Childhood medical and behavioral consequences of maternal cocaine use.

Reviewed available studies of the impact of fetal cocaine exposure on child medical and developmental outcome, as well as the current status of clinical psychological interventions and research strategies. Current studies are inconclusive but suggest that prenatal exposure to crack-cocaine can have significant effects on the growth and neurological development of the infant, with the potential of later learning and behavioral disabilities. Social-environmental correlates of maternal cocaine use are confounding factors with known negative effects on child outcome. Large, population-based studies using multivariate analyses are needed to determine the independent effects of cocaine on child outcome relative to other confounding variables.     

Associations between maternal and fetal serum levels of immune activation markers and fetal growth

During pregnancy, signs of maternal immunologic sensitization to fetal HLA and other fetoplacental alloantigens are often detectable in peripheral blood. Presumbly, this in part reflects immune activity at the maternal-fetal interface. This response may involve activation of maternal T cells, which stimulate placental growth via lymphokine production. To shed light on this mechanism, data on placental weight, neonatal anthropometry, gestational age, fetomaternal HLA relationships (reflecting a potential for HLA allosensitization), and serum levels of three immune activation markers in maternal and cord blood were collected in a sample of 61 primiparous women and their neonates. The activation markers were soluble CD8 antigen (sCD8), interleukin-2 receptor (sIL-2R), and beta-2 microglobulin (β₂m). Mean fetal and maternal sCD8 and β₂m levels, and mean fetal sIL-2R levels were significantly higher than published norms. Fetal means for all three markers exceeded maternal means, and both sIL-2R and β₂m were highly correlated between mother and fetus. This suggests that fetal sIL-2R and β₂m levels result in part from transport or diffusion from the maternal compartment. No associations were found between fetomaternal HLA relationships, activation markers, and placental weight. The difference between the fetal and maternal β₂m value was significantly correlated with birth weight, controlling for chest circumference and crown-heel length. Associations between birth weight and fetomaternal HLA relationships could not be interpreted with certainty. These findings suggest that maternal immune activation and diffusion or transport of β₂m into fetal compartment enhances fetal growth in fat-free body mass. © 1995 Wiley-Liss, Inc.     

Effects of magnesium on isolated human fetal and maternal uteroplacental vessels

The effects of Mg2+ were studied in human umbilical arteries, stem villous arteries and maternal intramyometrial arteries. The vessels were dissected and mounted in organ baths, and isometric tension was recorded. In all fetal preparations investigated, Mg2+ (0.5-6.0 mM) in a concentration-related way decreased pD2 values for prostaglandin F2 alpha responses. The maximum response to prostaglandin F2 alpha was depressed in umbilical arteries, but remained unaffected in stem villous artery preparations. In stem villous arteries pretreated in Ca2(+)-free medium, increasing concentrations of Mg2+ markedly depressed the response to Ca2+ after stimulation with K+ or prostaglandin F2 alpha, suggesting that Mg2+ inhibited transmembrane calcium influx and interfered with intracellular calcium effects. In both stem villous and intramyometrial arteries, increasing concentrations of Mg2+ increased EC50 values for responses to K+, whereas Emax values were unaffected. Mg2+ produced relaxation of agonist-induced contractions by up to 60% in stem villous arteries and up to 40% in intramyometrial artery preparations. The relaxant effect of Mg2+ did not seem to be mediated through the endothelium or through changes in the synthesis of prostanoids, since endothelial disruption and treatment with indomethacin left the responses to Mg2+ unaffected. Relaxation of vessels important for resistance regulation in the human uteroplacental vascular bed may be of benefit when uteroplacental blood flow is impaired, and the present results support the established use of magnesium sulphate in the treatment of pre-eclampsia.     

The effect of maternal exercise during pregnancy on abnormal fetal growth

Aim

To assess the effect of maternal physical activity during pregnancy on abnormal fetal growth.

