Congenital heart disease and prenatal exposure to exogenous sex hormones.

One-hundred and four infants with congenital heart disease were identified from their birth certificates and matched with normal controls. Their gestational histories were examined to see whether they had been exposed to exogenous sex hormones. Exposure was 8-5 times more common among the infants with malformations than among controls. A history of hormone exposure was more common among those patients with multiple malformations, and the exposed infants were also more likely to have died (and to have died earlier) than those who had not been exposed, which suggests that hormone exposure causes severe types of malformations. The commonest type of exposure was to hormone pregnancy tests, which was needless exposure. Only two of the mothers of malformed infants had inadvertently used oral contraceptives in the first trimester.     

VACTERL association and maternal diabetes: A possible causal relationship?

BACKGROUND: Some factors(s)/features(s) of maternal insulin‐dependent diabetes mellitus are considered common human teratogens. Although the variable association of cardiac, renal, and skeletal anomalies are commonly observed in infants from diabetic mothers, the relationship between VACTERL (i.e., the association of vertebral and cardiac defects, tracheo‐esophageal fistula, renal/radial malformations, and other limb anomalies) and maternal diabetes has not been sufficiently emphasized in the literature. CASE: We report on a 3‐year‐old boy presenting with a constellation of blastogenetic malformations strongly suggestive of VACTERL association. His mother was affected by insulin‐dependent diabetes since she was 7 years old and pregnancy history disclosed very high glucose and HbA1c levels, especially during the first 2 gestational months. CONCLUSIONS: In an attempt to properly counsel the parents, we reviewed the literature and identified four additional patients with VACTERL and first trimester exposure to maternal diabetes mellitus. Although this evidence does not strongly support a causal relationship between these two conditions, additional arguments may substantiate this hypothesis. The pathogenesis of diabetic embryopathy in relation to the VACTERL phenotype is also discussed. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Threatened abortion, hormone therapy and malformed embryos

Causal relations between maternal genital bleeding, supportive hormone therapy and external malformations of the embryos were investigated with special reference to the critical period of organogenesis. This was done using morphological and obstetrical data obtained by Nishimura and his associates from 667 undamaged embryos derived from induced abortions whose mothers had genital bleeding in early pregnancy. In addition, data from 90 embryos with polydactyly and 38 with limb reductions in the Nishimura collection were used for case history studies. Evidence was presented to demonstrate that, for major malformations such as CNS anomalies, cleft lip, polydactyly and limb reductions, maternal genital bleeding was not a cause but a consequence of the conception of an abnormal embryo. No indication was revealed that exogenous female hormones currently used in Japan for preventing miscarraiges could produce major malformations recognizable at the embryonic stage, including limb reductions, nor salvage the severely malformed embryos. This does not however mean to exclude the possible relationship of progestogens/estrogens intake during early pregnancy with an increased incidence at birth of certain internal and/or external malformations. It was suggested that most, if not all, of the minor anomalies observed at certain embryonic stages are kinds of normal variants without any functional impairment of embryonic development.     

Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations

BACKGROUND: Maternal use of selective serotonin re-uptake inhibitors (SSRIs) has recently been associated with an increased risk for certain malformations. METHODS: Using the Swedish Medical Birth Register, we identified women who had reported the use of SSRIs in early pregnancy and studied their infants, born between July 1, 1995 and the end of 2004. Congenital malformations were identified from that register, from the Register of Congenital Malformations, and from the Hospital Discharge Register. The effect of drug exposure was studied after adjustment for a number of identified maternal characteristics that could act as confounders. RESULTS: We identified 6,481 women who reported the use of SSRIs in early pregnancy and their 6,555 infants. There was no general increase in malformation risk. An increased risk for cystic kidneys was seen, but this was based on only nine malformed infants, and the pathology varied between these cases. An in-depth study of cardiovascular defects identified an association between such defects and notably ventricular and atrial septum defects and maternal use of paroxetine but not other SSRIs. No support for a postulated association between SSRI use and infant craniostenosis or omphalocele was found. CONCLUSIONS: Use of SSRIs in early pregnancy does not seem to be a major risk factor for infant malformations. The association between paroxetine use and infant cardiovascular defects may be a result of multiple testing, but is supported by other studies.     

Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring

The possible effect of chemical and physical factors during pregnancy on the occurrence of cardiovascular malformations in the offspring was studied in 573 cases and 1,055 controls. The cases represented all verified cardiovascular malformations in Finland during 1982-1984. The controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed by midwives approximately 3 months after delivery using a structured questionnaire. Maternal alcohol consumption during the first trimester of pregnancy was more common among the mothers of case infants (45.9%) than those of controls (39.6%). Exposure to organic solvents at work was slightly more prevalent among the ventricular septal defect group (12.1%) than the control mothers (7.8%). However, neither association was significant when adjusted for maternal age in logistic regression analysis. Moreover, one or both of these associations may be chance effects resulting from multiple comparisons. The risk of cardiovascular malformations was not associated with maternal smoking, or coffee, tea, or cola consumption, and was equal in urban and rural areas. Maternal exposures to anesthetic gases, pesticides, wood preservatives, microwave ovens, and video display terminals at work or home were not associated with the risk of cardiovascular malformations. It is concluded that some common environmental exposures during early pregnancy to physical and chemical factors should not necessarily be considered hazardous for the developing fetal heart. The causes of the majority of cardiovascular malformations remain unknown.     

First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage

BACKGROUND: Conflicting findings with regard to the teratogenic risks of first trimester use of paroxetine have prompted the FDA, Health Canada, and the manufacturer of the drug to issue warnings against its use during pregnancy. Given that untreated depression during pregnancy can lead to deleterious effect on the mother and her unborn fetus, data on the relationship between the dose and the range of malformations is warranted. This study attempts to quantify the association between first trimester exposure to paroxetine and congenital cardiac malformations, adjusting for possible confounders, and to quantify the dose-response relationship between paroxetine use and cardiac defects. METHODS: The Medication and Pregnancy registry was used. This population-based registry was built by linking three administrative databases (RAMQ, Med-Echo, and ISQ), and includes all pregnancies in Quebec between 01/01/1997 and 06/30/2003. Date of entry in the registry is the date of the first day of the last menstrual period. To be eligible for this study, women had to: 1) be 15-45 years of age at entry; 2) be covered by the RAMQ drug plan >or=12 months before and during pregnancy; 3) be using only one type of antidepressant during the first trimester; and 4) have a live birth. Two nested case-control studies were carried out comparing the prevalence of paroxetine use in the first trimester of pregnancy to the prevalence of other antidepressant exposures during the same time period. Cases were defined as: 1) any major malformations; or 2) any cardiac malformations diagnosed in the first year of life; controls were defined as no major or minor malformations. Multivariate logistic regression techniques were used to analyze data. RESULTS: Among the 1,403 women meeting inclusion criteria, 101 infants with major congenital malformations were identified; 24 had cardiac malformations. Adjusting for possible confounders, the use of paroxetine (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 0.49-3.92), and the use of other SSRIs (OR = 0.89, 95% CI = 0.28-2.84) during the first trimester of pregnancy did not increase the risk of congenital cardiac malformations compared with the use of non-SSRI antidepressants. When considering the dose, however, a dose-response relationship was observed, thus women exposed to >25 mg/day of paroxetine during the first trimester of pregnancy were at increased risk of having an infant with major congenital malformations (adjusted [adj] OR = 2.23, 95% CI = 1.19, 4.17), or major cardiac malformations (adj OR = 3.07, 95% CI = 1.00, 9.42). CONCLUSIONS: Gestational exposure to paroxetine is associated with major congenital malformations and major cardiac malformations for only first trimester exposure above 25 mg/day.     

Birth rate and mortality rate of infants with congenital malformations of the limbs in the Awajishima free-ranging group of Japanese monkeys (Macaca fuscata)

The birth rate and mortality rate of infants with congenital malformations of the limbs were examined in the Awajishima free-ranging group of Japanese macaques (Macaca fuscata). Of the 606 infants born between 1978 and 1995, 86 (14.2%) were malformed. The male-female ratio did not differ between malformed and normal infants. Most kin-groups included females who gave birth to malformed infants at least once. The mortality rate within the first year after birth for malformed infants (28.2%) was significantly higher than that for normal infants (10.0%). However, this indicates that more than 70% of malformed infants were able to survive for the first year of life, even though they were unable to cling to their mothers ventrum due to their limb deformities. This finding indicates that maternal care-taking is sufficient to enable malformed infants to survive during the early stages of development and that clinging by the infant is not necessary for the display of maternal care. Am. J. Primatol. 42:225–234, 1997. © 1997 Wiley-Liss, Inc.     

