Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants.

BACKGROUND: Intensive medical care of women with diabetes has reduced their risks of bearing infants with congenital anomalies. To assess the preventive potential of preconceptional care, the data of a population-based study of cardiovascular malformations (CVM) were analyzed to determine the morphogenetic specificity of maternal diabetes risks, the morbidity and mortality of the infants, and maternal characteristics that might affect these risks. METHODS: The Baltimore-Washington Infant Study was a case-control study (1981-1989) that included all live born infants with confirmed CVM; control infants were a representative sample of the birth cohort. A questionnaire administered in home visits recorded parental information on social, medical, occupational, and environmental factors. For these analyses of preconceptional diabetes risks, the case group excluded chromosomal and mendelian disorders and was divided into 3 developmental categories and 12 diagnostic groups. RESULTS: Preconceptional maternal diabetes was strongly associated with CVM of early embryonic origin (odds ratio [OR] = 4.7, 95% confidence interval [CI] 2.8-7.9) and with cardiomyopathy (OR = 15.1, 95% CI 5.5-41.3), but not with obstructive and shunting defects (OR = 1.4, 95% CI 0.7-3.0). There was heterogeneity within these developmental categories: among laterality defects, diabetes was associated only with cardiovisceral and atrioventricular discordance (OR = 10.0, 95% CI 3.7-27.0); among outflow tract anomalies, the risk was strongly associated with normally related great arteries (OR = 6.6, 95% CI 3.2-13.3) but not with simple transpositions; and among atrioventricular septal defects, diabetes was associated with the complete but not with the partial forms (OR = 22.8, 95% CI 7.4-70.5). The association in early CVM was strongest among infants with multisystem, predominantly VACTERL, anomalies. All-cause mortality of infants with CVM was 39% among those with diabetic mothers and 17.8% in those with nondiabetic mothers. Deceased infants of diabetic mothers were also more likely to have extracardiac anomalies (P = 0.041), to be born prematurely (P = 0.007), and to have low birth weight (P = 0.011). Multivariate analyses of maternal factors revealed no significant confounders of the diabetes associations. CONCLUSIONS: The evidence of diabetes-induced major cardiac defects is of urgent clinical significance. The effectiveness of early preconceptional care in the prevention of congenital anomalies has been demonstrated repeatedly.     

Risk factors and outcomes of maternal obesity and excessive weight gain during pregnancy

Objective:

The prevalence of overweight and obesity among women of reproductive age is increasing. We aimed to determine risk factors and maternal, fetal and childhood consequences of maternal obesity and excessive gestational weight gain.

Design and Methods:

The study was embedded in a population‐based prospective cohort study among 6959 mothers and their children. The study was based in Rotterdam, The Netherlands (2001–2005).

Results:

Maternal lower educational level, lower household income, multiparity, and FTO risk allel were associated with an increased risk of maternal obesity, whereas maternal European ethnicity, nulliparity, higher total energy intake, and smoking during pregnancy were associated with an increased risk of excessive gestational weight gain (all p‐values <0.05). As compared to normal weight, maternal obesity was associated with increased risks of gestational hypertension (OR 6.31 (95% CI 4.30, 9.26)), preeclampsia (OR (3.61, (95% CI 2.04, 6.39)), gestational diabetes (OR 6.28 (95%CI 3.01, 13.06)), caesarean delivery (OR 1.91 (95% CI 1.46, 2.50)), delivering large size for gestational age infants (OR 2.97 (95% CI 2.16, 4.08)), and childhood obesity (OR 5.02 (95% CI:2.97, 8.45)). Weaker associations of excessive gestational weight gain with maternal, fetal and childhood outcomes were observed, with the strongest effects for first trimester weight gain.

Conclusions:

Our study shows that maternal obesity and excessive weight gain during pregnancy are associated with socio‐demographic, lifestyle, and genetic factors and with increased risks of adverse maternal, fetal and childhood outcomes. As compared to prepregnancy overweight and obesity, excessive gestational weight gain has a limited influence on adverse pregnancy outcomes.     

Infants with single ventricle: a population-based epidemiological study

BACKGROUND: Single ventricle, a rare congenital cardiac defect, often occurs as part of a complex group of cardiovascular abnormalities. Little is known of its epidemiologic associations. METHODS: Using data from the Baltimore-Washington Infant Study [BWIS], (1981-89), a population based case-control study of cardiovascular malformations, infants with single ventricle were evaluated with respect to infant and family characteristics and maternal and paternal exposures. The cases were analyzed according to presence/absence of abnormal cardio-visceral situs. Controls were 3,572 infants without heart defects randomly selected from the regional cohort of live births. Odds ratios and 95% confidence intervals were used as measures of association. RESULTS: Single ventricle occurred in 1.25% of infants with congenital cardiovascular defects in the BWIS. Fifty-five infants had single ventricle. In 48 families (87.3%) the parents were interviewed. Thirty-three infants had normal situs and 15 had abnormal situs. Paternal alcohol consumption (OR = 2.0, 95% CI 1.1-3.9) and paternal cigarette smoking (OR = 2.4, 95% CI 1.1-5.1) were associated with all cases of single ventricle. These associations were even stronger in the subset of infants with abnormal situs. Maternal history of a previous induced abortion was also associated with infants born with abnormal situs (OR = 3.2, 95% CI 1.1-11.5). Paternal marijuana use was associated with cases of single ventricle in normal situs (OR = 2.2, 95% CI 1.0-5.2). CONCLUSIONS: Potential risk factors included paternal smoking and alcohol consumption, highlighting the need for future studies to consider environmental factors in the pathogenesis of this cardiac defect.     

Early pregnancy azathioprine use and pregnancy outcomes

BACKGROUND: Azathioprine (AZA) is used during pregnancy by women with inflammatory bowel disease (IBD), other autoimmune disorders, malignancy, and organ transplantation. Previous studies have demonstrated potential risks. METHODS: The Swedish Medical Birth Register was used to identify 476 women who reported the use of AZA in early pregnancy. The effect of AZA exposure on pregnancy outcomes was studied after adjustment for maternal characteristics that could act as confounders. RESULTS: The most common indication for AZA use was IBD. The rate of congenital malformations was 6.2% in the AZA group and 4.7% among all infants born (adjusted OR: 1.41, 95% CI: 0.98–2.04). An association between early pregnancy AZA exposure and ventricular/atrial septal defects was found (adjusted OR: 3.18, 95% CI: 1.45–6.04). Exposed infants were also more likely to be preterm, to weigh <2500 gm, and to be small for gestational age compared to all infants born. This effect remained for preterm birth and low birth weight when infants of women with IBD but without AZA exposure were used as a comparison group. A trend toward an increased risk of congenital malformations was found among infants of women with IBD using AZA compared to women with IBD not using AZA (adjusted OR: 1.42, 95% CI: 0.93–2.18). CONCLUSIONS: Infants exposed to AZA in early pregnancy may be at a moderately increased risk of congenital malformations, specifically ventricular/atrial septal defects. There is also an increased risk of growth restriction and preterm delivery. These associations may be confounded by the severity of maternal illness. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Association of Diabetes in Pregnancy with Child Weight at Birth,Age 12 Months and 5 Years – A Population-Based Electronic Cohort Study

Background

This study examines the effect of diabetes in pregnancy on offspring weight at birth and ages 1 and 5 years.

Methods

A population-based electronic cohort study using routinely collected linked healthcare data. Electronic medical records provided maternal diabetes status and offspring weight at birth and ages 1 and 5 years (n = 147,773 mother child pairs). Logistic regression models were used to obtain odds ratios to describe the association between maternal diabetes status and offspring size, adjusted for maternal pre-pregnancy weight, age and smoking status.

Findings

We identified 1,250 (0.9%) pregnancies with existing diabetes (27.8% with type 1 diabetes), 1,358 with gestational diabetes (0.9%) and 635 (0.4%) who developed diabetes post-pregnancy. Children whose mothers had existing diabetes were less likely to be large at 12 months (OR: 0.7 (95%CI: 0.6, 0.8)) than those without diabetes. Maternal diabetes was associated with high weight at age 5 years in children whose mothers had a high pre-pregnancy weight tertile (gestational diabetes, (OR:2.1 (95%CI:1.25–3.6)), existing diabetes (OR:1.3 (95%CI:1.0 to 1.6)).

Conclusion

The prevention of childhood obesity should focus on mothers with diabetes with a high maternal pre-pregnancy weight. We found little evidence that diabetes in pregnancy leads to long term obesity ‘programming’.     

Maternal birthplace and major congenital malformations among New York Hispanics

BACKGROUND: Little is known about the association between maternal nativity and congenital malformations among Hispanics living in the United States. METHODS: We conducted a cross-sectional study to investigate the association between maternal nativity and various congenital malformations among singleton live-births born to Hispanic women in New York from 1993 to 2001. Birth certificates, used to identify maternal birthplace, were linked with congenital malformation registry files to obtain birth defects outcome. We examined how the risk of birth defects varied by maternal birthplace by estimating the adjusted odds ratios (aORs) using logistic regression. RESULTS: A foreign maternal birth showed statistically negative associations with overall congenital malformations (aOR, 0.70; 95% CI, 0.68-0.73), cardiovascular defects (aOR, 0.85; 95% CI, 0.77-0.93), central nervous system defects (aOR, 0.76; 95% CI, 0.63-0.91), and multiple defects (aOR, 0.80; 95% CI, 0.74-0.86). Specifically, foreign-born Hispanic women were statistically at reduced risk to deliver live babies with cleft palate (aOR, 0.56; 95% CI, 0.40-0.80), atresia and stenosis of rectum or anus (aOR, 0.58; 95% CI, 0.35-0.97), and craniosynostosis (aOR, 0.71; 95% CI, 0.51-0.99). Hispanic mothers born in Puerto Rico had a similar risk of delivering children with birth defects compared to U.S.-born Hispanic mothers. In contrast, Hispanic mothers born in Mexico, or Cuba and Central and South America were at reduced risk of delivering infants with overall congenital malformations (aOR, 0.64; 95% CI, 0.60-0.67) and (aOR, 0.65; 95% CI, 0.63-0.68), respectively. CONCLUSIONS: Foreign-born Hispanic mothers had a slightly lower risk to deliver live-born singleton infants with major congenital malformations than did U.S. born Hispanic mothers.     

Association of Thyroid Function During Pregnancy With the Risk of Pre-eclampsia and Gestational Diabetes Mellitus

ObjectiveTo estimate the association of maternal thyroid dysfunction with the risk of gestational hypertension and diabetes. Whether the association was affected by gestational age at diagnosis and thyroid autoimmunity was further explored.MethodsA cohort study of 41 647 participants was conducted. Thyroid function (ie, thyroid-stimulating hormone [TSH] and free thyroxine [FT4]) was measured by electrochemiluminescence immunoassay. Thyroid antibody positivity (eg, thyroperoxidase, thyroglobulin, and TSH receptor antibody) was indicated if the values of these antibodies exceeded the upper targets of the reference range. The relationship between maternal thyroid dysfunction and the risk of pre-eclampsia (PE) and gestational diabetes mellitus (GDM) was assessed by multivariate logistic regression.ResultsIsolated hypothyroxinemia (defined as 5th ≤ TSH ≤ 95th percentile, FT4 < 5th percentile) was associated with the risk of PE (odds ratio [OR], 1.32; 95% CI, 1.10-1.58). Overt hypothyroidism (TSH > 95th percentile; FT4 < 5th percentile) was related to the risk of severe PE (OR, 2.59; 95% CI, 1.05-6.37). Being positive for TSH receptor antibody was associated with a decreased risk of GDM (OR, 0.49; 95% CI, 0.35-0.70). A marginally significant association between overt hypothyroidism detected at the first trimester and the risk of GDM was found (OR, 1.60; 95% CI, 1.00-2.83). The association of thyroid dysfunction with the risk of PE and GDM was stronger among pregnant women who were negative for autoantibodies.ConclusionSome types of thyroid dysfunction during pregnancy were associated with the risk of PE and GDM. The associations varied by gestational age at diagnosis and by thyroid autoantibody status.     

Total anomalous pulmonary venous return: familial and environmental factors. The Baltimore-Washington Infant Study Group

In total anomalous pulmonary venous return (TAPVR), the intrapulmonary venous plexus has failed to connect to the left atrium, so that the pulmonary veins drain into right atrial tributaries, frequently resulting in early postnatal circulatory distress. The Baltimore-Washington Infant Study (BWIS), a population-based exploratory case-control study of cardiovascular malformations (CVM), identified 41 cases of TAPVR during 1981-1987: 1.5% of all CVM (N = 2659), a regional prevalence of 6.8/100,000 live births. Of the TAPVR infants, 68% were diagnosed as neonates, 88% had surgery, and 51.2% were alive at 1 year of age. Noncardiac malformations were present in nine cases (22%); the male-female ratio was 0.78 (18.23). Compared with a control group representative of the birth cohort (N = 2,801), more TAPVR patients had low birthweight (less than 2,500 g: 16.2% vs. 6.9%, short gestational age (less than 38 weeks: 18.9% vs. 9.3%), and intrauterine growth retardation (IUGR) (26.8% vs. 5.8%). Sociodemographic findings were similar to those of controls, except that fewer TAPVR mothers received private pregnancy care (59.5% vs. 71.4%). Family history revealed no other TAPVR-affected members, but a significant linear trend of increased risk was found over the ordered malformation categories (familial noncardiac, cardiac, both). Bivariate analysis of TAPVR and exposure in life-style, hobbies, and work showed possible associations for exposure to lead (OR 2.9; 99% confidence interval [CI]: 1.2, 7.2), painting/paint stripping (OR 3.3; 99% CI: 1.3, 8.4), lead soldering (OR 13.3; 99% CI: 1.8, 99.2), and pesticides (OR 2.7; 99% CI: 1.2, 6.4). Multivariate analysis suggested an interaction between pesticide exposure and family history and, thus, a possible familial susceptibility to environmental teratogens. Although the number of TAPVR cases is small, this epidemiologic study identifies hypotheses that may be further explored in morphogenetic and epidemiology studies. Total anomalous pulmonary venous return (TAPVR) constitutes a well-defined clinical entity in which the pulmonary veins fail to enter the left atrium and instead drain into the right atrium or its systemic venous tributaries (Neill, '56; Rowe et al., '81). During intrauterine life, the malformation does not compromise the fetal circulation, since the pulmonary arterial resistance is high and the patent foramen ovale provides easy access of right atrial blood to the left side of the heart. At birth, however, the pulmonary vascular resistance begins to fall, and the presence of a severe hemodynamic disturbance becomes increasingly evident (Ferencz et al., '71).(ABSTRACT TRUNCATED AT 400 WORDS)     

Joint and Independent Associations of Gestational Weight Gain and Pre-Pregnancy Body Mass Index with Outcomes of Pregnancy in Chinese Women: A Retrospective Cohort Study

Objective

To explore the joint and independent effects of gestational weight gain (GWG) and pre-pregnancy body mass index (BMI) on pregnancy outcomes in a population of Chinese Han women and to evaluate pregnant women’s adherence to the 2009 Institute of Medicine (IOM) gestational weight gain guidelines.

Methods

This was a multicenter, retrospective cohort study of 48,867 primiparous women from mainland China who had a full-term singleton birth between January 1, 2011 and December 30, 2011. The independent associations of pre-pregnancy BMI, GWG and categories of combined pre-pregnancy BMI and GWG with outcomes of interest were examined using an adjusted multivariate regression model. In addition, women with pre-pregnancy hypertension were excluded from the analysis of the relationship between GWG and delivery of small-for-gestational-age (SGA) infants, and women with gestational diabetes (GDM) were excluded from the analysis of the relationship between GWG and delivery of large-for-gestational-age (LGA) infants.

Results

Only 36.8% of the women had a weight gain that was within the recommended range; 25% and 38.2% had weight gains that were below and above the recommended range, respectively. The contribution of GWG to the risk of adverse maternal and fetal outcomes was modest. Women with excessive GWG had an increased likelihood of gestational hypertension (adjusted OR 2.55; 95% CI = 1.92–2.80), postpartum hemorrhage (adjusted OR 1.30; 95% CI = 1.17–1.45), cesarean section (adjusted OR 1.31; 95% CI = 1.18–1.36) and delivery of an LGA infant (adjusted OR 2.1; 95% CI = 1.76–2.26) compared with women with normal weight gain. Conversely, the incidence of GDM (adjusted OR 1.64; 95% CI = 1.20–1.85) and SGA infants (adjusted OR 1.51; 95% CI = 1.32–1.72) was increased in the group of women with inadequate GWG. Moreover, in the obese women, excessive GWG was associated with an apparent increased risk of delivering an LGA infant. In the women who were underweight, poor weight gain was associated with an increased likelihood of delivering an SGA infant. After excluding the mothers with GDM or gestational hypertension, the ORs for delivery of LGA and SGA infants decreased for women with high GWG and increased for women with low GWG.

Conclusions

GWG above the recommended range is common in this population and is associated with multiple unfavorable outcomes independent of pre-pregnancy BMI. Obese women may benefit from avoiding weight gain above the range recommended by the 2009 IOM. Underweight women should avoid low GWG to prevent delivering an SGA infant. Pregnant women should therefore be monitored to comply with the IOM recommendations and should have a balanced weight gain that is within a range based on their pre-pregnancy BMI.     

Talipes equinovarus and maternal smoking: a population-based case-control study in Washington state

BACKGROUND: Talipes equinovarus (TEV), also called congenital idiopathic clubfoot, true clubfoot and common clubfoot, is one of the most common major birth defects. Its correction is often difficult and expensive. Its etiology is poorly understood and few analytic epidemiological studies have been devoted to exploring specific risk factors for TEV. METHODS: Our population-based study consists of 239 documented cases of idiopathic TEV obtained from hospital and outpatient sources and 365 controls identified via random digit dialing from five Western Washington counties. Structured maternal interviews were conducted by trained interviewers and multiple logistic regression used to evaluate associations between maternal smoking and birth of a child with TEV. RESULTS: Our study shows strong associations between maternal smoking and idiopathic TEV. Case mothers were more likely to have smoked during pregnancy (OR = 2.2; 95% CI = 1.5, 3.3). Increased TEV risk was seen with increased smoking and estimates ranged from 1.5 for the lightest smokers to 3.9 for the heaviest smokers. Gender specific differences in risk were also noted with risk estimates of 1.8 (95% CI = 1.2, 3.0) for boys whose mothers smoked during pregnancy and 2.8 (95% CI = 1.4, 5.4) for girls. Trends for increased risk with higher numbers of cigarettes were noted for both genders. For isolated TEV, the overall odds ratio (OR) for smoking was 2.4 (95% CI = 1.6, 3.6) with a range from 1.4-4.6. No confounders were noted. CONCLUSIONS: As postulated, maternal smoking during pregnancy appears to increase the risk of having a child with idiopathic clubfoot and the number of cigarettes smoked influence that risk. Further delineation of dose-response is warranted as are continued efforts to decrease maternal smoking during pregnancy.     

Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study

Background

Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births.

Methods and Findings

We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38–0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11–0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13–0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period.

Conclusions

This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth. Please see later in the article for the Editors'' Summary     

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.     

Fetal cardiac effects of maternal hyperglycemia during pregnancy

Maternal diabetes mellitus is associated with increased teratogenesis, which can occur in pregestational type 1 and type 2 diabetes. Cardiac defects and with neural tube defects are the most common malformations observed in fetuses of pregestational diabetic mothers. The exact mechanism by which diabetes exerts its teratogenic effects and induces embryonic malformations is unclear. Whereas the sequelae of maternal pregestational diabetes, such as modulating insulin levels, altered fat levels, and increased reactive oxygen species, may play a role in fetal damage during diabetic pregnancy, hyperglycemia is thought to be the primary teratogen, causing particularly adverse effects on cardiovascular development. Fetal cardiac defects are associated with raised maternal glycosylated hemoglobin levels and are up to five times more likely in infants of mothers with pregestational diabetes compared with those without diabetes. The resulting anomalies are varied and include transposition of the great arteries, mitral and pulmonary atresia, double outlet of the right ventricle, tetralogy of Fallot, and fetal cardiomyopathy. A wide variety of rodent models have been used to study diabetic teratogenesis. Both genetic and chemically induced models of type 1 and 2 diabetes have been used to examine the effects of hyperglycemia on fetal development. Factors such as genetic background as well as confounding variables such as obesity appear to influence the severity of fetal abnormalities in mice. In this review, we will summarize recent data on fetal cardiac effects from human pregestational diabetic mothers, as well as the most relevant findings in rodent models of diabetic cardiac teratogenesis. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment

BACKGROUND: We have previously reported on a malformation-prone Sprague-Dawley rat substrain (U), which presents a high frequency of micrognathia in the offspring of diabetic mothers. This malformation is related to impaired development of the cranial neural crest cells (NCC); the defect may be prevented by antioxidative treatment of the mother. METHODS: We have therefore investigated whether fetuses of diabetic rats display other malformations associated with altered cranial NCC development and whether maternal vitamin E supplementation may affect such malformations. RESULTS: Fetuses of diabetic rats showed low-set external ears, severely malformed Meckel's cartilage, small thyroid and thymus, and absence of parathyroid glands. Cardiac anomalies were frequently observed, including rightward displacement of the aorta, double outlet right ventricle (DORV), persistent truncus arteriosus (PTA) combined with ventricular septal defects due to a malaligned outlet septum. The malformations in the outflow tract included abnormalities of the great arteries; right-sided aortic arch/descending aorta, and double aortic arches. These defects tended to occur together within individual fetuses. Maternal dietary treatment with 2% vitamin E markedly reduced the severity of the malformations. CONCLUSIONS: The phenotypic appearance of these defects is strikingly similar to the DiGeorge anomaly in humans, which has been found in children of diabetic mothers together with an overrepresentation of PTA and DORV. The malformations associated with defective NCC development in the offspring of diabetic U rats show several morphological similarities to those in humans; hence the teratogenic mechanisms may be similar and accessible for study.     

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.     

Maternal Snuff Use and Smoking and the Risk of Oral Cleft Malformations - A Population-Based Cohort Study

Objective

To determine if maternal use of snuff (containing high levels of nicotine, low levels of nitrosamines and no combustion products) is associated with an increased risk of oral cleft malformations in the infant and whether cessation of snuff use or smoking before the antenatal booking influences the risk.

Method

A population-based cohort study was conducted on all live born infants, recorded in the Swedish Medical Birth Register from 1999 through 2009 (n = 1 086 213). Risks of oral clefts were evaluated by multivariate logistic regression analyses (using adjusted odds ratios, with 95% confidence intervals [CI]).

Results

Among 975 866 infants that had information on maternal tobacco use, 1761 cases of oral clefts were diagnosed. More than 50% of the mothers who used snuff or smoked three months prior pregnancy stopped using before the antenatal booking. Almost 8% of the mothers were smoking at the antenatal booking and 1,1% of the mothers used snuff. Compared with infants of non-tobacco users, the adjusted odds ratios (95% CI) of any oral cleft for infants of mothers who continued to use snuff or to smoke were 1.48 [1.00–2.21] and 1.19 [1.01–1.41], respectively. In contrast, in infants of mothers who stopped using snuff or stopped smoking before the antenatal booking, the corresponding risks were not increased (adjusted odds ratios [95% CI] were 0.71 [0.44–1.14] and 0.88 [0.73–1.05], respectively).

Conclusion

Maternal snuff use or smoking in early pregnancy is associated with an increased risk of oral clefts. Infants of mothers who stopped using snuff or stopped smoking before the antenatal booking had no increased risk of oral cleft malformations. Oral snuff or other sources of nicotine should not be recommended as an alternative for smoke-cessation during pregnancy.     

Maternal Gestational Smoking,Diabetes, Alcohol Drinking,Pre-Pregnancy Obesity and the Risk of Cryptorchidism: A Systematic Review and Meta-Analysis of Observational Studies

Background

Maternal gestational smoking, diabetes, alcohol drinking, and pre-pregnancy obesity are thought to increase the risk of cryptorchidism in newborn males, but the evidence is inconsistent.

Method

We conducted a systematic review and meta-analysis of studies on the association between maternal gestational smoking, diabetes, alcohol drinking, and pre-pregnancy obesity and the risk of cryptorchidism. Articles were retrieved by searching PubMed and ScienceDirect, and the meta-analysis was conducted using Stata/SE 12.0 software. Sensitivity analysis was used to evaluate the influence of confounding variables.

Results

We selected 32 articles, including 12 case—control, five nested case—control, and 15 cohort studies. The meta-analysis showed that maternal smoking (OR = 1.17, 95% CI: 1.11–1.23) or diabetes (OR = 1.21, 95%CI: 1.00–1.46) during pregnancy were associated with increased risk of cryptorchidism. Overall, the association between maternal alcohol drinking (OR = 0.97, 95% CI: 0.87–1.07), pre-pregnancy body mass index (OR = 1.02, 95% CI: 0.95–1.09) and risk of cryptorchidism were not statistically significant. Additional analysis showed reduced risk (OR = 0.89, 95% CI: 0.82–0.96) of cryptorchidism with moderate alcohol drinking during pregnancy. No dose—response relationship was observed for increments in body mass index in the risk of cryptorchidism. Sensitivity analysis revealed an unstable result for the association between maternal diabetes, alcohol drinking and cryptorchidism. Moderate heterogeneity was detected in studies of the effect of maternal alcohol drinking and diabetes. No publication bias was detected.

Conclusion

Maternal gestational smoking, but not maternal pre-pregnancy overweight or obesity, was associated with increased cryptorchidism risk in the offspring. Moderate alcohol drinking may reduce the risk of cryptorchidism while gestational diabetes may be a risk factor, but further studies are needed to verify this.     

The Relationship Between Maternal Serum Iron and Zinc Levels and Their Nutritional Intakes in Early Pregnancy with Gestational Diabetes

The aim of this study was to investigate the association between maternal iron/zinc serum levels and their nutritional intake in early pregnancy with gestational diabetes. The maternal serum zinc/iron levels were measured in 1,033 healthy singleton pregnant women aged 20–35 between 14 and 20 weeks of gestation, within two groups: namely, normal and gestational diabetes, and participants were followed up to 24–28 weeks of gestation. Food frequency questionnaire was used to assess nutritional intakes of iron/zinc. The main outcome was gestational diabetes screened with the 50-g glucose challenge test and diagnosed with oral glucose tolerance test at 24–28 weeks of gestation. Gestational diabetes occurred in 72 (6.96 %) of 1,033 women in study. There was a statistical relationship between early pregnancy maternal serum iron and gestational diabetes, mean (SD), 143.8 (48.7) vs. 112.5 (83.5)?μg/dl, P value of <0.0001. There was no statistical significant difference in zinc levels and iron/zinc nutritional intake between groups. The results remained unchanged after using regression model for adjustment of potential risk factors with an adjusted OR of 1.006 (95 % CI 1.002 to 1.009; P?=?0.001) for early pregnancy maternal serum iron to cause gestational diabetes. The receiver–operator characteristic curve identified that a maternal serum iron above 100 μg/dl in early pregnancy is the optimum cutoff value for predicting gestational diabetes, which showed a sensitivity and specificity of 80.6 and 50.7 %, respectively. In conclusion, high maternal serum iron in early pregnancy could increase the risk of gestational diabetes. Also, it could be used as a sensitive and specific predictor for gestational diabetes.     

Maternal Gestational Diabetes Mellitus and Offspring Body Mass Index from 1 to 4 Years

ObjectiveUsing the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria to diagnose gestational diabetes mellitus (GDM), the association between GDM and offspring body mass index (BMI) gains in early childhood in China remains unclear. We aimed to assess the association between GDM diagnosed by the IADPSG criteria and BMI gain and the risk for overweight/obesity in offspring from 1 to 4 years.MethodsThis prospective cohort study was based on the healthcare records data from the Medical Birth Registry in Xiamen, China. We included 10,412 mother-child pairs tested for GDM using IADPSG criteria.ResultsA total of 1,786 (17.2%) offspring were exposed to GDM. The offspring exposed to GDM had higher mean BMI Z-score (difference, 0.07; 95% confidence interval [CI], 0.02 to 0.12) and risk for overweight/obesity (odds ratio [OR], 1.22; 95% CI, 1.06 to 1.40) compared to those unexposed to GDM from 1 to 4 years of age. However, after adjustment for maternal pre-pregnancy BMI (Model 2), these associations attenuated towards the null (difference in BMI Z-score, 0.02; 95% CI, -0.03 to 0.07; OR for overweight/obesity, 1.09; 95% CI, 0.95 to 1.25).ConclusionThe associations between GDM diagnosed using IADPSG criteria and BMI Z-score and the risk for overweight/obesity in offspring at the age of 1 to 4 years were largely explained by maternal pre-pregnancy BMI. Reducing the prevalence of childhood overweight and obesity in China should focus on maternal weight status before pregnancy, in addition to glycemia during pregnancy.     

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.