Methods

The study group of 166 women in gestational week 6-8 exercised regularly three days per week at submaximal intensity during their entire pregnancy and the control group of 168 women received standard antenatal care. The main outcomes were macrosomia and intrauterine growth restriction.

Results

The study group had a lower frequency of macrosomia in newborns (6.0% vs 12.5%, P = 0.048) and gestational diabetes (1.8% vs 8.3%, P = 0.008) than the control-group, but there was no significant difference in intrauterine growth restriction (7.2% vs 6.5%). There was also no significant differences in other perinatal outcomes.

Conclusions

The beneficial effect of maternal physical activity on fetal growth may be caused the impact of aerobic exercise on glucose tolerance. Fitness trainers and kinesiologists, as well as health care providers, should be educated on the benefits of regular exercise during pregnancy and safe physical exercise for pregnant women.Intrauterine growth restriction (IUGR) and excessive birth weight are associated with numerous maternal and neonatal complications. Birth weight of over 4000 g causes higher incidence of postpartum hemorrhage, Cesarean sections, shoulder dystocia, birth traumas, and the risk of developing obesity and diabetes mellitus later in life (1,2). IUGR infants are at higher risk for complications of prematurity, including chronic lung disease and necrotizing enterocolitis (3). Childhood implications for IUGR include an increased risk of short stature, cognitive delays with decreased academic achievement, and neurological disorders, including cerebral palsy (4).The incidence of macrosomia and IUGR together amounts to 15%-20% (5,6), causing serious public health consequences, especially in developing countries. Factors associated with fetal development include maternal socioeconomic status, marital status, blood pressure, diabetes mellitus, smoking, life style, and prenatal care (7,8). An important additional effect could also be maternal physical activity in pregnancy, positive (9,10), negative (11-13), and neutral (14,15) effects of which have been described. The vast majority of studies have investigated the impact of short-term exercise programs (of only a few days’ or a few weeks’ duration) and few studies investigated longer exercise programs, especially in the third trimester of pregnancy. The aim of this study was to assess the effect of regular exercise performed during all trimesters of pregnancy on abnormal fetal growth.     

Effects of early maturation on fetal growth

While the association of young maternal age with low birthweight (LBW) is well known, the contribution of early menarche to this association has never been studied. We examined the effects of early menarche (less than or equal to 11 years) on LBW and its two major underlying causes: pre-term delivery and smallness-for-gestational-age (SGA). Results represent a narrow chronological age range, 17-18 years, of a larger geographically based cohort of 2789 pregnant adolescents. Adjusted odds ratios (AOR) indicated that early menarche was significantly associated with an increased risk of LBW which was specific to SGA. The attributable risk of SGA with early menarche exceeded 20%. Early age at menarche is also correlated with an earlier onset of sexual activity, pregnancy, and childbearing. Consequently, adolescents with early menarche are over-represented in a sample limited to young gravidae or a sample that contains a stratum of young gravidae. This may have previously obscured the effects or early menarche on foetal growth and attributed them to a more frequently measured characteristic, young maternal age. Thus, effects of secular change in age at menarche may not be wholly benign. Improvements in maternal fertility and nutritional status appear to be offset by intrauterine growth retardation in the offspring.     

The timing of maternal weight gain during pregnancy and fetal growth

The morbidity, mortality, and growth patterns of intrauterine growth retarded (IUGR) infants vary according to body proportionality, or the ponderal index. Much less in known, however, about the factors that give rise to the various forms of IUGR. This study tests that hypothesis that the rate of maternal weight gain during early/mid and late pregnancy are differentially related to body size and proportions at birth in a nutritionally stressed population in rural Malawi. The data consist of prospectively collected measurements of maternal weight and infant size at birth on 272 mother-infant pairs. The results reveal that early/mid and late weight gain are both related to birth weight and length, but not to the ponderal index. Late weight gain is particularly predictive of infant size among thin women (BMI ⩽ 18.5) and is several times stronger than early/mid weight gain. These findings do not support the timing hypothesis as previously stated in the literature, but do add to the suggestions arising from a disparate literature that growth acceleration in length may precede acceleration in weight-for-length during a period of nutritional replection in phases of the life cycle characterized by rapid growth. Am. J. Hum. Biol. 11:627–637, 1999. © 1999 Wiley-Liss, Inc.     

