Environmental Causes

[Summary] ((Beate Ritz, Fei Yu, Scott Fruin, Guadalupe Chapa, Gary M. Shaw and John A. Harris. Ambient Air Pollution and Risk of Birth Defects in Southern California American Journal of Epidemiology Vol. 155, No. 1 : 17-25, January 2002. See also: http://aje.oupjournals.org/cgi/content/abstract/155/1/17 AND http://www.niehs.nih.gov/centers/2002News/news2.htm [verified 22 March 2007]))
The authors of this study evaluated the effect of air pollution on the occurrence of birth defects ascertained by the California Birth Defects Monitoring Program in neonates and fetuses delivered in southern California in 1987‚­1993. By using measurements from ambient monitoring stations of carbon monoxide (CO), nitrogen dioxide, ozone, and particulate matter <10‚ µm in aerodynamic diameter, they calculated average monthly exposure estimates for each pregnancy. Conventional, polytomous, and hierarchical logistic regression was used to estimate odds ratios for subgroups of cardiac and orofacial defects. Odds ratios for cardiac ventricular septal defects increased in a doseresponse fashion with increasing second-month CO exposure. Similarly, risks for aortic artery and valve defects, pulmonary artery and valve anomalies, and conotruncal defects increased with second-month ozone exposure. The study was inconclusive for other air pollutants.

None of the four pollutants measured had a significant or dose-related effect on the risk of orofacial cleft defects. To quote from the report, “when exposure quartiles were used, first-month carbon monoxide exposure exhibited some effects on both isolated cleft types but lacked a doseresponse pattern for cleft palate, and effects were not observed consistently in single- and multiple-pollutant models. No other pollutant showed a consistent effect on isolated orofacial clefts.”

This is the first known study to link ambient air pollution during a vulnerable window of development to human malformations. The study concluded that confirmation by further studies is needed.

[Abstract] ((Allen J Wilcox et al. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 2007;334:464 (3 March). Available online http://www.bmj.com [verified 27 May 2007] SEE ALSO irishhealth.com))
Objective: To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts.
Design: National population based case-control study.
Setting: Infants born 1996-2001 in Norway.
Participants: 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls.
Main outcome measures: Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet.

Results: Folic acid supplementation during early pregnancy (400‚µg/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03).

Conclusions: Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.

[Abstract] ((Mahsa M. Yazdy, Margaret A. Honein, Jian Xing. Reduction in orofacial clefts following folic acid fortification of the U.S. grain supply. Birth Defects Research Part A: Clinical and Molecular Teratology, January 2007, 79 (1): 16-23. Published Online: 19 Dec 2006. Available at: http://www3.interscience.wiley.com/cgi-bin/jissue/114039049 [accessed 28 May 2007]))

BACKGROUND:
Folic acid fortification in the United States became mandatory January 1, 1998, to reduce the occurrence of neural tube defects (NTDs). We evaluated the impact of folic acid fortification on orofacial clefts using United States birth certificate data for 45 states and the District of Columbia.

METHODS:
Prevalence ratios (PRs) were calculated comparing orofacial cleft prevalence among births prefortification (1/1990-12/1996) and postfortification (10/1998-12/2002), based on fortification status at conception. The JoinPoint Regression Program and exponentially weighted moving average charts (EWMA) were used to assess the timing of any statistically significant changes in prevalence. Data were stratified by maternal race/ethnicity, age, smoking, and timing of prenatal care.

RESULTS:
Orofacial clefts declined following folic acid fortification (PR = 0.94; 95% CI: 0.92-0.96). The EWMA chart flagged a significant decrease in the fourth quarter of 1998. The JoinPoint graph had one change in slope, with a significant quarterly percent change (-0.34) between 1996 and 2002. The decline in orofacial clefts occurred in non-Hispanic Whites but not other racial/ethnic groups, nonsmokers but not women who reported smoking during pregnancy, and women who received prenatal care in the first trimester but not women who began receiving care later in pregnancy.

CONCLUSION:
Folic acid fortification in the United States was associated with a small decrease in orofacial cleft prevalence, with the timing of the decline consistent with the introduction of fortification. The decline is much smaller than that observed for NTDs, but nonetheless suggests an additional benefit of this public health intervention.

Extracts:
Orofacial clefts were reported on the birth certificates of 85.2 per 100,000 births during the period before folic acid fortification (1990-1996). This prevalence dropped to 80.2 per 100,000 births after folic acid fortification became mandatory (October 1998-December 2002) in the United States.

