Congenital malformations and maternal smoking during pregnancy

The relationship between smoking during pregnancy and congenital malformations was studied in prospective studies of 33,434 live births in the Kaiser-Permanente Birth Defects Study and 53,512 live births in the Collaborative Perinatal Project (CPP). In the Kaiser study, statistically significant positive associations (P less than .05) were observed for ventral hernias, omphaloceles, and "other major gut abnormalities," but, for each comparison the estimates were based on one or two unexposed cases. Statistically significant negative associations were found for ventricular septal defects (odds ratio, 0.5 [95% confidence interval, 0.2-0.96]), hydroceles (0.7 [0.6-0.9]), clubfoot (0.7 [0.6-0.9]), pigmented nevi (0.7 [0.6-0.9]), hemangiomas (0.8[0.7-0.98]) and Down syndrome (0.2 [0.1-0.9]). To determine if the findings noted above were an artifact of multiple comparisons, seven of these nine malformations were analyzed by smoking status for women in the CPP. All but one of the associations were not confirmed in the CPP. Previously described associations between smoking and specific congenital malformations were also tested using data from the CPP. We conclude that smoking is unlikely to be responsible for a large increase in malformations at birth.     

Congenital heart block and maternal systemic lupus erythematosus.

The association between infants with congenital heart block (CHB) and the presence or later development of maternal systemic lupus erythematosus or other connective-tissue disease (CTD) was reviewed in 67 cases. In 24 cases CHB was diagnosed at or before birth. Of nine necropsies on affected infants, seven showed endomyocardial fibrosis. The results suggest that one in three mothers who deliver babies with CHB have or will develop CTD. The association is probably explained by placental transfer of a maternal antibody. Awareness of the association may lead to prevention of the birth of children with CHB and better neonatal care of affected children.     

Impact of daily work-load during pregnancy on the microstructure of the rat heart in male offspring.

In two series of experiments the development of body weight, heart weight and the microstructure of the rat heart in the male offspring from exercised and control inactive mothers was followed. In 50-day-old male offspring the total body weight and heart weight did not differ; in 100-day-old male offspring the heart weight was significantly higher in those from mothers exercising daily for 1 hr (run on a treat-mill with the speed 14 to 16 m/min, i.e. mild exercise of an aerobic character) throughout pregnancy. As regards microstructure of the heart, the differences were significant both in younger and older animals. The number of exercised mothers. The capillary: fiber ratio was significantly higher and the diffusion distance significantly shorter in male offspring of exercised mothers. During the prenatal period a favorable effect of work-load for the offspring could be induced more easily even with mild aerobic and quite short daily exercise than later during postnatal life as shown by experiments reported previously.     

Vasoactive exposures during pregnancy and risk of microtia

BACKGROUND

Little is known about the etiology of nonsyndromic microtia. This study investigated the hypothesis that microtia is caused by vascular disruption.

METHODS

The study analyzed data from the population‐based National Birth Defects Prevention Study (NBDPS) for deliveries between 1997 and 2005. Four hundred eleven nonsyndromic cases of microtia, with or without additional defects, were compared to 6560 nonmalformed infants with respect to maternal exposures to vasoactive medications and smoking during the periconceptional period and conditions that have previously been associated with vascular events (multiple gestation, maternal history of type 1, type 2, or gestational diabetes, and hypertension). Odds ratios (ORs) were estimated with multivariable models, controlling for the effects of race/ethnicity, education, periconceptional folic acid use, and study center.

RESULTS

Risk estimates for vasoactive medications and smoking were not meaningfully increased. Maternal type 1/2 diabetes was diagnosed before or during the index pregnancy in 4% and 1% of cases, respectively, compared to 1% and 0.05% of controls; the adjusted OR for these two groups combined was 7.2 (95% confidence interval [CI], 3.9–13.1). Gestational diabetes was observed for 9% of cases and 6% of controls; the OR was moderately elevated (OR, 1.4; 95% CI, 0.9–2.0). ORs were also increased for multiple gestations (OR, 2.5; 95% CI, 1.5–4.2) and pre‐existing hypertension (OR, 1.6; 95% CI, 1.0–2.5).