Brief report: frequency of maternal cocaine use during pregnancy and infant neurobehavioral outcome

OBJECTIVE: To examine the effects of frequency of prenatal maternal cocaine use on infant neurobehavioral outcome beyond the immediate postpartum period, controlling for other substance use. METHODS: At 2 weeks postpartum, the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to infants (N = 55) and their mothers were asked about their prenatal drug use. Mother/infant dyads were placed in one of two groups based on the number of days of reported cocaine use during pregnancy: high frequency (n = 23, > 75th percentile reported days of use) or low frequency (n = 32, < 75th percentile). RESULTS: Infants in the high frequency cocaine group had worse BNBAS excitability scores than infants in the low frequency cocaine group, when other substance use was controlled statistically. CONCLUSIONS: High frequency of maternal cocaine use during pregnancy is associated with poorer infant neurobehavioral outcome beyond the early postpartum period, when other substance use is controlled.     

Effects of twin pregnancy and periconceptional undernutrition on maternal metabolism, fetal growth and glucose-insulin axis function in ovine pregnancy

Although twins have lower birthweights than singletons, they may not experience the increased disease risk in adulthood reportedly associated with low birthweight. In contrast, another periconceptional event, maternal undernutrition, does not reduce birthweight but does affect fetal and postnatal physiology in sheep. We therefore studied maternal and fetal metabolism, growth and glucose–insulin axis function in late gestation in twin and singleton sheep pregnancies, either undernourished from 60 days before until 30 days after conception or fed ad libitum . We found that twin-bearing ewes had decreased maternal food intake in late gestation and lower maternal and fetal plasma glucose and insulin levels. Twin fetuses had fewer everted placentomes, grew slower in late gestation, and had a greater insulin response to a glucose challenge, but lesser response to arginine. In contrast, periconceptional undernutrition led to increased maternal food intake and a more rapid fall in maternal glucose levels in response to fasting. Periconceptional undernutrition increased the number of everted placentomes, and abolished the difference in insulin responses to glucose between twins and singletons. Thus, the physiology of twin pregnancy is quite different from that of singleton pregnancy, and is probably determined by a combination of factors acting in both early and late gestation. The inconsistency of the relationships between low birthweight and postnatal disease risk of twins may lie in their very different fetal development. These data suggest that twin pregnancy may be another paradigm of developmental programming, and indicate that twins and singletons must be examined separately in any study of fetal or postnatal physiology.     

Pregnancy duration and fetal number: Effects on maternal behavior in rats

It was shown previously that in rats postpartum mothers are much more likely than pup sensitized virgin mothers to retrieve pups from a T-maze extension of their home cage. In the present experiment, the physiological basis of this difference was explored further by inducing maternal behavior (retrieving, crouching, licking) following hysterectomy-ovariectomy on Days 21, 16, and 10 of pregnancy. In general, the longer the duration of pregnancy, the shorter the latency to become maternal and the greater the propensity to retrieve pups from the T-maze. An additional group of Day 16 pregnancy terminated rats carrying six or fewer fetuses were not impaired with respect to onset of maternal behavior compared to their large-litter counterparts, but only a small percentage of these females retrieved in the T-maze. These findings suggest that both the late pregnancy estrogen surge and progesterone withdrawal after its peak and sustained secretion enhance maternal responsiveness and that T-maze pup retrieval (but not onset latency) may be additionally affected by the level of placental hormones.     