Women who reported smoking during pregnancy had a higher prevalence of infants with orofacial clefts than did women who did not report smoking during pregnancy both before fortification (119.0 vs. 82.2 per 100,000 live births) and after fortification (125.3 vs. 78.3 per 100,000 live births). Comparing data before and after folic acid fortification, the prevalence of orofacial clefts increased among infants whose mothers smoked during pregnancy, and declined significantly among infants whose mothers reported no use of tobacco during pregnancy.

Date: July 22, 1997 ((Mills, J., Simpson, J., Cunningham, G., et al., Vitamin A and birth defects. American Journal of Obstetrics and Gynecology, 1997 177 (1): 31-36. News release available at http://www.nichd.nih.gov/new/releases/vitama.cfm [verified 22 March 2007]))

Taking daily doses of 8-10,000 IU of vitamin A during pregnancy does not appear to cause birth defects, according to a study by the National Institute of Child Health and Human Development (NICHD) (chief investigator James Mills). The study also showed that it is very rare for women to take more than 10,000 IU of vitamin A each day. Dr. Mills added to the report that because few of the women in the study took large doses of vitamin A (more than 25,000 IU) it was not possible to ascertain whether large doses of the vitamin could cause birth defects.

The study compared 935 women pregnant with a child having a birth defect to 573 women pregnant with babies with no birth defect. 387 women in the former group were pregnant with a child having a cranial neural crest defect, a major class of birth defect resulting in cleft palate, facial abnormalities and heart valve abnormalities.

The study was carried out at Northwestern University in Chicago, Illinois, and at the California Public Health Foundation in Berkeley2 and appeared in the July, 1997 issue of the American Journal of Obstetrics and Gynecology.

Date: November 1995
[Summary] ((Rothman, Kenneth J., Moore, Lynn L., Singer, Martha R., et al., Teratogenicity of High Vitamin A Intake. The New England Journal of Medicine, November 23, 1995, 333 (21): 1369-73. Abstract available at http://content.nejm.org/content/vol333/issue21/index.shtml [verified 22 March 2007] Summary available at http://www.journalclub.org/vol1/a2.html [verified 22 March 2007]))
A study of 22,748 pregnant women in the United States, published in the New England Journal of Medicine, November 1995, indicated that women who take more than 10,000 IUs of vitamin A run more than twice (2.4) the risk of giving birth to a baby with a birth defect (including cleft lip, cleft palate, heart disease) as do women taking a daily dosage of 5,000 IUs. Women taking 20,000 IUs were four times more likely to give birth to children with birth defects. Another interpretation on these figures was that 56 of 57 babies born to women consuming large amounts of vitamin A had no birth defects. The increased frequency of defects was concentrated among the babies born to women who had consumed high levels of vitamin A before the 7th week of gestation.

The study recommended that pregnant women either limit their daily consumption of vitamin A to 4-8,000 IUs, or alternatively, take beta-carotene. Beta-carotene is thought not to cause birth defects, as high beta-carotene intake does not elevate vitamin A levels in the body enough to pose a problem with respect to birth defects. The body only converts beta-carotene to vitamin A as needed.

The study was conducted by the Boston University School of Medicine between October 1984 and June 1987. Of the 22,748 women, 339 had birth defects; 121 of these babies had defects originating in the cranial neural crest, one of these defects being cleft palate.

Proviso: There was much criticism of this report, generally to the effect that the risk of vitamin A overdose was overstated. Only 1.4% of the women in the study took supplements exceeding 10,000 IU a day.

[Summary] ((Birth Defects & Hazardous Waste Sites. The California Birth Defects Monitoring Program April 1999 3pp. Reference: http://www.cbdmp.org/ef_waste.htm [accessed 22 March 2007]))
The US in 1999 had over 1400 Superfund sites‚ hazardous waste sites included on the Environmental Protection Agency‚ National Priority List for cleanup. Does living near one raise the risk for birth defects?

In this large study by the California Birth Defects Monitoring Program, interviews were conducted with mothers of babies with 3 common birth defects as well as mothers of healthy infants‚ cover 2000 women in all. Interviews were conducted with mothers of 201 infants with conotruncal heart defects (84% of those identified), 439 mothers of infants with cleft lip and/or cleft palate (82% of those identified), and mothers of 455 infants without birth defects (72% of those identified). Subjects were drawn from more than 344,000 births from January 1987 to December 1988.

