Trajectories of prenatal alcohol exposure and behavioral outcomes: Findings from a community-based sample.

OBJECTIVE: To characterize patterns of prenatal alcohol exposure (PAE), and determine whether PAE trajectories were associated with behavior from a community-based sample of first-grade children. METHODS: Using data collected as part of the Collaboration of Fetal Alcohol Spectrum Disorders Prevalence study (n = 1663), we performed longitudinal cluster analysis on prenatal alcohol use reported for four time points around conception and pregnancy. From the sample, 638 respondents reported any alcohol use in pregnancy and were included in trajectories for average daily and maximum drinks per drinking day (max DDD). We then estimated the association with behavioral problems measured by the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF) with multivariable linear regression. The reference group had 1025 children with no reported PAE. RESULTS: Five trajectories were selected to describe max DDD patterns: very low/discontinuing (n = 186), low/discontinuing (n = 111), very low/continuing (n = 47), med/high (n = 245), and high (n = 49). Six trajectories best described average daily alcohol use: very low/discontinuing (n = 378), very low/continuing (n = 98), low/continuing (n = 56), low/discontinuing (n = 37), medium/high (n = 35), and high (n = 31). When assessing max DDD trajectories for both the CBCL and TRF, individuals with PAE in the two highest trajectories and the very low/continuing trajectory had more behavioral problems relative to children with no PAE, although confidence intervals for most estimates included the null. PAE modeled as average drinks per day did not predict behavior in any consistent pattern. CONCLUSIONS: In this community-based sample, select PAE trajectories were associated with behavior, even at relatively low levels of PAE that continued later in gestation.

The impact of micronutrient supplementation in alcohol-exposed pregnancies on reaction time responses of preschoolers in Ukraine.

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) on attentional regulation skills was explored in a randomized clinical trial conducted in Ukraine. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to one of three groups [No study-provided supplements, Multivitamin/Mineral Supplement (MVM), or MVM plus Choline]. Their offspring were seen in the preschool period and a reaction time task was administered. Participants were asked to press a response button as quickly as possible as 30 stimuli from the same category (animals) were presented consecutively and then followed by six stimuli from a novel category (vehicles). Number correct, mean latency of the response over trials, and variability in the latency were analyzed separately by sex. During the initial animal trials, boys whose mothers received MVM during pregnancy had more correct responses and reduced response latency compared to boys whose mothers had no MVM treatment. During vehicle trials, maternal choline supplementation was associated with increased response speed in males without a PAE history. Females receiving supplements did not show the same benefits from micronutrient supplementation and were more adversely impacted by prenatal alcohol exposure. Relationships between maternal levels of choline, betaine, and dimethylglycine (DMG) and task performance were also assessed. Although no effects were found for choline after adjusting for multiple comparisons, lower baseline DMG level was associated with greater accuracy and shorter latency of responses in the initial animal trials and shorter latency in the vehicle trials in female preschoolers. Level of betaine in Trimester 3 was associated with reduced variability in the latency of male responses during the animal trials. Maternal micronutrient supplementation in pregnancy appears to improve preschool reaction time performance, but the effects varied as a function of sex and PAE exposure status.

Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure.

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N = 149) and low or no alcohol-exposed (LNA) (N = 92) women were recruited into the study during mid pregnancy (mean of 19.8 ± 5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p = 0.020 and p = 0.036, respectively) and 12 months (p = 0.043 and p = 0.029, respectively), and with MDI scores at 12 months (p = 0.013 and p = 0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1ß, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1ß and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p = 0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

Autoimmune conditions and comorbid depression in pregnancy: examining the risk of preterm birth and preeclampsia.

OBJECTIVE: The objective of this study was to determine whether prenatal depression interacts with autoimmune conditions to further increase the risk of preterm birth or preeclampsia. STUDY DESIGN: Our sample included 3034 pregnant women with rheumatoid arthritis (RA), Crohn's disease (CD) or psoriasis, or controls that were prospectively enrolled into MothertoBaby pregnancy studies. We estimated the independent and joint effects of the three autoimmune conditions and depression on the select outcomes. RESULTS: We found an increased risk of preterm birth among women with RA (2.10; 95% confidence interval (CI) 1.54, 2.87), CD (1.87; 95% CI 1.25, 2.81) or psoriasis (1.88; 95% CI 1.27, 2.79) independent of depression status. RA was also independently associated with preeclampsia. Prenatal depression was not independently associated with preterm birth or preeclampsia, nor was there any synergism with autoimmune conditions. CONCLUSION: If these findings are confirmed, the absence of synergism should be encouraging news to the many women with select autoimmune conditions and depression in pregnancy.