The influence of antenatal and maternal factors on stillbirths and neonatal deaths in New South Wales, Australia

This study identified the influences of maternal socio-demographic and antenatal factors on stillbirths and neonatal deaths in New South Wales, Australia. Bivariate and multivariate analyses were used to explore the association of selected antenatal and maternal characteristics with stillbirths and neonatal deaths. The findings of this study showed that stillbirths and neonatal deaths significantly varied by infant sex, maternal age, Aboriginality, maternal country of birth, socioeconomic status, parity, maternal smoking behaviour during pregnancy, maternal diabetes mellitus, maternal hypertension, antenatal care, plurality of birth, low birth weight, place of birth, delivery type, maternal deaths and small gestational age. First-born infants, twins and infants born to teenage mothers, Aboriginal mothers, those who smoked during the pregnancy and those of lower socioeconomic status were at increased risk of stillbirths and neonatal deaths. The most common causes of stillbirths were conditions originating in the perinatal period: intrauterine hypoxia and asphyxia. Congenital malformations, including deformities and chromosomal abnormalities, and disorders related to slow fetal growth, short gestation and low birth weight were the most common causes of neonatal deaths. The findings indicate that very low birth weight (less than 2,000 g) contributed 75.6% of the population-attributable risks to stillbirths and 59.4% to neonatal deaths. Low gestational age (less than 32 weeks) accounted for 77.7% of stillbirths and 87.9% of neonatal deaths. The findings of this study suggest that in order to reduce stillbirths and neonatal deaths, it is essential to include strategies to predict and prevent prematurity and low birth weight, and that there is a need to focus on anti-smoking campaigns during pregnancy, optimizing antenatal care and other healthcare programmes targeted at the socially disadvantaged populations identified in this study.     

Incidence of anencephaly and other major malformations when oestriol excretion is very low.

A study of 533 women with very low urinary oestriol excretion during the third trimester of pregnancy showed an incidence of major fetal malformations among their infants of 7-1% and a perinatal mortality rate of 14-6%. Thirteen of the malformations were cases of anencephaly, and 26 of the 78 perinatal deaths were due to or associated with major fetal malformations. The incidence of these complications was higher when maternal oestriol excretion was lower. Routine screening by urinary oestriol assay, with fetal radiography when values below 20-8 mumol/24 hours (6 mg/24 h) are detected is the most reliable method of detecting anencephaly before birth.     

Maternal and neonatal factors influencing premature birth and low birth weight in Australia

This study identified the influences of neonatal and maternal factors on premature birth and low birth weight in New South Wales, Australia. Bivariate and multivariate analyses were used to explore the association of selected neonatal and maternal characteristics with premature birth and low birth weight. The findings of this study showed that premature birth and low birth weight rate significantly varied by infant sex, maternal age, marital status, Aboriginality, parity, maternal smoking behaviour during pregnancy and maternal hypertension. First-born infants, and infants born to mothers aged less than 20 years, or who were single, separated/divorced, Aboriginal or who smoked during the pregnancy, were at increased risk of being premature or of low birth weight. This study also found that risk factors for premature births and low birth weight were similar in both singleton and multiple births. Gestational age was confirmed to be the single most important risk factor for low birth weight. The findings of this study suggest that in order to reduce the incidence of low birth weight and premature births, health improvement strategies should focus on anti-smoking campaigns during pregnancy and other healthcare programmes targeted at the socially disadvantaged populations identified in the study.     

Maternal urinary tract infections and selected cardiovascular malformations

BACKGROUND: In a population‐based case‐control study, we investigated the association between congenital cardiovascular malformations (CVMs) and maternal urinary tract infections (UTIs). METHODS: Within the National Birth Defects Prevention Study, 3,690 women who had singleton livebirths with nonsyndromic CVMs, and 4,760 women who had infants without birth defects were identified. Affected infants had: conotruncal, septal, anomalous pulmonary venous return, atrioventricular septal defects, or left‐ or right‐sided obstructive heart defects. Mothers had a UTI if they reported having at least one infection during the first trimester. Adjusted ORs and 95% CIs were computed to determine the association between CVMs and UTIs. Stratified analyses were conducted to investigate if sulfonamide use and/or fever modified the effect between CVMs and UTIs. RESULTS: Women who had offspring with either left ventricular outflow tract obstructive defects or atrioventricular septal defects were more likely than controls to report a UTI. These associations remained among women who did not have fever or used sulfonamides. Maternal use of sulfonamides during the UTI did not appear to modify the relationship between CVM subtypes and maternal UTIs. CONCLUSIONS: In the National Birth Defects Prevention Study there was little evidence to support an association between CVMs and UTIs during the first trimester of pregnancy. Associations between left ventricular outflow tract obstructive defects and maternal UTI as well as between atrioventricular septal defects and maternal UTI were found. Our findings, while not conclusive, suggest that the possible association between maternal UTI and CVMs should be investigated further. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Steroid contraceptive use and pregnancy outcome

Contraceptive use in relation to pregnancy outcome was studied in 8,816 births in Chiang Mai, northern Thailand, by examination of newborn infants and interviews with their mothers. Four thousand twenty-three women used no contraception before the index pregnancy, 1,229 used the injectable contraceptive Depo Provera (DMPA), and 3,038 used oral contraceptives prior to or during pregnancy. No differences were observed between these groups with respect to still births, multiple pregnancies, and birthweight. Women who used oral contraceptives had unexpectedly low rates of major defects and may have been affected by self-selection bias, whereas the noncontraceptors had rates similar to other populations. There was a significantly increased association of polysyndactyly among infants of DMPA users relative to the other groups, which was most pronounced in offspring of women under age 30 years, and persisted after exclusion of subjects with a family history or infants with multiple abnormalities. However, in five out of the ten polysyndactyly cases, the last injection of DMPA occurred more than 9 months before conception, and only three cases had definite gestational exposure. The association of chromosomal anomalies was also significantly increased in infants of mothers who used DMPA. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptional exposure to DMPA in many cases, and chance effects due to multiple statistical comparisons make a causal association unlikely. Other birth defects that had been previously reported in some publications to be associated with progestational steroid exposure, such as neural tube defects, heart malformations, and limb reduction defects, were not found in this study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maternal severe migraine and risk of congenital limb deficiencies

BACKGROUND: Migraines occurs frequently during pregnancy; however, there are no published data on their possible teratogenic potential in a controlled epidemiological study. Therefore, we examined the risk of congenital abnormalities in infants born to women who had migraines and other headaches during pregnancy. METHODS: Between 1980 and 1996, the Hungarian Case-Control Surveillance of Congenital Abnormalities evaluated 22,843 cases (newborns or fetuses) with congenital abnormalities, 38,151 control newborn infants without any abnormalities, and 834 malformed controls with Down syndrome. RESULTS: Migraines anytime during pregnancy occurred in 565 (2.5%) mothers of the case group compared with 713 (1.9%) mothers in the control group (crude prevalence odds ratio [POR], 1.3; 95% confidence interval [CI], 1.2-1.5) and 24 (2.9%) pregnant women in the malformed control group (crude POR, 0.9; 95% CI, 0.6-1.3) The mothers of 247 cases, 533 controls, and 21 malformed controls had severe migraines during the second and/or third months of pregnancy. There was only 1 congenital abnormality group: limb deficiencies, which had a higher rate of maternal migraines during the second and third months of pregnancy both at the comparison of cases and matched controls (adjusted POR, 2.5; 95% CI, 1.1-5.8) and of cases and malformed controls (adjusted POR, 1.7; 95% CI, 1.3-3.0). There was no association between other headaches and different congenital abnormalities at the comparison of cases and controls. CONCLUSIONS: Our data showed that maternal severe migraines during the second and/or third months of pregnancy were associated with an increased risk of congenital limb deficiencies. A similar association was not detected between congenital anomalies and other headaches during pregnancy. Our study was not based on a prior hypothesis; therefore, these data can be considered only as a signal that needs confirmation by independent data sets.     

Limb reduction defects in the first generation and deafness in the second generation of intrauterine exposed fetuses to diethylstilbestrol

Maternal treatment with diethylstilbestrol (DES) during pregnancy can produce vaginal adenocarcinoma and other abnormalities of the vagina in her daughters when they reach adolescence or adulthood, miscarriages and absence of full term infants. Concerning malformations in newborns whose mothers were treated with DES, clitoromegaly and malformations of the uterus were reported in females and genital lesions in males. However, the frequencies of major congenital anomalies were not greater than expected. We report three cases of limb reduction defects (LRD) in the first generation of children whose mothers were treated with DES during pregnancy, and two children (one male, one female) with deafness in the second generation after intrauterine exposure to DES. The LRD were not associated with other congenital anomalies. The malformed children with LRD were born between 1965 and 1973. The deafness was also isolated. The two mothers who have no hearing problems and who are healthy were exposed in utero to DES in 1963 and 1965, respectively. Their children were born in 1989 and 1994, respectively. In conclusion, the association of LRD and hearing loss with intrauterine exposure to DES could be coincidental. However, some hypothesis may explain these associations. Congenital hearing loss in the second generation may suggest a transgenerational effect.     

Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy.

To test the effect of maternal habits and home exposures during early pregnancy on the occurrence of congenital heart disease in the offspring, 406 cases and 756 controls were studied. The cases included all cardiovascular malformations detected in Finland during 1982-1983, while the healthy controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed after delivery using a structured and pre-tested questionnaire. Maternal overall drug consumption during the first trimester was as prevalent among case mothers (13.3%) as controls (14.6%). Neither was the risk of congenital heart disease associated with maternal use of contraceptive pills, salicylates, diazepam, or sweetening agents separately. Maternal exposures to disinfectants, dyes, lacquers, paints, pesticides, or glues at home were equally prevalent in case and control groups. Several earlier miscarriages was a predictor of an infant born with congenital heart disease (OR = 2.7, CI95 = 1.4-5.3). Maternal ultrasound examination was performed during the first 16 weeks of pregnancy more often among the case group (28.3%) than among the control group (22.0%). However, the association between ultrasound examination and the risk of congenital heart disease in the offspring was not statistically significant (OR = 1.2, 95% confidence interval 0.9-1.7) when adjusted for confounding factors such as the threat of miscarriage in logistic regression analysis. It is concluded that maternal ultrasound examination, intake of some common drugs, and exposure to a number of environmental factors at home during early pregnancy are probably not harmful for the developing fetal heart.     

Maternal occupational exposure to ionizing radiation and birth defects

So far, only a few studies investigated occupational exposure to ionizing radiation in pregnancy to cause birth defects (BDs). No association between BDs and ionizing radiation, although described for high-dose exposure, could ever be confirmed for employees, or specific job titles. Here, an explorative analysis of a prospective population-based birth cohort used to quantify the prevalence of BDs in infants between 1/2007 and 2/2008 is presented. An active examination of all livebirths by specially trained paediatricians in two defined areas was performed. Additionally, a study-specific questionnaire distributed among all becoming mothers in the surveyed regions included questions on maternal occupational exposure to ionizing radiation within the first trimester of pregnancy. In 3,816 births (including 165 infants with BDs; 4.3%), maternal answers concerning possible exposures to medical and occupational ionizing radiation were available. Relative risk (RR) estimates in mothers surveyed for occupational exposure to ionizing radiation (wearing a radiation dosimeter) and BDs in the offspring were calculated exploratively. A higher prevalence of infants with BDs (n = 4; 13.8%) was documented in newborns of the 29 surveyed mothers compared to that in 3,787 births from unexposed mothers (n = 161; 4.3%), corresponding to a RR of 3.2 (1.2–8.7). Excluding deformations, the RR increased to 4.0 (1.5–10.7). Adjustment for possible confounders did not change the results substantially.     

Congenital malformations in Utah

The rate of malformed children in Utah of 11.7 per 1,000 liver births, derived from 128,857 birth certificates, ws not high compared with other non-Utah studies. Rates of selected malformations also were not high. The rate of malformed children varied by county of residence. San Juan County reported the highest percentage of mothers receiving late or infrequent prenatal care, the lowest mean level of public education, and the highest rate of malformed children in the state. The rate was not significantly associated with the large population of Indians residing in that county since by controlling for residence, the variation by race was eliminated. The overall rate was positively associated with maternal age rimarily due to an increased frequency of Down's syndrome. The impact of the "maternal age effect" on the state malformation rate, however, was not large. By controlling for maternal age, the slight association between increased rate of malformed children and increasing birth order was eliminated. The rate of malformed children was higher for parents having a low level of education, infrequent prenatal care, or who were not married. There was also a strong negative association of birth weight with the rate of malformation. Analysis of rates of selected malformations suggested that the low birth weight was a sequela to intrauterine growth retardation caused by severe congenital malformation. The validity and etiologic implications of these results await further investigation.     

Maternal fever and neural tube defects

It has been proposed that hyperthermia in the pregnant woman is associated with neural tube defects in her offspring. We analyzed retrospective interview data for a maternal history of probable febrile illness during the first trimester of pregnancy among mothers of infants with anencephaly or spina bifida. There were two control groups--mothers of infants with Down syndrome and mothers of infants with cleft lip or palate. With the Down syndrome group serving as controls, the incidence of febrile illness among mothers of all infants with neural tube defects was significantly elevated. With the cleft group as controls, the fever incidence was not significantly increased in the neural tube defect groups. When the combined cleft and Down syndrome controls were used, only mothers of the spina bifida group had an elevated fever incidence. Epidemiology data suggest an association of maternal fever during pregnancy with neural tube defects in the offspring.