Sex differences in fetal growth responses to maternal height and weight

Sex differences in fetal growth have been reported, but how this happens remains to be described. It is unknown if fetal growth rates, a reflection of genetic and environmental factors, express sexually dimorphic sensitivity to the mother herself. This analysis investigated homogeneity of male and female growth responses to maternal height and weight. The study sample included 3,495 uncomplicated singleton pregnancies followed longitudinally. Analytic models regressed fetal and neonatal weight on tertiles of maternal height and weight, and modification by sex was investigated (n = 1,814 males, n = 1,681 females) with birth gestational age, maternal parity, and smoking as covariates. Sex modified the effects of maternal height and weight on fetal growth rates and birth weight. Among boys, tallest maternal height influenced fetal weight growth before 18 gestational weeks of age (P = 0.006), and prepregnancy maternal weight and body mass index subsequently had influence (P < 0.001); this was not found among girls. Additionally, interaction terms between sex, maternal height, and maternal weight identified that males were more sensitive to maternal weight among shorter mothers (P = 0.003) and more responsive to maternal height among lighter mothers (P ≤ 0.03), compared to females. Likewise, neonatal birth weight dimorphism varied by maternal phenotype. A male advantage of 60 g occurred among neonates of the shortest and lightest mothers (P = 0.08), compared to 150 and 191 g among short and heavy mothers, and tall and light‐weight mothers, respectively (P = 0.01). Sex differences in response to maternal size are under‐appreciated sources of variation in fetal growth studies and may reflect differential growth strategies. Am. J. Hum. Biol., 2010. © 2009 Wiley‐Liss, Inc.     

Asthma medication use in pregnancy and fetal growth

BACKGROUND: Given the high prevalence of asthma in pregnancy, it is important to understand the relationship between asthma medications and fetal growth in the context of appropriate treatment. OBJECTIVE: This study examines the effect of inhaled corticosteroids, systemic corticosteroids, and beta(2)-agonists on fetal growth in 654 infants born to women with asthma compared with 303 infants born to controls without asthma. METHODS: Subjects for this prospective study were enrolled throughout North America between 1998 and 2003 and followed up by the Organization of Teratology Information Services. Incidence of small for gestational age (SGA) infants and mean birth size measures were compared among groups. RESULTS: Mean birth weight of full-term infants born to mothers who used systemic corticosteroids (3373 g) was lower than in the beta(2)-agonist group (3552 g) and controls without asthma (3540 g; P < .05) after adjustment for other risk factors. However, no differences in the incidence of SGA for weight were observed among groups. Adjusted mean birth length was slightly shorter in the systemic steroid group compared with controls (P=.02). Incidence of SGA for length and head circumference and mean head circumference did not vary among groups (P>.05). CONCLUSION: The treatment of asthma with systemic corticosteroids resulted in a deficit of about 200 g in birth weight compared with controls and exclusive beta(2)-agonist users and no increased incidence of SGA. These results suggest that asthma management with beta(2)-agonists and/or inhaled corticosteroids during pregnancy does not impair fetal growth, whereas systemic corticosteroids have a minimal effect which should be weighed against the necessity to control severe asthma.     

Timing of the influence of maternal nutritional status during pregnancy on fetal growth

This study, which used data from a longitudinal nutrition study of mothers and infants in rural Guatemala, tested a hypothesis that the influence of maternal nutritional status on various measurements of fetal growth is trimester-specific. The relationships between various measures of newborn size and the changes of maternal anthropometry at various stages of pregnancy were analyzed by ordinary least squares multiple regression techniques. The sample included 235 mother-infant pairs who had complete anthropometry for both the newborns (weight, length, and head circumference) and their mothers at 3, 6, and 9 months of pregnancy (weight, height, circumferences of mid-upper arm and thigh, skinfold thicknesses at biceps, triceps, calf, thigh, and subscapular sites). Each kilogram of maternal weight gain in the second and third trimester was associated with statistically significant increases in birth weight of 62 g (P < 0.001) and 26 g (P < 0.05), respectively. Newborn length and head circumference were significantly associated with maternal weight gain and the changes in maternal thigh skinfolds in mid-pregnancy only. The overall results suggest that maternal nutritional status in mid-pregnancy rather than in late pregnancy is a more important determinant of fetal growth in weight, length, and head circumference. Am. J. Hum. Biol. 10:529–539, 1998. © 1998 Wiley-Liss, Inc.     

Effects of prenatal cocaine exposure and maternal separation on heart rate,orienting response habituation,and retention

Effects of the presence or absence of the dam during testing and the retention interval on pretone heart rate (HR) and habituation and retention of an HR orienting response to tone were examined in prenatally cocaine-exposed and nontreated Sprague Dawley rat pups in two experiments. On postnatal day 16, each pup received two test sessions, separated by a 4-hr retention interval during which pups were either isolated or placed with their dam and siblings. For testing, each pup was placed in the test apparatus in the presence or absence of an anesthetized dam where, after a 15-min adaptation period, 10 tone presentations were given, each separated by a 65-s intertrial interval, with HR measured during a 5-s pretone period and throughout the 10-s tone for each trial. Experiment 1 used offspring from the regular breeding colony and observed the typical HR lowering effect of maternal presence during testing, an effect that was surprisingly potentiated, however, following the retention interval in animals that were isolated during this interval. This apparent potentiation by prior isolation of the HR lowering effect of the dam was confirmed in Experiment 2 in nontreated offspring, but did not emerge convincingly in offspring of either dams subcutaneously injected with 40 mg/kg of cocaine HCl daily from gestational days 8 to 20 (C40) or dams injected with saline and pair-fed 4 days (PF4) to mimic the acute anorexic effects of cocaine administration. Consistent with prior work, C40 offspring also were found to exhibit better retention of the habituated orienting response than offspring of NT dams and to some extent PF4 dams as well, a retention effect that was not significantly influenced, however, by social context during the retention interval.     

Altered transmission of maternal angiotensin II receptor haplotypes in fetal growth restriction

Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955T>A (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052T>G (OR, 0.18 (0.06-0.48); P<0.001), and g.5612A>G (OR, 0.21 (0.08-0.55); P < 0.001) in FGR. There were no differences in maternal haplotype frequencies between normal pregnancy and FGR for AGTR1 or AGTR2 (P > 0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor.     

Effects of paternal and maternal undernutrition on growth of offspring in rats

In adult males, undernutrition is associated with altered spermatogenesis. The present study was performed to evaluate the possible role of paternal undernutrition on growth and development of rat offspring and to compare those effects with undernutrition in pregnant animals. Male rats were fed 100%, 80% or 60% of their ad lib food intake for eight weeks and were then bred to untreated females. Pregnant rats were mated with untreated males and received their food allotments throughout pregnancy. Although male body weights and rate of successful matings were decreased by paternal undernutrition, offspring litter size, birth weights, and weights at 21 days were not significantly altered. By contrast, maternal undernutrition was associated with decreased maternal weight gain, lower offspring birth weights and body weights at weaning.     

Fetal cells in maternal blood of pregnancies with severe fetal growth restriction

The aim of this study was to examine whether, in pregnancies with severe early onset fetal growth restriction, the number of fetal erythroblasts in maternal blood is increased. The percentage of fetal erythroblasts in maternal blood, enriched by triple density gradient centrifugation and anti-CD71 magnetic cell sorting, was determined in 10 singleton pregnancies with severe intrauterine growth restriction in which there was Doppler ultrasound evidence of impaired placental perfusion. The values were compared to those of 10 normal pregnancies at the same gestational range of 22-26 weeks. In the growth restricted pregnancies the median number of fetal erythroblasts per 100 nucleated cells in maternal blood enriched for fetal cells was significantly higher than the median value in the control pregnancies (8.5% compared with 1%; P < 0.001). These data suggest that impaired uteroplacental perfusion and severe fetal growth restriction may be associated with placental damage leading to increased feto-maternal cell traffic. Alternatively the rate of transfer of fetal cells into the maternal circulation is not altered but in growth restriction the proportion of fetal erythroblasts in fetal blood is increased.