CONCLUSIONS

Because ORs were only elevated for diabetes and not for vasoactive exposures or other potential vascular events, findings suggest that some microtia occurrences may be part of the diabetic embryopathy rather than manifestations of vascular disruption. Birth Defects Research (Part A), 2013. © 2012 Wiley Periodicals, Inc.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

Hormonal basis of hysterectomy-induced maternal behavior during pregnancy in the rat.

Hysterectomy during the last half of pregnancy (i.e., Day 10–19) induces a rapid onset of maternal behavior; ovariectomy in addition to hysterectomy, prevents this effect. Estradiol and progesterone were tested for their ability to restore short-latency maternal behavior in hysterectomized-ovariectomized (HO) females operated on the 10th, 13th, 16th and 19th days of pregnancy. A single injection of either 20 μg/kg or 100 μg/kg estradiol benzoate (EB) immediately following HO either alone or followed by 0.5 mg progesterone (P) 44 hr later restored short-latency maternal behavior similar to that observed following hysterectomy only. The lower dose of EB was found to be equally effective at all stages of pregnancy and P was unnecessary to induce maternal behavior. The effectiveness of EB in inducing maternal behavior was discussed in relation to the hormonal changes which follow hysterectomy during pregnancy and to those which are associated with the normal onset of maternal behavior around parturition.     

Poor maternal environment enhances offspring disease resistance in an invertebrate

Natural populations vary tremendously in their susceptibility to infectious disease agents. The factors (environmental or genetic) that underlie this variation determine the impact of disease on host population dynamics and evolution, and affect our capacity to contain disease outbreaks and to enhance resistance in agricultural animals and disease vectors. Here, we show that changes in the environmental conditions under which female Daphnia magna are kept can more than halve the susceptibility of their offspring to bacterial infection. Counter-intuitively, and unlike the effects typically observed in vertebrates for transfer of immunity, mothers producing offspring under poor conditions produced more resistant offspring than did mothers producing offspring in favourable conditions. This effect occurred when mothers who were well provisioned during their own development then found themselves reproducing in poor conditions. These effects likely reflect adaptive optimal resource allocation where better quality offspring are produced in poor environments to enhance survival. Maternal exposure to parasites also reduced offspring susceptibility, depending on host genotype and offspring food levels. These maternal responses to environmental conditions mean that studies focused on a single generation, and those in which environmental variation is experimentally minimized, may fail to describe the crucial parameters that influence the spread of disease. The large maternal effects we report here will, if they are widespread in nature, affect disease dynamics, the level of genetic polymorphism in populations, and likely weaken the evolutionary response to parasite-mediated selection.     

Impacts of ceftriaxone exposure during pregnancy on maternal gut and placental microbiota and its influence on maternal and offspring immunity in mice

This study aimed to investigate the association between microbiota found in the maternal gut and placenta, and whether ceftriaxone exposure during pregnancy could alter these microbiota, and consequently affect the immunity of the mothers and their offspring. The microbiota in the feces and placenta of the dams were comprehensively analyzed using16S rRNA sequencing. Furthermore, viable bacteria in the placentas and blood of pups were also isolated by plate cultivation then taxonomically identified in detail by clone sequencing. Serum cytokines collected from dams and pups were quantitatively profiled using Luminex. The spleen organ index of dams was significantly lower and the offspring serum interleukin-6 levels were significantly higher in ceftriaxone-treated mice compared with the control group. The maternal fecal microbiota community was drastically altered in ceftriaxone-treated mice with significantly decreased diversity, depletion of Bacteroidetes and the blooming of Tenericutes. However, the placenta microbiota was dominated by Proteobacteria especially characteristically by Ralstonia, which was distinct from the maternal gut microbiota, regardless of whether ceftriaxone treatment or not. Viable bacteria have been found in placenta and blood cultures. These results indicated that ceftriaxone exposure in pregnancy could dramatically alter maternal intestinal microbiota, which affected the immunity of the mothers and their offspring at least partly, characteristically by enhanced pro-inflammatory responses. This study also indicated that the placenta might harbor its own microbes and the microbes were distinct from maternal gut microbiota, which may not be affected by oral administration of ceftriaxone during pregnancy.     

