Maternal obesity, gestational diabetes, and central nervous system birth defects

BACKGROUND: Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects. METHODS: This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n=477) were mothers of offspring with anencephaly (n=120), spina bifida (n=184), holoprosencephaly (n=49), or isolated hydrocephaly (n=124). Controls (n=497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index > or =30.0 kg/m) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks. RESULTS: After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio=2.3; 95% confidence interval=1.2-4.3), spina bifida (2.8; 1.7-4.5), or isolated hydrocephaly (2.7; 1.5-5.0), but not holoprosencephaly (1.4; 0.5-3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale. CONCLUSIONS: Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.     

Birth rate among patients with epilepsy: a nationwide population-based cohort study in Finland

Few reports on population-based studies of birth rate among epilepsy patients have been published. In most previous studies, fertility has been lower among epilepsy patients than in the rest of the population. However, conflicting results have also been reported. Because of small samples and selective material, the generalizability of these results is also limited. The authors conducted a population-based cohort study of birth rate (1985-2001) in a nationwide Finnish cohort of patients with newly diagnosed epilepsy and a population-based reference cohort. All patients (n = 14,077) approved as eligible for reimbursement for antiepileptic medication from the Social Insurance Institution of Finland (KELA) for the first time between 1985 and 1994 were identified from the KELA database. A reference cohort (n = 29,828) was identified from the Finnish Population Register Center, with frequency-matching on age. Information on follow-up status and livebirths were also obtained from the Finnish Population Register Center. The birth rate was lower in patients with epilepsy than in the reference cohort among both men (hazard ratio = 0.58, 95% confidence interval: 0.54, 0.62) and women (hazard ratio = 0.88, 95% confidence interval: 0.83, 0.93). There were a clear decreasing trend by age at observation in men with epilepsy and a moderate decreasing trend by age at start of follow-up in women with epilepsy.     

Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations

This study was designed to assess the association between pregnancy-related exposures to antibiotics recommended for use in the event of a bioterrorism attack and major congenital malformations. A retrospective cohort study included 30 049 infants from Tennessee Medicaid born between 1985 and 2000 identified from computerised state databases. Infants with fetal exposures to ciprofloxacin, azithromycin, doxycycline and amoxicillin (antibiotics recommended for potential bioterrorism attacks) ( n  = 24 521) and erythromycin (included as a positive control) ( n  = 2128) were compared with infants with no fetal exposure to any antibiotics ( n  = 3400). Major congenital malformations identified from computerised records were confirmed through medical record review.
Overall, 869 (2.9%) of infants in the cohort had a confirmed major congenital malformation, with major malformations ranging from 2.5% to 3.0% among the antibiotic-specific exposure groups. No increased risk was present in multivariable analyses for any malformations and for malformations of specific organ systems. In conclusion, these data suggest that ciprofloxacin, azithromycin, doxycycline or amoxicillin use by pregnant women should not result in a greater incidence of overall major congenital malformations in infants whose mothers take these medications, though a large increase in risk cannot be ruled out.     

Adverse pregnancy outcomes around incinerators and crematoriums in Cumbria,north west England, 1956-93

STUDY OBJECTIVE: To investigate the risk of stillbirth, neonatal death, and lethal congenital anomaly among babies of mothers living close to incinerators and crematoriums in Cumbria, north west England, 1956-93. DESIGN: Retrospective cohort study. Logistic regression was used to investigate the risk of each outcome in relation to proximity at birth to incinerators and crematoriums, adjusting for social class, year of birth, birth order, and multiple births. Continuous odds ratios for trend with proximity to sites were estimated. SETTING: All 3234 stillbirths, 2663 neonatal deaths, and 1569 lethal congenital anomalies among the 244 758 births to mothers living in Cumbria, 1956-1993. Main results: After adjustment for social class, year of birth, birth order, and multiple births, there was an increased risk of lethal congenital anomaly, in particular spina bifida (odds ratio 1.17, 95% CI: 1.07 to 1.28) and heart defects (odds ratio 1.12, 95% CI: 1.03 to 1.22) around incinerators and an increased risk of stillbirth (odds ratio 1.04, 95% CI: 1.01 to 1.07) and anencephalus (odds ratio 1.05, 95% CI: 1.00 to 1.10) around crematoriums. CONCLUSIONS: The authors cannot infer a causal effect from the statistical associations reported in this study. However, as there are few published studies with which to compare our results, the risk of spina bifida, heart defects, stillbirth, and anencephalus in relation to proximity to incinerators and crematoriums should be investigated further, in particular because of the increased use of incineration as a method of waste disposal.     