Only 0.6% of the mothers interviewed lived within 1/4 mile of a Superfund site during early pregnancy. About half of these women lived on military bases. Consequently, hazardous waste sites were a possible factor in only a small number of birth defects cases: 8 of the 507 babies with neural tube defects and 3 of the 201 babies with heart defects were born to mothers living within 1/4 mile of Superfund sites.

However,the study did draw the conclusion that women who lived within 1/4 mile of a Superfund site during the first 3 months of pregnancy had a greater risk of having babies with certain birth defects (contruncal heart defects – four times as likely; neural tube defects – 2 times as likely). Cleft lip and cleft palate occurred no more frequently than expected (quote) amongst those resident within 1/4 mile of a site.

Women who lived farther than 1/4 mile from sites were not at higher risk.

The very small number of cases around hazardous waste sites means the findings do not have strong statistical power. However, they do support earlier research hinting at higher risk.

[Original Abstract] ((L. Park-Wyllie et al. Faculty of Pharmacy, University of Toronto, Toronto, Canada. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology, 62(6):385-92, December 2000))
BACKGROUND: Corticosteroids are first-line drugs for the treatment of a variety of conditions in women of childbearing age. Information regarding human pregnancy outcome with corticosteroids is limited.

METHODS: Evidence was collected prospectively and 184 women exposed to prednisone in pregnancy and 188 pregnant women who were counseled by Motherisk for nonteratogenic exposure were followed up. The primary outcome was the rate of major birth defects. A meta-analysis of all epidemiological studies was conducted. The Mantel-Haenszel summary odds ratio was calculated for the pooled studies with 95% confidence intervals. A cumulative summary odds ratio was also calculated by combining studies in chronological order. Chi-squared for homogeneity was determined to establish the comparability of the studies.

RESULTS: In this prospective study, there was no statistical difference in the rate of major anomalies between the corticosteroid-exposed and control groups. In the meta-analysis, the Mantel-Haenszel summary odds ratio for major malformations with all cohort studies was 1.45 [95% CI 0.80, 2.60] and 3.03 [95% CI 1.08, 8. 54] when Heinonen et al. (’77) was removed. This suggests a marginally increased risk of major malformations after first-trimester exposure to corticosteroids. In addition, summary odds ratio for case-control studies examining oral clefts was significant (3.35 [95% CI 1.97, 5.69]).

CONCLUSIONS: Although prednisone does not represent a major teratogenic risk in humans at therapeutic doses, it does increase by an order of 3.4-fold the risk of oral cleft, which is consistent with the existing animal studies.

[Original Abstract] ((Carmichael SL, Shaw GM. March of Dimes/California Birth Defects Monitoring Program. Maternal corticosteroid use and risk of selected congenital anomalies. American Journal of Medical Genetics. 1999 Sep 17;86(3):242-4. Abstract available at http://www3.interscience.wiley.com/cgi-bin/abstract/64000732/ABSTRACT [verified 22 March 2007]))
Evidence for the teratogenicity of corticosteroids in humans is limited and has resulted in inconsistent recommendations regarding their use during early pregnancy. This study examined the association between women’s corticosteroid use during the periconceptional period (1 month before to 3 months after conception) and delivering infants with selected congenital anomalies.

Data were derived from a population-based case-control study that included cases of orafacial clefts (n = 662), conotruncal heart defects (n = 207), neural tube defects (n = 265), and limb reduction defects (n = 165). Information on medication use was collected via maternal telephone interviews.

Corticosteroid use was associated with an increased risk for isolated cleft lip with or without cleft palate (odds ratio 4.3, 95% confidence interval 1.1-17.2) and isolated cleft palate (odds ratio 5.3, 95% confidence interval 1.1-26.5). Increased risks were not observed for the other anomaly groups studied.

These data in conjunction with other epidemiologic data suggest a possible causal association between cleft lip and palate and corticosteroid use.

[Summary from: American Family Physician, May 15, 1999 http://www.aafp.org/afp/] ((Kallen B, et al. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol March 1999;93:392-5))
Asthma is relatively common in pregnant women, but use of asthma medications in early pregnancy raises concerns about birth defects. Systemic glucocorticoids, such as budesonide and other inhaled steroids, have been linked to cleft lip and cleft palate in animal studies. In the United States, these steroids are classified as category C agents, indicating a teratogenic risk in animals and insufficient data in humans. Kallen and colleagues (Ref.) evaluated data on births in Sweden to identify an association between inhaled budesonide and congenital malformations.

Medical records of women who used inhaled budesonide during early pregnancy were identified from the Swedish Medical Birth Registry database. Information on possible congenital malformations in infants was obtained from coding information recorded at birth and from the Registry of Congenital Malformations. Data from these two sources were thought to identify 80 to 90 percent of all infants with severe malformations. A total of 2,014 infants of women who had used budesonide in early pregnancy were identified. Most of the women (1,675) had also used other asthma medications. Seventy-five infants in the study group (3.8 percent) had severe congenital malformations, compared with 3.5 percent of infants in the general population. About one half of these infants had major structural defects, such as facial clefts and cardiac defects, and the rest had what are considered mild anomalies.

Overall, the incidence of birth defects in the study group was similar to that of the general population. The authors conclude that use of inhaled budesonide in early pregnancy is unlikely to be associated with a significant teratogenic risk.
[ANNE D. WALLING]

[Summary] ((Summary by David Derbyshire, Medical Correspondent, Daily Telegraph newspaper. Filed: 11/04/2002. Source: http://www.telegraph.co.uk/))

Women who take drugs for epilepsy while pregnant may be trebling the risks of birth defects and learning difficulties in their unborn babies. A study has shown that a range of health problems, including hernias, cleft palates, heart defects and autism, are higher if women take some of the most common treatments for controlling seizures. But the authors of the paper (SEE Abstract below) warned that giving up drugs for epilepsy “was not an option”. Several women die every year because they stop taking epilepsy medication while pregnant. One in 200 pregnant women in Britain are given epilepsy drugs.

According to the study, published in the Journal of Medical Genetics, the drugs increased the number of defects or learning difficulties from about 2.5 per cent to nearly 10 per cent. Congenital malformations, particularly hernias, but also hip dislocation, heart disease, cleft palate and abnormal genital development, were three times as common among the children whose mothers had taken anti-epileptic treatment during pregnancy. Almost one in five had developmental or speech delays, more than five times the rate among children not exposed to the drugs. Woman with epilepsy are advised to seek counselling and consider moving to safer drugs before they become pregnant.

J C S Dean, H Hailey, S J Moore, D J Lloyd, P D Turnpenny and J Little

[Abstract] (( C S Dean et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. Journal of Medical Genetics 2002;39:251-259 [http://jmg.bmjjournals.com/cgi/content/abstract/39/4/251]))
Objective: To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero.

Design: Retrospective population based study.

Setting: Population of the Grampian region of Scotland.

Participants: Mothers taking antiepileptic drugs in pregnancy between 1976 and 2000 were ascertained from hospital obstetric records and 149 (58% of those eligible) took part. They had 293 children whose health and neurodevelopment were assessed.

Main outcome measures: Frequencies of neonatal withdrawal, congenital malformations, childhood onset medical problems, developmental delay, and behaviour disorders.

Results: Neonatal withdrawal was seen in 20% of those exposed to antiepileptic drugs. Congenital malformations occurred in 14% of exposed pregnancies, compared with 5% of non-exposed sibs, and developmental delay in 24% of exposed children, compared with 11% of non-exposed sibs. After excluding cases with a family history of developmental delay, 19% of exposed children and 3% of non-exposed sibs had developmental delay, 31% of exposed children had either major malformations or developmental delay, 52% of exposed children had facial dysmorphism compared with 25% of those not exposed, 31% of exposed children had childhood medical problems (13% of non-exposed sibs), and 20% had behaviour disorders (5% of non-exposed).

Conclusion: Prenatal antiepileptic drug exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformation.

[Summary] ((California Birth Defects Monitoring Program Funded through the California Departemnt of Health Services and jointly administered with the March of Dimes Birth Defects Foundation. http://www.cbdmp.org/ef_stress.htm [verified 22 March 2007]))
Stressful Life Events and Birth Defects: Women who experience at least one stressful event, such as divorce, death of someone very close, or job loss, are more likely to have a baby with isolated cleft lip and palate, spinal defects, and certain heart defects.

This report indicated that stressful life events were 30% to 50% more common among mothers whose babies had any of the birth defects studied: serious heart defects, neural tube defects, oral clefts, and limb defects.

The Report does state however that while stressful life events are common, the vast majority of women who experience these events deliver babies without birth defects.

Date: April 2001

[Summary] ((Original article: Shaw, Gary M., et al. “Maternal Periconceptional Alcohol Consumption and Risk for Orofacial Clefts”. The Journal of Pediatrics, 1999, 134(3), pp.293-303. http://www.ncemch.org/alert/alert051499.htm National Center for Education in Maternal and Child Health, Arlington, Virginia [verified 22 March 2007]))
Women who consume higher quantities of alcohol before and during early pregnancy show an increased risk for having babies with orofacial clefts, according to a study published in the March 1999 issue of The Journal of Pediatrics.

Women who consumed five or more drinks at least once a week were about four times more likely to have a baby with a cleft lip or palate than were non-drinkers.

There appeared to be no discernable difference in the risk factor between women who drank less than this amount and non-drinking women.

The study was carried out in California and involved telephone interviews with 731 mothers of babies born with cleft lip or palate and 734 mothers of babies born with no malformation.

[Abstract] ((C Lorente et al. Tobacco and alcohol use during pregnancy and risk of oral clefts. Occupational Exposure and Congenital Malformation Working Group American Journal of Public Health 2000, 90(3):415-419))
OBJECTIVES: This study examined the relationship between maternal tobacco and alcohol consumption during the first trimester of pregnancy and oral clefts.

METHODS: Data were derived from a European multicenter case-control study including 161 infants with oral clefts and 1134 control infants.

RESULTS: Multivariate analyses showed an increased risk of cleft lip with or without cleft palate associated with smoking (odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.07, 3.04) and an increased risk of cleft palate associated with alcohol consumption (OR = 2.28, 95% CI = 1.02, 5.09). The former risk increased with the number of cigarettes smoked.

CONCLUSIONS: This study provides further evidence of the possible role of prevalent environmental exposures such as tobacco and alcohol in the etiology of oral clefts.

[Abstract] ((Munger RG et al. Maternal alcohol use and risk of orofacial cleft birth defects. Teratology July 1996, 54(1):27-33))
Maternal alcohol use during pregnancy is a known cause of birth defects associated with the fetal alcohol syndrome, but its role in more common, isolated, craniofacial birth defects is not well understood.

A population-based, case-control study of orofacial clefts was conducted in Iowa using births during 1987-1991. Cases were identified by the Iowa Birth Defects Registry and classified as having a cleft lip with or without cleft palate (CLP) or cleft palate only (CP) and whether the cleft was isolated or occurred with other birth defects. Controls were selected from normal Iowa births.

Maternal alcohol use during pregnancy was classified according to self-reported drinks consumed per month. Results are based on 302 controls and the following numbers in each case group: 118 isolated CLP, 56 isolated CP, 51 CLP with multiple defects, and 62 CP with multiple defects.

Compared to women who did not drink alcohol during pregnancy, the relative odds of isolated CLP rose with increasing level of maternal drinking as follows: 1-3 drinks per months, 1.5; 4-10 drinks per month, 3.1; more than 10 drinks per month, 4.7 (chi-square test for trend, P = 0.003). Adjustment for maternal smoking, vitamin use, education, and household income did not substantially alter these results.

RESULT: No significant association was found between alcohol use and isolated cleft palate or clefts in children with multiple birth defects. Alcohol use during pregnancy may be a cause of isolated cleft lip with or without cleft palate.

Date: March 6, 2000
[Summary] ((Chung, K. C. et al. (2000) Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plastic and Reconstructive Surgery, February, 105(2):485-91. Abstract available from PubMed at http://www.ncbi.nlm.nih.gov [Do keyword search using title words]))
According to a study published in Plastic and Reconstructive Surgery [February, 2000], the official medical journal of the American Society of Plastic Surgeons, mothers who smoke during pregnancy run a greater risk of having a baby with cleft lip or palate.

Comparisions were made between 2,207 live births with cleft lips or palates and 4,414 controls without any congenital abnormality. Women who smoked 1 to 10 cigarettes a day saw a risk increase of 50%; smoking between 11 to 20 cigarettes a day increased the risk by 55%; and smoking more than 21 cigarettes a day saw this figure rise to 78%.

The study utilized data from the National Center for Health Statistics 1996 Natality Database of Details on 3,891,494 live births.

[Abstract] ((Shaw GM et al. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. American Journal of Human Genetics March 199, 58(3):551-61))
Results of studies to determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting.

Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa.

We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked > or =20 cigarettes/d. Analyses controlling for the potential influence of other variables did not reveal substantially different results. Clefting risks were even greater for infants with the TGFa allele previously associated with clefting whose mothers smoked > or =20 cigarettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups.

Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks.

This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele.