Little and Elwood, 1991; Becerra et al., 1990; Myrianthopoulos and Melnick, 1987), although other studies reported no association between maternal diabetes and NTDs (Aberg et al., 2001). Maternal common cold in the first trimester of pregnancy has been reported to increase risk of anencephaly and spina bifida (Zhang and Cai, 1993). Hypothyroidism does not appear to be associated with NTDs, although risk of encephalocele but not spina bifida or anencephaly may be increased with hyperthyroidism (Khoury et al., 1989).
Maternal weight has been associated with NTD risk. Obesity has been linked to increased NTD rates (Kalen, 1998; Shaw et al., 1996; Watkins et al., 1996; Werler et al., 1996; Waller et al., 1994). However, a more recent study failed to find any association between maternal weight and NTD risk (Feldman et al., 1999). The authors of the latter study have suggested that the earlier studies may have suffered from bias in recording of maternal weight or selection of controls. One investigation identified increased risk of NTDs with maternal hyperinsulinemia and suggested that this association may at least partially account for the observed association between maternal obesity and NTD risk (Hendricks et al., 2001). Another study reported higher NTD rates among women who gained less weight during pregnancy (Shaw et al., 2001b). Since weight gain during early pregnancy, the time when NTDs occur, is small and is not consistent, it is not likely that low weight gain is causal for NTDs. More likely, carrying an NTD-affected fetus caused low weight gain throughout the pregnancy, or both conditions are the consequence of a common factor.
Maternal psychosocial or emotional stress during pregnancy may increase risk of having an infant with an NTD (Carmichael and Shaw, 2000).
Epilepsy, and valproic acid and carbamazepine, medications used to treat epilepsy, have been found to increase risk of spina bifida (Arpino et al., 2000; Owen et al., 2000; Lindhout and Omtzigt, 1994; Little and Elwood, 1991). Risk of spina bifida may be related to dosage and to antiepileptic medications used in combination (Lindhout and Omtzigt, 1994). The relationship between maternal smoking and NTD prevalence is unclear (Wasserman et al., 1996; Little and Elwood, 1991; Van Den Eeden et al., 1990; Ericson et al., 1988). One study found not link between paternal smoking and NTD risk (Wasserman et al., 1996).
Increased NTD prevalence has not been associated with maternal infection (Little and Elwood, 1991), alcohol (Little and Elwood, 1991), caffeine (Rosenberg et al., 1982), vitamin A (Mills et al., 1997; Shaw et al., 1997), oral contraceptives (Little and Elwood, 1991), contraceptive spermicides (Louik et al., 1987), ovulation-inducing drugs (Werler et al., 1994), subfertility treatments such as Clomiphene (Whiteman et al., 2000), cough medicines containing dextromethorphan (Martinez-Frias and Rodriguez-Pinilla, 2001), or illicit drugs (Little and Elwood, 1991). A recent study reported increased risk of spina bifida with maternal tea consumption (Correa et al., 2000). NTDs have been associated with maternal use of the antibiotic oxytetracycline but not cephalosporin antibiotics during pregnancy (Czeizel et al., 2001a; Czeizel and Rockenbauer, 2000). Recent studies reported no association between maternal use of nalidixic acid, used to treat bacterial infections, oral antituberculosis medications, or ampicillin and NTDs (Czeizel et al., 2001b; Czeizel et al., 2001c; Czeizel et al., 2001d). A case-control study failed to identify any association between encephalocele risk and misoprostol, a synthetic prostaglandin used for elective termination (Orioli and Castilla, 2000). Another investigation reported no relationship between maternal use of calcium channel blockers and NTDs (Sorensen et al., 2001). Maternal use of the benzodiazepines nitrazepam, medazepam, tofisopam, alprazolum, and clonazepam have not been associated with NTD risk (Eros et al., 2002).
Maternal occupation and maternal exposures have not been clearly or consistently linked to increased NTD risk (Little and Elwood, 1991). However, one study reported increased risk for women working in agricultural occupations or as cleaning women (Blatter et al., 1996). Another investigation identified higher risk of anencephaly and spina bifida with maternal nursing occupation (Matte et al., 1993). One study noted no significant association between NTDs and a variety of paternal occupations (Irgens et al., 2000).
NTD prevalence is increased among women who may have been exposed to glycol ethers (Cordier et al., 1997) and occupational radiation (Sever, 1995; Matte et al., 1993). The literature on the relationship between NTDs and anesthetic gases have reported conflicting results (Sylvester et al., 1994; Matte et al., 1993). Arsenic and lead have also been proposed as potential risk factors for NTDs (Irgens et al., 1998; Bound et al., 1997; Shalat et al., 1996). However, a recent investigation found no association between levels of lead in the water and NTD rates and suggested that previous associations may have been confounded by socioeconomic factors (Macdonell et al., 2000). Another investigation reported higher levels of lead in the amniotic fluid of NTD-affected pregnancies than in pregnancies without NTDs (Dawson et al., 1999). NTDs have not been positively associated with combined chemical exposures (Shaw et al., 2001c).
Paternal exposure to radiation, solvents, pesticides, and mercury, and paternal occupation as a painter have been tentatively linked to increased NTD risk (Sever, 1995), although other investigations reported no association between paternal exposure to pesticides and ionizing radiation and NTDs (Doyle et al., 2000; Shaw et al., 1999b). Several studies have reported increased risk of spina bifida as a result of paternal exposure to the herbicides (including Agent Orange) used in Vietnam (Wolfe et al., 1995; Erickson et al., 1984). Higher rates of spina bifida have also been reported from pesticide use by parental farmers (Kristensen et al., 1997). Increased risk of NTDs has also been reported for pesticides applied to homes (Shaw et al., 1999b).
Living in proximity to hazardous waste sites, landfill sites, and agricultural crops has been reported to increase NTD risk (Elliott et al., 2001; Shaw et al., 1999b; Dolk et al., 1998; Croen et al., 1997; Sever, 1995), as have drinking water contaminants such as disinfection byproducts (Klotz and Pyrch, 1999; Bove et al., 1995; Sever, 1995). However, not all studies reported an association between water disinfection byproducts or chlorination and NTDs (Jaakkola et al., 2001; Kallen and Robert, 2000; Doddes et al., 1999). A recent study found increased risk of anencephaly, but not spina bifida, with exposure to nitrate in drinking water but not in the diet (Croen et al., 2001). Another study reported an association between bromodichloromethane but not chloroform in drinking water and NTDs (Dodds and King, 2001). One investigation reported higher rates of anencephaly with proximity to textile industry, spina bifida with proximity to soap and detergents, iron and steel, machinery, photographic, and rubber industries, and encephalocele with proximity to fur dressing and dyeing industry (Castilla et al., 2000). Another study found increased risk of spina bifida with maternal occupational exposure to electromagnetic fields and increased risk of anencephaly with paternal occupational exposure to electromagnetic fields; however, exposure was based on linkage to census data and exposure assessments by an expert panel (Blaasaas et al., 2002).
Maternal periconceptional use of folic acid has been found to reduce the risk of both recurrent and occurrent NTDs (Locksmith and Diff, 1998; Watkins, 1998; Czeizel et al., 1996). This reduction occurs both in regions of high NTD rates and in regions of low NTD rates (Berry et al., 1999), although several studies have found reduction in risk to be more modest among Hispanics (Suarez et al., 2000; Shaw et al., 1995). This association between NTDs and folic acid is supported by research that has shown that folic acid antagonists, such as aminopterin, methotrexate, valproic acid, carbamazepine, and trimethoprim may increase NTD risk (Czeizel et al., 2001e; Hernandez-Diaz et al., 2001; Campbell et al., 1986). However, a study that examined co-trimoxazole, a combination of trimethoprim and sulfamethoxazole that is a folic acid antagonist, failed to find any association between the medication and NTDs (Czeizel, 1990). Also, thalassemia carriers frequently have low folate levels. One study found a higher NTD risk among thalassemia carriers (Lam and Tang, 1999). It is not known whether folic acid reduces risk of NTDs associated with antiepileptic medications (Lindhout and Omtzigt, 1994).
Exactly how folic acid prevents NTDs is not clear. Folic acid may not reduce NTD risk to the same degree in all racial/ethnic groups (Suarez et al., 2000; Shaw et al., 1995), suggesting that a genetic component may be involved. Recent investigations have suggested that the influence of folic acid use may relate to defects in homocysteine metabolism such as mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (De Marco et al., 2001; Martinez de Villarreal et al., 2001; Volcik et al., 2000; Finnell et al., 1998; Ou et al., 1996; Mills et al., 1995; van der Put et al., 1995; Whitehead; 1995). One study observed an association between reduced folate carrier protein (RFC) gene polymorphism and NTD risk (De Marco et al., 2001), while another study found no such association between the gene and spina bifida (Shaw et al., 2002b). A recent study (Velie and Shaw, 1999) has also suggested that periconceptional intake of zinc can reduce NTD risk, and another study reported methionine use decreases NTD risk (Shoob et al., 2000).
A recent investigation reported no association between mutations in the transcription factor gene ZIC2 and neural tube defects. However, the data did suggest a potential association between a histidine tract polymorphism in the gene and neural tube defects (Brown et al., 2002).
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