Early pregnancy agricultural pesticide exposures and risk of gastroschisis among offspring in the San Joaquin Valley of California

Background: Prevalence of gastroschisis has inexplicably been increasing over the past few decades. Our intent was to explore whether early gestational exposures to pesticides were associated with risk of gastroschisis. Methods: We used population‐based data, accompanied by detailed information from maternal interviews as well as information on residential proximity to a large number of commercial pesticide applications during early pregnancy. The study population derived from the San Joaquin Valley of California ( ). Cases were 156 infants/fetuses with gastroschisis and controls were 785 infants without birth defects. Results: Among 22 chemical pesticide groups analyzed, none had an elevated odds ratio with an associated confidence interval that excluded 1.0, although exposure to the triazine group showed borderline significance. Among 36 specific pesticide chemicals analyzed, only exposure to petroleum distillates was associated with an elevated risk, odds ratio = 2.5 (1.1–5.6). In general, a substantially different inference was not derived when analyses were stratified by maternal age or when risk estimation included adjustment for race/ethnicity, body mass index, folic acid supplement use, and smoking. Conclusion: Our study rigorously adds to the scant literature on this topic. Our a priori expectation was that we would observe certain pesticide compounds to be particularly associated with young age owing to the disproportionate risk observed for young women to have offspring with gastroschisis. We did not observe an exposure profile unique to young women. Birth Defects Research (Part A), 100:686–694, 2014. © 2014 Wiley Periodicals, Inc.     

Exercise during pregnancy mitigates Alzheimer-like pathology in mouse offspring

Physical activity protects brain function in healthy individuals and those with Alzheimer's disease (AD). Evidence for beneficial effects of parental exercise on the health status of their progeny is sparse and limited to nondiseased individuals. Here, we questioned whether maternal running interferes with offspring's AD-like pathology and sought to decipher the underlying mechanisms in TgCRND8 mice. Maternal stimulation was provided by voluntary wheel running vs. standard housing during pregnancy. Following 5 mo of standard housing of transgenic and wild-type offspring, their brains were examined for AD-related pathology and/or plasticity changes. Running during pregnancy reduced β-amyloid (Aβ) plaque burden (-35%, P=0.017) and amyloidogenic APP processing in transgenic offspring and further improved the neurovascular function by orchestrating different Aβ transporters and increasing angiogenesis (+29%, P=0.022). This effect was accompanied by diminished inflammation, as indicated by reduced microgliosis (-20%, P=0.002) and down-regulation of other proinflammatory mediators, and resulted in less oxidative stress, as nitrotyrosine levels declined (-28%, P=0.029). Moreover, plasticity changes (in terms of up-regulation of reelin, synaptophysin, and ARC) were found not only in transgenic but also in wild-type offspring. We conclude that exercise during pregnancy provides long-lasting protection from neurodegeneration and improves brain plasticity in the otherwise unstimulated progeny.     

Maternal corticotropin-releasing hormone levels during pregnancy and offspring adiposity

Objective: Animal models suggest that fetal exposure to glucocorticoids can program adiposity, especially central adiposity, later in life. We examined associations of maternal corticotropin‐releasing hormone (CRH) levels in the late 2nd trimester of pregnancy, a marker of fetal glucocorticoid exposure, with child adiposity at age 3 years. Research Methods and Procedures: We analyzed data from 199 participants in Project Viva, a prospective cohort study of pregnant women and their children, At age 3 years, the main outcomes were age‐sex‐specific BMI z score and the sum of subscapular (SS) and triceps (TR) skinfold thicknesses to represent overall adiposity, and ratio of SS to TR (SS:TR) to represent central adiposity. Results: Mean (standard deviation) maternal 2nd trimester log CRH was 4.94 (0.56) pg/mL. At age 3, mean (standard deviation) for BMI z score was 0.52 (1.02); for SS + TR, 16.51 (3.94) mm; and for SS:TR, 0.67 (0.17). Log CRH was mildly inversely correlated with birth weight (r = ?0.08), chiefly because of its association with length of gestation (r = ?0.21) rather than fetal growth (r = ?0.004). After adjustment for sociodemographic factors, maternal smoking, BMI, and gestational weight gain, fetal growth, length of gestation, breastfeeding duration, and (for SS:TR only) child's 3‐year BMI, each increment of 1 unit of log CRH was associated with a reduction in BMI z score [?0.43; 95% confidence interval (CI), ?0.73, ?0.14; p = 0.004] and possible reduction in SS + TR (?1.10; 95% CI, ?2.33, 0.14; p = 0.08). In contrast, log CRH was associated with higher SS:TR (0.07; 95% CI, 0.02, 0.13; p = 0.007). Discussion: Fetal exposure to glucocorticoids, although associated with an overall decrease in body size, may cause an increase in central adiposity.     

Effects of feed restriction during pregnancy on maternal reproductive outcome,foetal hepatic IGF gene expression and offspring performance in the rabbit

Primiparous female rabbits have high nutritional requirements and, while it is recommended that they are subjected to an extensive reproductive rhythm, this could lead to overweight, affecting reproductive outcomes. We hypothesised that restricting food intake during the less energetic period of gestation could improve reproductive outcome without impairing offspring viability. This study compares two groups of primiparous rabbit does in an extensive reproductive programme, one in which feed was restricted from Day 0 to Day 21 of gestation (R021), and another in which does were fed ad libitum (control) throughout pregnancy. The mother and offspring variables compared were (1) mother reproductive outcomes at the time points pre-implantation (Day 3 postartificial insemination [AI]), preterm (Day 28 post-AI) and birth; and (2) the prenatal offspring characteristic IGF system gene expression in foetal liver, liver fibrosis and foetus sex ratio, and postnatal factor viability and growth at birth, and survival and growth until weaning. Feed restriction did not affect the conception rate, embryo survival, or the number of morulae and blastocysts recovered at Day 3 post-AI. Preterm placenta size and efficiency were similar in the two groups. However, both implantation rate (P < 0.001) and the number of foetuses (P = 0.05) were higher in the R021 mothers than controls, while there was no difference in foetal viability. Foetal size and weight, the weights of most organs, organ weight/BW ratios and sex ratio were unaffected by feed restriction; these variables were only affected by uterine position (P < 0.05). Conversely, in the R021 does, foetal liver IGBP1 and IGF2 gene expression were dysregulated despite no liver fibrosis and a normal liver structure. No effects of restricted feed intake were produced on maternal fertility, prolificacy, or offspring birth weight, but control females weaned more kits. Litter weight and mortality rate during the lactation period were also unaffected. In conclusion, pre-implantation events and foetal development were unaffected by feed restriction. While some genes of the foetal hepatic IGF system were dysregulated during pregnancy, liver morphology appeared normal, and the growth of foetuses and kits until weaning was unmodified. This strategy of feed restriction in extensive reproductive rhythms seems to have no significant adverse effects on dam reproductive outcome or offspring growth and viability until weaning.     

Smoking during pregnancy and offspring fat and lean mass in childhood

Objective: Maternal smoking during pregnancy has been shown to be associated with obesity in the offspring, but findings have been based mainly on BMI, which is derived from height and weight. This study examined the association between maternal and partner smoking during pregnancy and offspring total fat, truncal fat, and lean mass in childhood. Research Methods and Procedures: Analysis was based on 5689 white singletons born in 1991–1992 and enrolled in the Avon Longitudinal Study of Parents and Children, with maternal smoking data recorded for at least one trimester in pregnancy and their own body composition assessed by DXA at mean age 9.9 years. Results: Smoking at any time during pregnancy was associated with higher offspring BMI [0.18 (95% confidence interval, 0.12 to 0.25) standard deviation units] and total fat mass [0.17 (95% confidence interval, 0.12 to 0.23) standard deviation units], after adjustment for age, sex, height, and height squared for total fat mass. These associations were not attenuated by adjustment for the confounding factors that were measured. Maternal smoking was also associated with lean mass and, to a lesser extent, truncal fat mass. Associations with partner's smoking were in the same direction but weaker than those of the mother's for all outcomes. Discussion: Maternal smoking at any time during pregnancy is associated with higher offspring total fat mass at mean age 9.9 years. However, as the associations with partner smoking were only a little weaker than those with maternal smoking, confounding by social factors rather than a direct effect of maternal smoking is a possible explanation.     

Congenital heart disease and the specification of left-right asymmetry

Complex congenital heart disease (CHD) is often seen in conjunction with heterotaxy, the randomization of left-right visceral organ situs. However, the link between cardiovascular morphogenesis and left-right patterning is not well understood. To elucidate the role of left-right patterning in cardiovascular development, we examined situs anomalies and CHD in mice with a loss of function allele of Dnaic1, a dynein protein required for motile cilia function and left-right patterning. Dnaic1 mutants were found to have nodal cilia required for left-right patterning, but they were immotile. Half the mutants had concordant organ situs comprising situs solitus or mirror symmetric situs inversus. The remaining half had randomized organ situs or heterotaxy. Looping of the heart tube, the first anatomical lateralization, showed abnormal L-loop bias rather than the expected D-loop orientation in heterotaxy and nonheterotaxy mutants. Situs solitus/inversus mutants were viable with mild or no defects consisting of azygos continuation and/or ventricular septal defects, whereas all heterotaxy mutants had complex CHD. In heterotaxy mutants, but not situs solitus/inversus mutants, the morphological left ventricle was thin and often associated with a hypoplastic transverse aortic arch. Thus, in conclusion, Dnaic1 mutants can achieve situs solitus or inversus even with immotile nodal cilia. However, the finding of abnormal L-loop bias in heterotaxy and nonheterotaxy mutants would suggest motile cilia are required for normal heart looping. Based on these findings, we propose motile nodal cilia patterns heart looping but heart and visceral organ lateralization is driven by signaling not requiring nodal cilia motility.     

High intensity exercise during pregnancy of rats. Effects on mother and offspring

We see in this study the effect of high intensity exercise (90% VO₂ max) in pregnant rats and their offspring depending on the length of pregnancy. The findings were compared with those obtained for sedentary pregnant rats and non-pregnant rats for similar exercise. This allowed for analysing the isolated effects of exercise (against the sedentary non-pregnant rat control group), of pregnancy and of the interaction between the two factors. For checking the effect of the length of pregnancy, each group of rats was subdivided into those with pregnancy terminated or sacrificed on the seventh, fourteenth or twentieth day of the experiment. VO₂ max, post-exertion blood lactic acid level, body weight gain, food intake, feed efficiency, glucose, triglyceride, total cholesterol, total protein and albumin plasmatic concentrations in adult rats, and weight and number of offspring of pregnant rats were determined. Pregnancy increased weight gain and feed efficiency from the first week of the study, accompanied by a greater food intake (from the twelfth day). In the group of pregnant rats subjected to exercise, there was a reduction in weight gain percentage and feed efficiency in the first and third weeks, staying the same in the second week. A greater food intake during the period accompanied this recovery in the second week. In the group of non-pregnant rats subjected to exercise, food intake did not vary. As the weight gain percentage was less in relation to the non-pregnant control group, feed efficiency decreased. Pregnancy induced a drop in blood sugar level starting in the second week, and the exercise performed during pregnancy did not change this behavior. Pregnancy produced, however, an increase in plasmatic concentration of triglycerides and total cholesterol during the third week of pregnancy. Exercise performed by pregnant rats also did not change this behavior, but the increase observed in the third week was less. Exercise performed by non-pregnant rats did not change the blood sugar level and plasmatic concentration of triglycerides and total cholesterol during the entire experiment. Plasmatic concentration of total proteins and albumin showed a drop in the third week of pregnancy, probably due to high fetal use of proteins in this stage. Exercise performed by the pregnant group caused a lower protein drop in the third week, and in the non-pregnant group, determined an increase in plasmatic protein concentrations. The weight of the offspring of mother rats exercised until the end of the second and third weeks of pregnancy was found to be reduced in relation to the sedentary pregnant group. The group exercised until the third week showed a reduction in the number of offspring, indicating a possible fetal reabsorption. These findings confirmed that high intensity exercise can produce deleterious effects on the mother and fetus, especially when applied up to the last stage of pregnancy.