Clusters of malformations in Sweden: A study with central registers

Clustering of malformations and especially of spina bifida in Sweden was studied using the Register of Malformations and the Medical Birth Records Register. The incentive to this study was provided by the observation of a cluster of malformations, notably spina bifida, and perinatal deaths, locally thought to be related to the use of herbicides in forestry. This cluster was verified but it was shown that a high rate of spina bifida existed in the region before the introduction of herbicides in forestry. Some other clusters of spina bifida were identified and also a number of clusters of other malformations. Case-history studies were performed but revealed no lead to an explanation. Principles in the origin of the clusters and their analysis are discussed.     

Ethnic differences in congenital malformations in the Netherlands: analyses of a 5-year birth cohort

Congenital malformations are among the major causes of perinatal mortality and morbidity at present. Research into the ethnic diversity of congenital malformations can form a basis both for aetiological studies and for health care advice and planning. This study compared the overall prevalence of congenital malformations, the prevalence in different organ systems and of several specific malformations between different maternal ethnic groups in the Netherlands using a 5-year national birth cohort (1996-2000) containing 881 800 births. Maternal ethnic groups considered were Dutch; Mediterranean (Moroccan/Turkish); other European; Black; Hindu and Asian. Mediterranean women had a 20% higher risk of having a child with a congenital malformation than Dutch women (age-adjusted OR = 1.21 [95% CI 1.16, 1.27]). They showed an increased risk of malformations in several organ systems such as the central nervous system and sensory organs, the urogenital system and skin and abdominal wall. Further, they had an increased risk of the group of chromosomal malformations/multiple malformations/syndromes. For the specific group of multiple malformations the maternal age adjusted OR was 1.80 [95% CI 1.47, 2.20]. The Black group showed a significantly increased risk of skeletal and muscular malformations (age adjusted OR = 1.76 [95% CI 1.53, 2.02]) with a sixfold increased risk of polydactyly compared with the Dutch group. For Mediterranean women, the largest and fastest growing group of immigrants in the Netherlands, this study demonstrated an increased risk of congenital malformations.     

Prenatal tea consumption and risks of anencephaly and spina bifida

PURPOSE: To evaluate the relationship between prenatal tea consumption and risk of anencephaly and spina bifida.METHODS: Data from the population-based Atlanta Birth Defects Case-Control Study were examined. Cases were infants with anencephaly (n = 122) or spina bifida (r = 154) and no other associated anomalies, and identified between 1968 and 1980. Controls were infants without birth defects (n = 3029) identified from birth certificates of the same birth cohort and frequency matched to cases by race, period of birth, and hospital of birth.RESULTS: Maternal tea consumption during the periconceptional period (3 months before through the first trimester of pregnancy) was reported at 82, 83.6, and 92.9% among controls, anencephaly, and spina bifida cases, respectively. With subjects whose mothers consumed no tea as a reference, odds ratios (OR) for tea consumption during the periconceptional period (adjusted for gender, race, period of birth, maternal age, education, alcohol consumption, smoking, and periconceptional multivitamins) were: anencephaly 0.9 (95% confidence limits (CI) 0.5-1.5); spina bifida 2.3 (CI 1.2-4.4). Odds ratios for spina bifida and number of cups of tea consumed/day were: 1-2 cups 2.1 (CI 1.1-4.0); 3+ cups 2.8 (CI 1.4-5.6). Consumption of other caffeinated beverages was not associated with risk for anencephaly or spina bifida.CONCLUSIONS: Further studies are warranted to corroborate and elucidate the observed association between tea consumption and spina bifida.     

Spina bifida and cleft lip among newborns of Norwegian women with epilepsy: changes related to the use of anticonvulsants.

OBJECTIVES: This study examined the connection between the use of anticonvulsants for epilepsy during or before pregnancy and the risk of spina bifida and cleft lip in newborns. METHODS: Among mothers registered from 1967 to 1992 by the Medical Birth Registry of Norway, 7588 who had epilepsy were identified and their newborns' prevalence of spina bifida and cleft lip examined. RESULTS: The odds ratio of spina bifida in children of mothers with epilepsy compared with other children increased from 1.5 in 1967 through 1980 (95% confidence interval [CI] = 0.3, 4.5) to 4.4 in 1981 through 1992 (95% CI = 2.0, 8.5). The odds ratio of cleft lip, however, decreased from 3.0 before 1981 (95% CI = 1.6, 5.1) to 1.1 after 1981 (95% CI = 0.4, 2.3). CONCLUSIONS: This shift toward more serious birth defects is consistent with the different teratogenic effects of newer and older anticonvulsants.     

Is diabetes mellitus a teratogen or a coteratogen?

The risk of major and minor congenital malformations was compared in the offspring of diabetic (n = 2,639) and nondiabetic (n = 2,144) women who delivered at the Johns Hopkins Hospital in Baltimore, Maryland, between January 1, 1946 and December 31, 1970. In spite of ample power, there was little evidence of an increased malformation risk in offspring born prior to the onset of overt diabetes in the mother. In offspring born after onset, the overall malformation risk was not increased, but severe multi-organ birth defects occurred at approximately twice the control group rate. It is postulated, therefore, that diabetes may act as a coteratogen enhancing the teratogenic effect of other insults but may not itself cause malformations. That some of its effects may be specific is suggested by the especially high risk of vertebral, lower limb, and urogenital defects, a pattern similar to that reported for the caudal dysgenesis syndrome. To better understand the teratogenic effects associated with diabetes, it may be necessary to consider interactions with other factors and to explore the association between maternal diabetes and caudal dysgenesis.     

Congenital malformations and death among the offspring of Danish pharmacy assistants

Congenital malformations, stillbirth, and infant mortality were studied in a cohort of all female pharmacy assistants in Denmark under the age of 40 years who were members of the national union in 1979 to 1984 (4,939). Data on all births and deaths during first year of life during the study period were identified through the national birth register. Information on type of work, exposures, and life-style variables were obtained by postal questionnaires, to which 93% responded. In general, pharmacy assistants had a low frequency of congenital malformation and death among their offspring. Compared with an internal reference group, pharmacy assistants engaged in production or packing of pharmaceutical products experienced an increased prevalence of congenital malformations among their offspring. Working with identification and controls showed a slightly increased risk of death during the first year of life of the children. This could indicate occupational risks, but other explanations cannot be excluded.     

Monthly and seasonal variations in the frequency of congenital anomalies

Three large and comparable series of births were used to test the working hypothesis that if there is a real seasonal variation in the frequency of a given congenital malformation; it would have to be shown by adequate analysis; to be more overt in non-tropical areas; and to be six months out of phase in northern and southern hemispheres. The data set were hospital births from tropical (287,165 births) and non-tropical (582,585 births) South America, and from Italy (508,536 births). Sixteen well-defined malformation types were tested: anencephaly, spina bifida, cephalocoele, hydrocephaly, microtia, cleft palate, cleft lip, oesophageal atresia, anal atresia, hypospadias, pes equino-varus, pes talovalgus, postaxial polydactylyl, pre-axial polydactylyl, diaphragmatic hernia, and Down's syndrome. No seasonal variation was proven (p less than 0.01) for any malformation type in any of the three series of data by means of Walter and Elwood's test, or Hewitt et al's non-parametric test2 applied to seven instances with sample sizes smaller than 50 cases. Variations of borderline significance (p less than 0.05) included oesophageal atresia in tropical South America, none in non-tropical South America, and anencephaly in Italy. It is concluded that seasonal variation in the occurrence of congenital malformations is a rare phenomenon when tests are strictly used within their recommended limitations.     

中国出生缺陷高发地区出生缺陷的发生水平和流行病学特征

目的研究中国出生缺陷高发地区出生缺陷的发生水平,分析主要出生缺陷的分布和流行病学特征。方法在出生缺陷高发的山西省选择2个高发县作为调查现场,对调查地区2002年1月1日至2004年12月31日期间孕满20周及以上的所有出生人口开展了以人群为基础的出生缺陷回顾性调查。结果调查地区2002—2004年出生缺陷发生率为844.2/万,发生率位于前五位的出生缺陷包括腹股沟疝(182.2/万)、无脑儿(104.4/万)、先天性智力低下(79.4/万)、先天性心脏病(73.2/万)和脊柱裂(63.9/万),前五位出生缺陷占全部出生缺陷的60%。国内外出生缺陷统计分析一般不包括腹股沟疝、鞘膜积液、隐睾和先天性智力低下,如果不包括这四类出生缺陷,调查地区出生缺陷发生率为537.2/万,位于前五位的出生缺陷分别为无脑儿、先天性心脏病、脊柱裂、脑积水(40.5/万)和脑膨出(31.2/万)。男性出生缺陷发生率为966.2/万,明显高于女性(640.4/万)。孕产妇年龄<20岁组和>30岁组出生缺陷发生率明显高于20～24岁和25～29岁年龄组。低龄孕妇发生神经管畸形和先天性心脏病的风险甚至显著高于高龄孕妇,孕产妇年龄<20岁组神经管畸形和先天性心脏病的发生率分别是408.8/万和188.7/万,而>30岁组两类出生缺陷的发生率分别为204.8/万和91.0/万。出生缺陷发生率随着孕产次的增加而明显提高。结论中国高发地区出生缺陷的发生呈现出与其他地区不同的流行病学特征,尤其是神经管畸形异常高发。不仅是高龄孕妇,20岁以下的低龄孕妇同样是一些出生缺陷发生的高危险因素。     

Miscarriage, stillbirth and congenital malformation in the offspring of UK veterans of the first Gulf war

OBJECTIVES: To assess whether the offspring of UK veterans of the first Gulf war are at increased risk of fetal death or congenital malformation. METHOD: This was a retrospective reproductive cohort study of UK Gulf war veterans and a demographically similar comparison group who were in service at the time but were not deployed to the Gulf. Reproductive history was collected by means of a validated postal questionnaire between 1998 and 2001. RESULTS: In all, 27 959 pregnancies reported by men and 861 pregnancies reported by women were conceived after the first Gulf war and before November 1997. The risk of reported miscarriage was higher among pregnancies fathered by Gulf war veterans than by non-Gulf war veterans (OR = 1.4, 95% CI: 1.3, 1.5). Stillbirth risk was similar in both groups. Male Gulf war veterans reported a higher proportion of offspring with any type of malformation than the comparison cohort (OR = 1.5, 95% CI: 1.3, 1.7). Examination by type of malformation revealed some evidence for increased risk of malformations of the genital system, urinary system (renal and urinary tract), and 'other' defects of the digestive system, musculo-skeletal system, and non-chromosomal (non-syndrome) anomalies. These associations were weakened when analyses were restricted to clinically confirmed conditions. There was little or no evidence of increased risk for other structural malformations, specific syndromes, and chromosomal anomalies. Among female veterans, no effect of Gulf war service was found on the risk of miscarriage. The numbers of stillbirths and malformations reported by women were too small to allow meaningful analyses. CONCLUSION: We found no evidence for a link between paternal deployment to the Gulf war and increased risk of stillbirth, chromosomal malformations, or congenital syndromes. Associations were found between fathers' service in the Gulf war and increased risk of miscarriage and less well-defined malformations, but these findings need to be interpreted with caution as such outcomes are susceptible to recall bias. The finding of a possible relationship with renal anomalies requires further investigation. There was no evidence of an association between risk of miscarriage and mothers' service in the gulf.     

A case-control study of maternal smoking and congenital malformations

Summary. We conducted a population-based case-control study to assess the association between maternal smoking during pregnancy and the risk of giving birth to a child with a congenital malformation. Cases were all singleton livebirths with a congenital malformation recorded on the 1984–1986 Washington State Birth Records (n = 3284). The smoking histories of these mothers were compared to a randomly selected group of mothers with a singleton livebirth of a child without a malformation during these same years (n = 4500). When all malformations were taken as a group, there was no association with maternal smoking (relative risk (RR) = l.0, 95% CI 0.9–1.1). However, increased risks were observed for a number of specific malformations, including microcephalus (RR = 2.0, 95% CI 1.0–4.0), cleft defects (RR=1.4, 95% CI 1.0–2.0), and club foot (RR= 1.4, 95% CI 1.0–2.0). We did not find any association with Down's syndrome (RR=0.8, 95% CI 0.5–1.3) or any other malformation. We conclude that maternal smoking during pregnancy may be associated with an increased risk for some malformations.     

Young maternal age and congenital malformations: a population-based study.

This study examined the prevalence of congenital malformations across the maternal age spectrum and identified specific malformation types that contributed to the overall prevalence among mothers under the age of 20 years. Data were derived from the California Birth Defects Monitoring Program for 1983 through 1988 live births. The distribution of prevalences of all nonchromosomal malformations was U-shaped across maternal age. Furthermore, several specific malformation types, representing nearly every organ system, were elevated among the infants of women under 20 years of age in comparison with those of women 25 to 29 years old.     

Pregnancy outcomes among female hairdressers who participated in the Danish National Birth Cohort

OBJECTIVES: The Danish National Birth Cohort (DNBC) was used to examine pregnancy outcomes among female hairdressers and neurodevelopment in their offspring. METHODS: A population-based cohort study was conducted of 550 hairdressers and 3216 shop assistants (reference group) by using data from the Danish National Birth Cohort between 1997 and 2003. Information on job characteristics was reported by the women in the first interview (around 17 weeks of gestation). Pregnancy outcomes were obtained by linkage to the national registers. Developmental milestones were reported by the mother at the fourth interview, when the child was approximately 19 months old. Cox regression was applied to analyze fetal loss and congenital malformation. Logistic regression was used to analyze other pregnancy outcomes and developmental milestones. RESULTS: We found no significant differences in fetal loss, multiple births, gender ratio, preterm birth, small-for-gestational age, congenital malformations, or achievement of developmental milestones among the children of hairdressers and shop assistants. CONCLUSIONS: The results do not indicate that children of hairdressers in Denmark currently have a high risk of fetal impairment or delayed psychomotor development.     

Spina bifida and parental occupation: Results from three malformation monitoring programs in Europe

As the evidence for an association between spina bifida and parental agricultural occupations is inconclusive, we evaluated this association and the potential associations between spina bifida and other parental occupations. Three register-based case–referent studies were conducted in Sweden, Spain, and Hungary. From the registries of congenital malformations in each country, 482, 478, and 1119 cases with spina bifida were identified, respectively. Identified as referents were 964, 434, and 1489 children without abnormalities. Information on parental occupation was available in the registries from questionnaires or interviews conducted among the parents. Occupations with a potential for physical or chemical exposure were compared to non-exposed occupations. Increased odds ratios (ORs) were observed for women in agricultural occupations in Sweden (OR: 1.8, 95% CI: 0.8–4.2) and in Spain (OR: 2.2, 95% CI: 0.8–5.9), but not in Hungary (OR: 1.1, 95% CI: 0.7–1.7). Several other parental occupations were analysed, but the associations with spina bifida were inconsistent. Concluding, the results are not totally consistent but point to an increased risk of spina bifida among women in agricultural occupations.     

Congenital malformations and maternal occupation: a registry based case-control study.

OBJECTIVES: To investigate the relations between congenital malformations and maternal occupation during pregnancy with a registry based case-control study. METHODS: Analysis was performed on data derived from the Florence Eurocat registry surveillance programme. The study included cases with isolated conditions, including chromosomal anomalies (n = 1351), cases with multiple anomalies registered during the 1980-91 period (n = 440), and babies with no congenital malformations recognised at birth who were born from 1982 to 1989 and selected as controls (n = 3223). 11 categories were defined, 10 including cases with isolated malformations and one for cases with multiple congenital anomalies. Four categories of maternal occupation were selected for the study. Odds ratio (OR) values were adjusted for maternal origin, maternal and paternal education, number of previous live births, illness during pregnancy, and maternal age when the group of chromosomal anomalies was analysed. RESULTS: A notable and significant association between oral clefts and mothers involved in leather and shoe manufacturing was found (adjusted OR 3.9; 99% confidence interval (99% CI) 1.5 to 9.8) and the risk consistently increased when considering cases with isolated cleft palate separately (OR 5.4; 95% CI 1.8 to 13.4). Moreover, a significant risk was identified for the association between multiple anomalies and textile dye workers (adjusted OR 1.9; 99% CI 1.0 to 3.8). CONCLUSIONS: This study indicates a notable, significant relation between maternal occupation as a pelt or leather worker and orofacial clefts in offspring. This finding is in agreement with the suggested inheritance models. The dilution effect due to studying large and heterogeneous groups of workers and occupations limits the value of the study; but it provides a good example of the use of a large database to search for teratogenic risk with the aid of malformation registries.     

Congenital malformations related to maternal exposure to specific agents in biomedical research laboratories

OBJECTIVE: To investigate major congenital and neural crest malformations (NCM; craniofacial and conotruncal defects) in the offspring of laboratory employees. METHODS: Data for 1951 females was linked to the Medical Birth Register (3003 pregnancies). Exposure information was based on questionnaires. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: The prevalence of "major malformations" were 2.3% (n = 41; exposed) and 1.9% (n = 23; unexposed). For the major malformations, solvent exposure before the third trimester gave an OR of 1.8 (CI = 1.0-2.9); "laboratory work in general," of 1.2 (CI = 0.7-2.0) unadjusted. OR for benzene use around conception/organogenesis was 5.3 (CI = 1.4-21.1) for NCM. CONCLUSION: No significant risk for laboratory work in general was seen, but there was an increased ratio for NCM relative to solvents, especially benzene. These results are based on small numbers and should be interpreted cautiously.     

A case-control study of maternal smoking and congenital malformations

We conducted a population-based case-control study to assess the association between maternal smoking during pregnancy and the risk of giving birth to a child with a congenital malformation. Cases were all singleton livebirths with a congenital malformation recorded on the 1984-1986 Washington State Birth Records (n = 3284). The smoking histories of these mothers were compared to a randomly selected group of mothers with a singleton livebirth of a child without a malformation during these same years (n = 4500). When all malformations were taken as a group, there was no association with maternal smoking (relative risk (RR) = 1.0, 95% CI 0.9-1.1). However, increased risks were observed for a number of specific malformations, including microcephalus (RR = 2.0, 95% CI 1.0-4.0), cleft defects (RR = 1.4, 95% CI 1.0-2.0), and club foot (RR = 1.4, 95% CI 1.0-2.0). We did not find any association with Down's syndrome (RR = 0.8 95% CI 0.5-1.3) or any other malformation. We conclude that maternal smoking during pregnancy may be associated with an increased risk for some malformations.