Evaluation of the Safety of Drugs and Biological Products Used During Lactation: Workshop Summary.

This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies. This workshop is part of continuing efforts to raise the awareness of the public for women who choose to breastfeed their infants.

Risk of preterm birth among women using drugs during pregnancy with elevated α-fetoprotein.

OBJECTIVE: Examine the risk of preterm birth (PTB) among women who use drugs during pregnancy and have elevated α-fetoprotein (AFP). STUDY DESIGN: The sample included California singleton live births in 2005 to 2010 contained within a hospital discharge database linked to the Prenatal Screening Program. A selection of mothers who did not use drugs was selected at a ratio of 4:1. Risk of PTB was calculated using adjusted odds ratios and 95% confidence intervals (CIs) for women who did or did not use drugs by their AFP percentile. RESULTS: We identified 7190 women who used drugs and selected 28 760 women who did not. Of women using cocaine with AFP ⩾95th percentile, 43.8% delivered prematurely. Women using drugs with AFP ⩾95th percentile were 11 to 35 times as likely to deliver <32 weeks. CONCLUSION: The combination of drug use and elevated AFP results in high rates of PTB. This combination results in an additive risk.

Maternal use of selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn.

Use of selective serotonin reuptake inhibitors (SSRIs) in late pregnancy has been associated with persistent pulmonary hypertension of the newborn (PPHN), a rare condition with substantial infant mortality and morbidity. Although the increase in absolute risk is small on a population level, it may be of concern to many patients. It remains unclear the extent to which the increased risks reported for PPHN are explained by the underlying maternal illness rather than the use of SSRIs.

The impact of micronutrient supplementation in alcohol-exposed pregnancies on information processing skills in Ukrainian infants.

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) was explored in a clinical trial conducted in Ukraine. Cardiac orienting responses (ORs) during a habituation/dishabituation learning paradigm were obtained from 6 to 12 month-olds to assess neurophysiological encoding and memory. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to a group (No study-provided supplements, multivitamin/mineral supplement, or multivitamin/mineral supplement plus choline supplement). Heart rate was collected for 30 s prior to stimulus onset and 12 s post-stimulus onset. Difference values (∆HR) for the first 3 trials of each condition were aggregated for analysis. Gestational blood samples were collected to assess maternal nutritional status and changes as a function of the intervention. Choline supplementation resulted in a greater ∆HR on the visual habituation trials for all infants and for the infants with no PAE on the dishabituation trials. The latency of the response was reduced in both conditions for all infants whose mothers received choline supplementation. Change in gestational choline level was positively related to ∆HR during habituation trials and levels of one choline metabolite, dimethylglycine (DMG), predicted ∆HR during habituation trials and latency of responses. A trend was found between DMG and ∆HR on the dishabituation trials and latency of the response. Supplementation did not affect ORs to auditory stimuli. Choline supplementation when administered together with routinely recommended multivitamin/mineral prenatal supplements during pregnancy may provide a beneficial impact to basic learning mechanisms involved in encoding and memory of environmental events in alcohol-exposed pregnancies as well as non- or low alcohol-exposed pregnancies. Changes in maternal nutrient status suggested that one mechanism by which choline supplementation may positively impact brain development is through prevention of fetal alcohol-related depletion of DMG, a metabolic nutrient that can protect against overproduction of glycine, during critical periods of neurogenesis.

Alpha-2A adrenergic receptor gene variants are associated with increased intra-individual variability in response time.

Intra-individual variability in response time has been proposed as an important endophenotype for attention deficit hyperactivity disorder (ADHD). Here we asked whether intra-individual variability is predicted by common variation in catecholamine genes and whether it mediates the relationship between these gene variants and self-reported ADHD symptoms. A total of 402 non-clinical Australian adults of European descent completed a battery of five cognitive tasks and the Conners' Adult ADHD Rating Scale. Exclusion criteria included the presence of major psychiatric or neurologic illnesses and substance dependency. A total of 21 subjects were excluded due to incomplete data or poor quality cognitive or genotyping data. The final sample comprised 381 subjects (201 males; mean age=21.2 years, s.d.=5.1 years). Principal components analysis on variability measures yielded two factors (response selection variability vs selective attention variability). Association of these factors with catecholamine gene variants was tested using single-step linear regressions, with multiple comparisons controlled using permutation analysis. The response selection variability factor was associated with two ADRA2A single-nucleotide polymorphisms (SNPs) (rs1800544, rs602618), p corrected=0.004, 0.012, respectively, whereas the selective attention variability factor was associated with a TH SNP (rs3842727), p corrected=0.024. A bootstrapping analysis indicated that the response selection variability factor mediated the relationship between the ADRA2A SNP rs1800544 and self-reported ADHD symptoms. Thus this study finds evidence that DNA variation in the ADRA2A gene may be causally related to ADHD-like behaviors, in part through its influence on intra-individual variability. Evidence was also found for a novel association between a TH gene variant and intra-individual variability.

Change in paternity and select perinatal outcomes: causal or confounded?

Select social, behavioural and maternal characteristics were evaluated to determine if they were confounding factors in the association between paternity change and pre-eclampsia, small for gestational age (SGA) and pre-term delivery, in a sample of 1,409 women. Multivariate logistic regression analysis was used to determine if any of these risk factors modified the association between changing paternity and the selected perinatal outcomes. Results of the analysis showed that women who changed partners were more likely to possess potentially confounding risk factors compared with those who had not. Paternity change was 2.75 times more likely to be associated with the development of pre-eclampsia (95% CI 1.33; 5.68) and 2.25 times more likely to be associated with an SGA infant on weight (95% CI 1.13; 4.47), after adjusting for selected risk factors. Paternity change remains a significant risk factor for pre-eclampsia and SGA in the presence of select risk factors.

Pregnancy outcome in women exposed to leflunomide before or during pregnancy.

OBJECTIVE: Findings from animal studies have suggested that leflunomide may be a human teratogen. In the only human cohort study published to date, an increase in adverse outcomes in pregnancies after exposure to leflunomide was not detected. The aim of the present analysis was to expand on the previously published data with a description of birth outcomes among women who did not meet the previous cohort study criteria but who were exposed to leflunomide either during pregnancy or prior to conception. METHODS: Data on pregnancy exposures and outcomes were collected from 45 pregnant women who had contacted counseling services of the Organization of Teratology Information Specialists in the US or Canada between 1999 and 2009. Sixteen women were exposed to leflunomide during the first trimester of pregnancy and 29 women were exposed preconception. RESULTS: All 16 of the pregnancies with leflunomide exposure during pregnancy and 27 (93%) of the pregnancies with exposure prior to conception resulted in liveborn infants. There were 2 infants with major malformations from mothers who were exposed during pregnancy, and no malformations reported in the preconception group. There was a potential known alternative etiology for at least some of the defects observed. CONCLUSION: These data provide additional reassurance to women who inadvertently become pregnant while taking leflunomide and who undergo the washout procedure, as well as women who discontinue the medication prior to conception but have no prepregnancy documentation of drug clearance. However, until more conclusive data become available, women receiving leflunomide should be advised to use contraceptive methods and avoid pregnancy.

Dopamine transporter genotype predicts behavioural and neural measures of response inhibition.

The ability to inhibit unwanted actions is a heritable executive function that may confer risk to disorders such as attention deficit hyperactivity disorder (ADHD). Converging evidence from pharmacology and cognitive neuroscience suggests that response inhibition is instantiated within frontostriatal circuits of the brain with patterns of activity that are modulated by the catecholamines dopamine and noradrenaline. A total of 405 healthy adult participants performed the stop-signal task, a paradigmatic measure of response inhibition that yields an index of the latency of inhibition, termed the stop-signal reaction time (SSRT). Using this phenotype, we tested for genetic association, performing high-density single-nucleotide polymorphism mapping across the full range of autosomal catecholamine genes. Fifty participants also underwent functional magnetic resonance imaging to establish the impact of associated alleles on brain and behaviour. Allelic variation in polymorphisms of the dopamine transporter gene (SLC6A3: rs37020; rs460000) predicted individual differences in SSRT, after corrections for multiple comparisons. Furthermore, activity in frontal regions (anterior frontal, superior frontal and superior medial gyri) and caudate varied additively with the T-allele of rs37020. The influence of genetic variation in SLC6A3 on the development of frontostriatal inhibition networks may represent a key risk mechanism for disorders of behavioural inhibition.

Potentially modifiable risk factors for adverse pregnancy outcomes in women with psoriasis.

BACKGROUND: Data on pregnancy outcomes among women with psoriasis are lacking. However, there are several known comorbidities of psoriasis, including obesity, smoking and depression, each of which increases the risk for negative birth outcomes. OBJECTIVES: To determine if pregnant women with psoriasis have an excess of potentially modifiable risk factors for adverse pregnancy outcomes. METHODS: Prospectively collected data from the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project were analysed to compare the prevalence of selected risk factors between 170 pregnant women with psoriasis and 158 nondiseased controls. RESULTS: Women with psoriasis were more likely to be overweight/obese prior to pregnancy (P < 0.0001), to smoke (P < 0.0001), or to have a diagnosis of depression (P = 0.03), and were less likely to have been taking preconceptional vitamin supplements (P = 0.004). After controlling for race/ethnicity and socioeconomic status, women with psoriasis were 2.37 (95% confidence interval 1.45-3.87) times more likely to be overweight/obese as women without psoriasis. Duration of disease, age at onset, measures of disease impact during pregnancy, or use of biologics in pregnancy were not significant predictors of overweight/obesity in the subset of psoriatic women. CONCLUSIONS: Pregnant women with psoriasis may be at increased risk for adverse pregnancy outcomes due to comorbidities or other health behaviours associated with the disease. These should be taken into consideration during clinical treatment of women with psoriasis who are in their childbearing years.

Can prenatal ultrasound detect the effects of in-utero alcohol exposure? A pilot study.

OBJECTIVES: The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions. METHODS: We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner. RESULTS: From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval-calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05). CONCLUSIONS: Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD.

Drug safety in pregnant women and their babies: ignorance not bliss.

Although clinical trials address questions regarding drug safety for most segments of the population, pregnant women constitute one special group that is "orphaned" with respect to this issue. The lack of adequate pregnancy safety information for the vast majority of medications, combined with a need to make appropriate treatment decisions and to communicate risk information to a potentially vulnerable population, are some of the most challenging and critical women's health issues.

Dopaminergic genotype biases spatial attention in healthy children.

In everyday life, our sensory system is bombarded with visual input and we rely upon attention to select only those inputs that are relevant to behavioural goals. Typically, humans can shift their attention from one visual field to the other with little cost to perception. In cases of 'unilateral neglect', however, there is a persistent bias of spatial attention towards the same side as the damaged cerebral hemisphere. We used a visual orienting task to examine the influence of functional polymorphisms of the dopamine transporter gene (DAT1) on individual differences in spatial attention in normally developing children. DAT1 genotype significantly influenced spatial bias. Healthy children who were homozygous for alleles that influence the expression of dopamine transporters in the brain displayed inattention for left-sided stimuli, whereas heterozygotes did not. Our data provide the first evidence in healthy individuals of a genetically mediated bias in spatial attention that is related to dopamine signalling.

Postmarketing surveillance for human teratogenicity: a model approach.

BACKGROUND: Most congenital defects associated with prenatal exposures are notable for a pattern of major and minor malformations, rather than for a single major malformation. Thus, traditional epidemiological methods are not universally effective in identifying new teratogens. The purpose of this report is to outline a complementary approach that can be used in addition to other more established methods to provide the most comprehensive evaluation of prenatal exposures with respect to teratogenicity. METHODS: We describe a multicenter prospective cohort study design involving dysmorphological assessment of liveborn infants. This design uses the Organization of Teratology Information Services, a North American network of information providers who also collaborate for research purposes. Procedures for subject selection, methods for data collection, standard criteria for outcome classification, and the approach to analysis are detailed. RESULTS: The focused cohort study design allows for evaluation of a spectrum of adverse pregnancy outcomes ranging from spontaneous abortion to functional deficit. While sample sizes are typically inadequate to identify increased risks for single major malformations, the use of dysmorphological examinations to classify structural anomalies provides the unique advantage of screening for a pattern of malformation among exposed infants. CONCLUSIONS: As the known human teratogens are generally associated with patterns of structural defects, it is only when studies of this type are used in combination with more traditional methods that we can achieve an acceptable level of confidence regarding the risk or safety of specific exposures during pregnancy.