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ImpactFindings from this study provide further reassuring evidence that infant exposure through human milk received from lactating individuals who require treatment with remdesivir is negligible.

OBJECTIVE:: Antiphospholipid syndrome (APS) and autoimmune rheumatic diseases (ARDs) are known to increase the risk for cardiovascular events (CVEs) in the general population., However, research in pregnancy is limited. We compared the occurrence of acute CVEs in pregnant women with and without ARDs or primary APS using a Californian population-based cohort. STUDY DESIGN:: This was a retrospective cohort study of pregnant individuals who delivered singleton infants in California between 2005 and 2020. Birth certificates were linked by the Study of Outcomes of Mothers and Infants to maternal records. The study was approved by institutional review boards of the State of California and the University of California San Diego. Pregnancies with ARDs were identified by ≥1 International Classification of Diseases (ICD) code for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthritis, Sjogren’s syndrome, and other ARDs (systemic sclerosis, inflammatory myositis, and vasculitides) in maternal hospital discharge, emergency, or ambulatory surgery records. Lupus nephritis (LN) was defined as SLE plus glomerulonephritis, renal failure, nephritic or nephrotic syndrome, or proteinuria. Primary APS included women with APS without concurrent ARDs. Women without ARDs or APS comprised the reference group. Acute CVEs during pregnancy and up to 6 weeks postpartum were identified by ICD codes and compared between groups. CVEs were classified as myocardial infarction, cardiovascular accident, heart failure and peripartum cardiomyopathy, inflammatory heart diseases, cardiac dysrhythmias, and venous thromboembolism (VTE). Covariates identified and adjusted for include age, race and ethnicity, insurance, education, prepregnancy body mass index, preexisting hypertension, diabetes, hyperlipidemia, depression, and substance use disorders. A log linear regression with a Poisson distribution was used to estimate the adjusted relative risks (aRRs) and 95% confidence intervals (CIs) for the associations of ARDs and APS with CVEs. Analyses were performed using Statistical Analysis Software (SAS), version 9.4 (SAS Institute, Cary, NC). Causal mediation analyses were performed for potential mediators, such as gestational diabetes, gestational hypertension, and preeclampsia. RESULTS:: Overall, 19,340 women had ARDs, 7758 had primary APS, and 7,004,334 had neither condition. The ARD and APS groups had more traditional cardiovascular risk factors. Acute CVEs were observed in 2.0% of ARD cases (388/19,340), 7.0% of primary APS cases (540/7,758), and 0.4% of reference group cases (24,402/7,004,334). The aRR for CVEs in the ARD and APS groups in comparison with the reference group was 4.1-fold (95% CI, 3.7–4.5) and 14.7-fold (95% CI, 13.5–16.0), respectively (Table). Of the 388 CVEs that occurred in women with ARDs, 164 (42%) were VTEs, 96 (25%) were heart failure or peripartum cardiomyopathy, and 92 (24%) were cardiac dysrhythmias. In primary APS cases, 453 of 540 (83%) CVEs were VTE. Acute CVEs occurred in 3.1% (159/8,422) of patients with overall SLE, in 10.7% (55/513) of patients with SLE with APS, and in 8.5% (77/903) of patients with SLE with LN (Table). The aRR for CVEs was 6-fold higher among those with SLE (95% CI, 5.3–6.8) and was notably increased with concurrent APS or LN, with aRRs of 18.1 (95% CI, 13.9–23.6) and 12.7 (95% CI, 10.1–15.9), respectively (Figure). The risks for both VTE and non-VTE CVEs was increased among pregnancies affected by ARD and APS (Figure). Five of 6 in-hospital deaths in ARD pregnancies (5/388 or 1.3%) occurred among women with acute CVEs (Table). The risks for CVEs were higher during all perinatal periods. In mediation analyses, 11.2% of the excess risk for CVE in ARD pregnancies was mediated by preeclampsia, whereas

The proposed symptoms for Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE) were evaluated in children who participated in the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence study. Children at-risk for ND-PAE (n = 204) were contrasted to children with no prenatal alcohol exposure, alcohol-related dysmorphia or growth deficits (n = 908). Symptoms were defined based on neuropsychological testing using two diagnostic threshold levels (1.0 and 1.5 STD). Individuals at risk for ND-PAE had higher endorsement rates of the self-regulation and adaptive impairments at the 1.0 threshold and of the neurocognitive and self-regulation impairments at the 1.5 threshold. Endorsement of the disorder significantly differed at the 1.0 threshold. Receiver operating characteristic curve analysis indicated that having an IQ below 70 was not predictive of the diagnosis but modifications of the IQ criterion improved predictive validity. Discrimination validity was poor without documentation of PAE which continues to be a necessity for a diagnosis of ND-PAE.

INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

We studied T-cell responses to SARS-CoV-2 in 19 pregnant subjects at different gestational weeks who received three doses of mRNA-based vaccination to prevent COVID-19. SARS-CoV-2 peptide pools were used for T-cell recognition studies: peptides were 15 amino acids long and had previously been defined in COVID-19-convalescent subjects. T-cell activation was evaluated with the AIM assay. Most subjects showed coordinated, spike-specific CD4+ and CD8+ T-cell responses and the development of T cell memory. Non-spike-specific T cells in subjects who were not aware of previous COVID-19 infection suggested a prior undetected, asymptomatic infection. CD4- CD8- double negative (DN) T cells were numerous, of which a percentage was specific for SARS-CoV-2 spike peptides. Regulatory T cells (Treg), both spike- and non-spike-specific, were also greatly expanded. Two Treg populations were defined: a population differentiated from naïve T cells, and pTreg, reverting from pro-inflammatory T cells. The Treg cells expressed CCR6, suggesting homing to the endometrium and vaginal epithelial cells. The pregnant women responded to SARS-CoV-2 vaccination. Asymptomatic COVID-19 was revealed by the T cell response to the non-spike peptides. The numerous DN T cells and Treg pointed our attention to new aspects of the adaptive immune response in vaccine recipients.

In neonatal, symptomatic tetralogy of Fallot (sTOF), data are lacking on whether high-risk groups would benefit from staged (SR) or complete repair (CR). We studied the association of gestational age (GA) at birth and z-score for birth weight (BWz), with management strategy and outcomes in sTOF. California population-based cohort study (2011-2017) of infants with sTOF (defined as catheter or surgical intervention prior to 44 weeks corrected GA) was performed, comparing management strategy and timing by GA and BWz categories. Multivariable models evaluated composite outcomes and days alive and out of hospital (DAOOH) in the first year of life. Among 345 patients (SR = 194; CR = 151), management strategy did not differ by GA or BWz with complete repair defined as prior to 44 weeks corrected gestational age; however, did differ by GA with regard to complete/timely repair (defined as complete repair within first 30 days of life). Full-term and early-term neonates underwent CR 20 (95%CI: - 27.1, - 14.1; p

Human milk oligosaccharides (HMOs) are a set of complex carbohydrates and the third largest solid component of human milk, after lactose and lipids. To date, over 150 HMOs have been identified and the diversity of structures produced by lactating women is influenced by maternal genetics as well as other maternal, infant, and environmental factors. While the concentrations of individual HMOs have been shown to vary between individuals and throughout the course of lactation, the variability of HMO concentration profiles following different pregnancies occurring in the same woman is presently unknown. As such, the objective of this study was to compare HMO concentrations in human milk samples provided by the same women (n = 34) following repeat pregnancies. We leveraged existing human milk samples and metadata from the UC San Diego Human Milk Research Biorepository (HMB) and measured the concentrations of the 19 most abundant HMOs using high-performance liquid chromatography with fluorescence detection (HPLC-FL). By assessing dissimilarities in HMO concentration profiles, as well as concentration trends in individual structures between pregnancies of each participant, we discovered that HMO profiles largely follow a highly personalized and predictable trajectory following different pregnancies irrespective of non-genetic influences. In conclusion, this is the first study to assess the interactions between parity and time following delivery on variations in HMO compositions.

Background and objectiveKnowledge about exposure to cannabidiol (CBD) in breastfed infants can provide an improved understanding of potential risk. The aim was to predict CBD exposure in breastfed infants from mothers taking CBD and CBD-containing products.MethodsCannabidiol concentrations in milk previously attained from data collected through an existing human milk research biorepository were used to simulate infant doses and identify subgroups. A developed pediatric physiologically based pharmacokinetic model produced virtual breastfed infants administered the simulated CBD doses. Predicted breastfed infant exposures and upper area under the curve ratios were compared to the lowest therapeutic dose for approved indications in children.ResultsThe existing human milk research biorepository contained 200 samples from 181 unique breastfeeding mothers for whom self-reported administration data and CBD concentrations had previously been measured. Samples that were above the lower limit of quantification with only one maternal administration type revealed that administration type, i.e., joint/blunt or edible versus oil or pipe, resulted in significantly different subgroups in terms of milk concentrations. Resulting simulated infant doses (ng/kg) were described by lognormal distributions with geometric means and geometric standard deviations: 0.61 ± 2.41 all concentrations, 0.10 ± 0.37 joint/blunt or edible, and 2.23 ± 8.15 oil or pipe. Doses administered to breastfed infants had exposures magnitudes lower than exposures in children aged 4-11 years administered the lowest therapeutic dose for approved indications, and low upper area under the curve ratios.ConclusionsBased on real-world use, breastfeeding infants are predicted to receive very small exposures of CBD through milk. Studies examining adverse reactions will provide further insight into potential risk.

OBJECTIVE: In a large multi-racial/ethnic cohort of women, we examined racial/ethnic disparities in preterm birth (PTB) risk stratified by autoimmune rheumatic disease (ARD) type, which included systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: Birth records linked to hospital discharge data of singleton births in California from 2007 to 2012 were leveraged for a retrospective cohort study including women with SLE or RA. The relative risk of PTB (< 37 versus ≥ 37 weeks gestation) was compared among different racial/ethnic groups (Asian, Hispanic, Non-Hispanic (NH) Black, and NH White) and stratified by ARD type. Results were adjusted for relevant covariates using Poisson regression. RESULTS: We identified 2874 women with SLE and 2309 women with RA. NH Black, Hispanic, and Asian women with SLE were 1.3 to 1.5 times more likely to have PTB compared to NH White women. NH Black women with RA were 2.0 to 2.4 times more likely to have PTB compared to Asian, Hispanic, or NH White women. The NH Black-NH White and NH Black-Hispanic disparity in PTB risk was significantly higher in women with RA compared to SLE or the general population. CONCLUSION: Our findings highlight the racial/ethnic disparities for risk of PTB among women with SLE or RA and highlight that several of the disparities are higher for women with RA compared to those with SLE or the general population. These data may provide important public health information for addressing racial/ethnic disparities in the risk of preterm birth, particularly among women with RA. Key Points • There is an unmet need for studies that evaluate racial/ethnic disparities in birth outcomes specifically in women with RA or SLE. • This is one of the first studies describing racial/ethnic disparities in PTB risk for women with RA, and to draw conclusions regarding Asian women in the USA with rheumatic diseases and PTB. • These data provide important public health information for addressing racial/ethnic disparities in the risk of preterm birth among women with autoimmune rheumatic diseases.

BACKGROUND: Previous studies demonstrated that children with Fetal Alcohol Spectrum Disorders (FASD) are more likely to have vision impairments. However, existing human clinical and epidemiological investigations are few and include limited sample sizes. This study aimed to explore the association between ophthalmologic abnormalities and FASD in a sample of 5-7 year old children in the general population. METHODS: This was a cross-sectional study nested in a larger study intended to estimate the prevalence of FASD in San Diego, California, conducted between 2012 and 2014. Prenatal exposure to alcohol, dysmorphology examinations, and a neurobehavioral testing battery were collected for each child and an FASD diagnosis was assigned. Parents of participating children were asked to release their childs vision screening or diagnostic records. RESULTS: Vision records were obtained for 424 participants in the larger prevalence study. Of these, 53 children were classified as having FASD. A statistically significant association was found between FASD and a diagnosis of strabismus; 5/42 (11.9%) of children who were classified as having FASD had strabismus compared to 6/290 (2.1%) of children who were not classified as having FASD (p = .01). All five cases of strabismus in the FASD group occurred in 19 children classified as having partial fetal alcohol syndrome (pFAS). No association was found between FASD and vision impairment (p = .23), refractive errors (p = .66), glasses/contact lens prescription (p = .30), or having one or more ophthalmological abnormalities (p = .97). CONCLUSIONS: An association between strabismus and FASD, specifically partial FAS, suggests that the effect of alcohol exposure on risk of strabismus must be severe enough to result in facial features consistent with FASD. This emphasizes the importance of vision screening in children with FASD.

Antibiotics are an essential tool for perinatal care. While antibiotics can play a life-saving role for both parents and infants, they also cause collateral damage to the beneficial bacteria that make up the host gut microbiota. This is especially true for infants, whose developing gut microbiota is uniquely sensitive to antibiotic perturbation. Emerging evidence suggests that disruption of these bacterial populations during this crucial developmental window can have long-term effects on infant health and development. Although most current studies have focused on microbial disruptions caused by direct antibiotic administration to infants or prenatal exposure to antibiotics administered to the mother, little is known about whether antibiotics in human milk may pose similar risks to the infant. This review surveys current data on antibiotic transfer during lactation and highlights new methodologies to assess drug transfer in human milk. Finally, we provide recommendations for future work to ensure antibiotic use in lactating parents is safe and effective for both parents and infants.

BackgroundOne potential mechanism for protection from SARS-CoV-2 in children is through passive immunity via breast milk from a mother infected with the novel coronavirus. The primary objectives of this study were to establish the presence of SARS-CoV-2-specific IgA and IgG and to characterize the antigenic regions of SARS-CoV-2 proteins that were reactive with antibodies in breast milk.MethodsBetween March 2020 and September 2020, 21 women with confirmed SARS-CoV-2 infection were enrolled in Mommy's Milk. Participants donated serial breast milk samples around their time of illness. Breast milk samples were used to probe a multi-coronavirus protein microarray containing full-length and variable-length overlapping fragments of SARS-CoV-2 proteins. Samples were also tested against S and N proteins by electrochemiluminescence assay.ResultsThe breast milk samples contained IgA reactive with a variety of SARS-CoV-2 antigens. The most IgA-reactive SARS-CoV-2 proteins were N (42.9% of women responded to ≥1 N fragment) and S proteins (23.9% responded to ≥1 fragment of S1 or S2). IgG responses were similar. A striking observation was the dissimilarity between mothers in antibody recognition, giving distinct antibody reactivity and kinetic profiles.ConclusionsIndividual COVID-19 cases had diverse and unique milk IgA profiles following the onset of symptoms.ImpactIn this observational longitudinal case series of 21 women with confirmed SARS-CoV-2 infection, IgA binding to SARS-CoV-2 proteins detected by orthologous proteome microarray and electrochemiluminescence assays was observed in >75% of women, but there was heterogeneity in which antigens and how many were reactive between women. Immunological profiles of protein regions recognized by each woman were distinct. Diverse repertoires of mucosal breast milk antibody to SARS-CoV-2 reflect heterogeneous passive transfer of maternal antibody to exposed breastfeeding infants.

BackgroundThe chemical composition of human milk has long-lasting effects on brain development. We examined the prognostic value of the human milk metabolome and exposome in children with the risk of neurodevelopmental delay (NDD).MethodsThis retrospective cohort study included 82 mother-infant pairs (40 male and 42 female infants). A total of 59 milk samples were from mothers with typically developing children and 23 samples were from mothers of children at risk. Milk samples were collected before 9 months of age (4.6 ± 2.5 months, mean ± SD). Neurocognitive development was assessed by maternal report at 14.2 ± 3.1 months using the Ages and Stages Questionnaires-2.ResultsMetabolome and exposome profiling identified 453 metabolites and 61 environmental chemicals in milk. Machine learning tools identified changes in deoxysphingolipids, phospholipids, glycosphingolipids, plasmalogens, and acylcarnitines in the milk of mothers with children at risk for future delay. A predictive classifier had a diagnostic accuracy of 0.81 (95% CI: 0.66-0.96) for females and 0.79 (95% CI: 0.62-0.94) for males.ConclusionsOnce validated in larger studies, the chemical analysis of human milk might be added as an option in well-baby checks to help identify children at risk of NDD before the first symptoms appear.ImpactMaternal milk for infants sampled before 9 months of age contained sex-specific differences in deoxysphingolipids, sphingomyelins, plasmalogens, phospholipids, and acylcarnitines that predicted the risk of neurodevelopmental delay at 14.2 months of age. Once validated, this early biosignature in human milk might be incorporated into well-baby checks and help to identify infants at risk so early interventions might be instituted before the first symptoms appear.

Background: The objectives of this study were to describe trends in the prevalence of postpartum suicidal behaviors in California, 2013-2018, and to estimate associations between adverse perinatal outcomes and suicidal behaviors. Materials and Methods: We used data from a population-based cohort derived from all birth and fetal death certificates. Records were individually linked to maternal hospital discharge records for the years before and after delivery. We estimated the prevalence of postpartum suicidal ideation and attempt by year. Then, we estimated crude and adjusted associations between adverse perinatal outcomes and these suicidal behaviors. The sample included 2,563,288 records. Results: The prevalence of postpartum suicidal ideation and attempt increased from 2013 to 2018. People with postpartum suicidal behavior were younger, had less education, and were more likely to live in rural areas. A greater proportion of those with postpartum suicidal behavior were Black and publicly insured. