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.     

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 hair zinc concentration in neural tube defects in Turkey

Hair zinc concentration was measured in samples taken from 57 mothers who delivered infants with neural tube defects (NTD) (mainly anencephaly). Control groups consisted of 30 healthy mothers with normal offspring and 37 nonpregnant women from middle-income backgrounds. Zinc concentration was also measured in the hair of eight infants with NTD (four being anencephalic). The mean maternal hair zinc concentration in the NTD group (128.2 +/- 38.9 micrograms/g) was lower than that of the control women (p less than 0.001), whereas the mean hair zinc level of malformed babies (250.4 +/- 85.2 micrograms/g) was significantly higher than that of normal infants (193.4 +/- 39.2 micrograms/g) (p less than 0.05). Maternal nutritional zinc deficiency was thought to be one of the factors responsible for NTD in Turkey.     

Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis.

OBJECTIVE--To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. DESIGN--All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian perinatal and abortion statistics collections, birth defects register, and state maternal serum alpha fetoprotein screening programme. SETTING--Southern Australia. SUBJECTS--All 1058 births and terminations of pregnancy affected by neural tube defects in 1966-91. MAIN OUTCOME MEASURES--Total prevalence and birth prevalence of individual and all neural tube defects. The proportion of screened cases detected prenatally. RESULTS--Total prevalence of neural tube defects during 1966-91 was 2.01/1000 births with no upward or downward trend. However, birth prevalence fell significantly (by 5.1% a year), with an 84% reduction from 2.29/1000 births in 1966 to 0.35/1000 in 1991 (relative risk = 0.16, 95% confidence interval 0.07 to 0.34). The fall was 96% for anencephaly and 82% for spina bifida. 85% of defects, both open and closed, were detected before 28 weeks'' gestation in women screened by serum alpha fetoprotein or mid-trimester ultrasonography, or both, in 1986-91 (99.0% for anencephaly and 75.7% for spina bifida). CONCLUSIONS--While the total prevalence of neural tube defects in South Australia remained stable, prenatal diagnosis and termination of pregnancy resulted in an 84% fall in birth prevalence during 1966-91. Screening detected over four fifths of cases in 1986-91.     

Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden.

Folic acid is recommended to reduce the risk of neural tube defects and other congenital malformations. Data from the Swedish Medical Birth Registry were used to study frequency of twinning in women who in early pregnancy reported the use of folic acid. Women (n = 2,569) who in early pregnancy reported the use of folic acid had an increased rate of twin deliveries after consideration of maternal age and of length of involuntary childlessness, both variables being significant confounders. The effect of folic acid was seen also in women who did not report involuntary childlessness. A similar but not statistically significant trend was seen after use of multivitamins without simultaneous use of folic acid tablets (n = 1,979). The increased risk seems to be limited to dizygotic twinning (relative risk = 2.13, 95% CI 1.64-2.74). If this association is causal, wide-spread supplementation with folic acid may represent a hazard larger than the postulated beneficial effect on neural tube defects, at least in low-risk areas.     

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.     

Maternal serum alpha-fetoprotein screening: report of a Canadian pilot project.

A pilot project of maternal serum alpha-fetoprotein (MSAFP) screening was carried out in Ontario from 1982 to 1985 to examine the feasibility and acceptability of screening a prenatal population for open fetal neural tube defects. A total of 8140 patients at low genetic risk were screened. Patient acceptance was excellent. Blood samples were taken at 16 to 18 weeks'' gestation. If the MSAFP level was elevated, the assay was repeated and an ultrasound examination performed. Amniocentesis was offered to 67 women with unexplained persistently elevated levels. The outcome of pregnancy was known in 7473 patients (91.8%). Seven of nine known open fetal neural tube defects were detected. All were confirmed, and no unaffected fetuses were aborted on the basis of the screening results. The rates of perinatal death (6.7%), intrauterine growth retardation (11.7%) and prematurity (23.3%) were significantly higher among the patients with unexplained elevated MSAFP levels than among those with normal levels (p less than 0.001). Of 20 patients with unexplained low levels, 10 subsequently had spontaneous abortions and 10 gave birth to term appropriate-for-gestational-age infants. Seven of nine patients who gave birth to infants with autosomal trisomy had MSAFP values below the median. The findings indicate that MSAFP screening is feasible, accurate and acceptable in a low-risk area.     

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

Objectives To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects.Design Retrospective cohort study of births monitored by birth defect registries.Setting 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review.Main outcome measures Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable).Results The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects.Conclusions Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.     

Trends in rates of multiple vascular disruption defects, Atlanta, 1968-1989: is there evidence of a cocaine teratogenic epidemic?

Research suggests that, perhaps through mechanisms initiated by vasoconstriction and leading to vessel thrombosis or embolism, cocaine causes vascular disruption defects, and that frequent cocaine use during early pregnancy could disrupt multiple organ systems in the fetus. We hypothesized that if cocaine is an important cause of multiple vascular disruption defects, a rising prevalence of cocaine use by mothers during pregnancy should be accompanied by rising rates of these defects in their offspring. Using data from the Metropolitan Atlanta Congenital Defects Program, we identified all infants born in Atlanta from 1968 through 1989 who had nonsyndromic, provisional vascular disruption defects affecting more than one organ system: 61 infants (78%) had gastrointestinal and genitourinary defects, 7 (9%) had gastrointestinal and abdominal wall defects, 2 (3%) had gastrointestinal and limb reduction defects, 2 (3%) had limb reduction and abdominal wall defects, 2 (3%) had central nervous system and gastrointestinal defects, 2 (3%) had genitourinary and limb reduction defects, 1 (1%) had genitourinary and abdominal wall defects, and 1 (1%) had central nervous system and genitourinary defects. The prevalence of Atlanta infants with more than one vascular disruption defect is 0.13 per 1,000 live births. Chi-square analysis for trends showed no increase in prevalence during the study period. Our data are from one of the first population-based studies in which trends for defects potentially caused by maternal cocaine use are examined; the results of our study show no significant change in the prevalence of multiple vascular disruption defects over time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced severity of Rh-haemolytic disease after anti-D immunoglobulin.

A total of 2459 Rh-negative women who received anti-D immunoglobulin after a Rh-positive pregnancy were followed up in at least one subsequent pregnancy. There was a failure of protection rate of 1-6%. Follow-up of 53 subsequent infants of mother in whom protection had failed showed that the infants were less severely affected than would have been expected. This was confirmed by a comparative statistical analysis of the present series and a series of first affected cases before anti-D immunoglobulin was available, using the antibody titre during pregnancy and the haemoglobin levels at delivery.     

Folic acid supplementation in pregnancy and implications in health and disease

Maternal exposure to dietary factors during pregnancy can influence embryonic development and may modulate the phenotype of offspring through epigenetic programming. Folate is critical for nucleotide synthesis, and preconceptional intake of dietary folic acid (FA) is credited with reduced incidences of neural tube defects in infants. While fortification of grains with FA resulted in a positive public-health outcome, concern has been raised for the need for further investigation of unintended consequences and potential health hazards arising from excessive FA intakes, especially following reports that FA may exert epigenetic effects. The objective of this article is to discuss the role of FA in human health and to review the benefits, concerns and epigenetic effects of maternal FA on the basis of recent findings that are important to design future studies.     

Is lack of morning sickness teratogenic? A prospective controlled study

BACKGROUND: Case-control studies have suggested that the nausea and vomiting of pregnancy (NVP) may have a protective effect against specific malformations. These suggestions have been interpreted as if the lack of NVP may put mothers at an increased teratogenic risk. METHODS: A prospective, cohort-controlled study was done comparing pregnancy outcome in women not experiencing NVP with those experiencing NVP at two levels of clinical severity. Women who called the Motherisk program about first-trimester exposure to drugs and who had not experienced NVP were included as the study group. The NVP Healthline enrolled two control groups of women with NVP treated with a doxylamine-pyridoxine combination for morning sickness. These women were exposed during the first trimester of gestation to either higher than the standard dose (5-12 tablets/day) or a standard dose (1-4 tablets/day) of doxylamine-pyridoxine. The women in all three groups were followed up four to six months after the expected date of birth to ascertain pregnancy outcomes and child health. RESULTS: There were no major malformations among offspring of 130 women not experiencing NVP. There were two major malformations among 246 women experiencing NVP. The two control groups of women with NVP had similar distributions of gestational ages, birth rates, as well as rates of miscarriages and stillbirths, as in the no-NVP group. CONCLUSIONS: This study did not show an association between lack of NVP and an increase in the overall rates of major malformations.     

Evaluation of preterm births and birth defects in liveborn infants of US military women who received smallpox vaccine

BACKGROUND: Women serving in the US military have some unique occupational exposures, including exposure to vaccinations that are rarely required in civilian professions. When vaccinations are inadvertently given during pregnancy, such exposures raise special concerns. These analyses address health outcomes, particularly preterm births and birth defects, among infants who appear to have been exposed to maternal smallpox vaccination in pregnancy. METHODS: This retrospective cohort study included 31,420 infants born to active‐duty military women during 2003–2004. We used Department of Defense databases to define maternal vaccination and infant health outcomes. Multivariable regression models were developed to describe associations between maternal smallpox vaccination and preterm births and birth defects in liveborn infants. RESULTS: There were 7,735 infants identified as born to women ever vaccinated against smallpox, and 672 infants born to women vaccinated in the first trimester of pregnancy. In multivariable modeling, maternal smallpox vaccination in pregnancy was not associated with preterm or extreme preterm delivery. Maternal smallpox vaccination in the first trimester of pregnancy was not significantly associated with overall birth defects (OR 1.40; 95% CI: 0.94, 2.07), or any of seven specific defects individually modeled. CONCLUSIONS: Results may be reassuring that smallpox vaccine, when inadvertently administered to pregnant women, is not associated with preterm delivery or birth defects in liveborn infants. Birth Defects Research (Part A) 2008. © 2008 Wiley‐Liss, Inc.     

Maternal Obesity and Infant Heart Defects

Objective: This study determined whether obese women have an increased risk of cardiovascular defects in their offspring compared with average weight women. Research Methods and Procedures: In a case‐control study, prospectively collected information was obtained from Swedish medical health registers. The study included 6801 women who had infants with a cardiovascular defect and, as controls, all delivered women (N = 812, 457) during the study period (1992 to 2001). Infants with chromosomal anomalies or whose mothers had pre‐existing diabetes were excluded. Obesity was defined as BMI >29 kg/m², and morbid obesity was defined as BMI >35 kg/m². Comparisons were made with average weight women (BMI = 19.8 to 26 kg/m²). Results: In the group of obese mothers, there was an increased risk for cardiovascular defects compared with the average weight mothers [adjusted odds ratio (OR) = 1.18; 95% CI, 1.09 to 1.27], which was slightly more pronounced for the severe types of cardiovascular defects (adjusted OR = 1.23; 95% CI, 1.05 to 1.44). With morbid obesity, the OR for cardiovascular defects was 1.40 (95% CI, 1.22 to 1.64), and for severe cardiovascular defects, the OR was 1.69 (95% CI, 1.27 to 2.26). There was an increased risk for all specific defects studied among the obese women, but only ventricular septal defects and atrial septal defects reached statistical significance. Discussion: In this sample, a positive association was found between maternal obesity in early pregnancy and congenital heart defects in the offspring. A suggested explanation is undetected type 2 diabetes in early pregnancy, but other explanations may exist.     

Antenatal diagnosis of neural tube defects in Canada: extension of a collaborative study.

Experience with the diagnosis of neural tube defects from alpha1-fetoprotein (AFP) concentrations in amniotic fluid is reported from a prospective study of five laboratories testing for 13 Canadian genetic centres. The results of the study indicate that antenatal diagnosis of open neural tube defects is being carried out effectively in Canada (in 99.2% of cases the AFP measurements were interpreted correctly). Amniocentesis should be recommended to women at high risk for having a child with a neural tube defect (i.e., those who have a child, a parent or a sibling with a neural tube defect). The rate of neural tube defects in 182 high-risk pregnancies was 2.2% for an open defect and 1.1% for a closed defect, whereas the rate in 673 pregnancies in which amniocentesis was being performed for other reasons was 0.3%. This suggests that the AFP concentration should be measured in any sample of amniotic fluid collected for other reasons (usually fetal karyotyping). There were three instances of false-negative results, for a rate of 0.4%. Two closed neural tube defects were not detected; this limitation of the test has also been found by others. One of the six fetuses with an open neural tube defect, who died in utero, had a large myelocele in the neck that was not recognized. There were also four instances of false-positive results, for a rate of 0.5%. The findings suggest that AFP values that are more than 2 but less than 7 standard deviations (SDs) above the mean may indicate a neural tube defect, and that values 7 or more SDs above the mean very likely indicate such a defect, although other reasons for such high values (e.g., fetal erythrocytes in the amniotic fluid, intrauterine death and mistaken gestational age) must be ruled out by other methods.     

Can prepregnancy care of diabetic women reduce the risk of abnormal babies?

OBJECTIVE--To see whether a prepregnancy clinic for diabetic women can achieve tight glycaemic control in early pregnancy and so reduce the high incidence of major congenital malformation that occurs in the infants of these women. DESIGN--An analysis of diabetic control in early pregnancy including a record of severe hypoglycaemic episodes in relation to the occurrence of major congenital malformation among the infants. SETTING--A diabetic clinic and a combined diabetic and antenatal clinic of a teaching hospital. PATIENTS--143 Insulin dependent women attending a prepregnancy clinic and 96 insulin dependent women managed over the same period who had not received specific prepregnancy care. MAIN OUTCOME MEASURE--The incidence of major congenital malformation. RESULTS--Compared with the women who were not given specific prepregnancy care the group who attended the prepregnancy clinic had a lower haemoglobin AI concentration in the first trimester (8.4% v 10.5%), a higher incidence of hypoglycaemia in early pregnancy (38/143 women v 8/96), and fewer infants with congenital abnormalities (2/143 v 10/96; relative risk among women not given specific prepregnancy care 7.4 (95% confidence interval 1.7 to 33.2]. CONCLUSION--Tight control of the maternal blood glucose concentration in the early weeks of pregnancy can be achieved by the prepregnancy clinic approach and is associated with a highly significant reduction in the risk of serious congenital abnormalities in the offspring. Hypoglycaemic episodes do not seem to lead to fetal malformation even when they occur during the period of organogenesis.     

Pregnancy outcomes after first trimester exposure to phentermine/fenfluramine

BACKGROUND: Fenfluramine was withdrawn from the U.S. market in 1997 because of its association with cardiac-valve abnormalities in adults. The combination of fenfluramine and phentermine had been widely used to promote weight loss, and many women were inadvertently exposed during the first trimester of pregnancy. The possible effect on the developing fetus has not been studied. METHODS: Controlled prospective cohort study comparing 98 women who had taken phentermine/fenfluramine to 233 women who had not, all of whom contacted the California Teratogen Information Service during pregnancy. RESULTS: The proportion of liveborn infants with major structural anomalies was similar in the two groups (3.6% vs. 1.0%, relative risk (RR) 3.59; 95% confidence interval (CI) 0.61, 21.10), as was the proportion of infants with >or=3 minor anomalies (11.7% vs. 7.6%, RR 1.53; 95% CI 0.61, 3.82). Furthermore, no pattern of malformation was identified. There were no significant differences between the groups in spontaneous pregnancy loss (6.1% vs. 8.2%, P = 0.65) or premature delivery (8.6% vs. 7.7%, P = 0.95). Birth weight and head circumference were significantly increased in the exposed group; however, these differences were not associated with anorexiant use itself. The rate of gestational diabetes was significantly increased in pregnant women who took phentermine/fenfluramine during the first trimester of pregnancy. CONCLUSIONS: Although it is not possible from this study to rule out weak to moderate associations, the lack of an increased risk of spontaneous pregnancy loss, and major or minor anomalies in the offspring of women who took phentermine/fenfluramine at the recommended daily dose during the first trimester of pregnancy is reassuring.     

Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect

BACKGROUND: Folic acid supplementation reduces the occurrence of neural tube defects (NTDs); however, it is not clear whether it protects against teratogenic effects of antiepileptic drugs. METHODS: We report the cases of four pregnant women receiving valproic acid therapy, who all had NTD-affected offspring, despite periconceptional 5 mg/day of folic acid supplementation (cases), and investigated homocysteine metabolism, linked with folate metabolism. Their plasma homocysteine, folates, and vitamin B6 and B12 results were compared with values of two other women, who were also receiving valproic acid and folic acid complement, but who had normal pregnancies (valproic acid controls), and values of 40 pregnant women who had normal pregnancies and were not receiving any therapy (controls without therapy). Because of the possible existence of a genetic susceptibility, polymorphisms in homocysteine metabolism were sought. RESULTS: Two cases showed a decreased phosphopyridoxal level, compared with levels in the controls not receiving therapy. The genotype TT (C677T) is an NTD genetic susceptibility, but it was observed in only one valproic acid control. Various polymorphisms were observed in the cases, but were also common in the controls. Several studies have reported that valproic acid therapy lowers vitamin B6 levels. Our case with the greatest decrease in plasma phosphopyridoxal, who was taking periconceptional folic acid plus pyridoxine therapy, had a normal second pregnancy outcome. CONCLUSIONS: In addition to folates, other vitamins, such as vitamin B6, may have played a role in NTDs in our patients taking an antiepileptic drug.     

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.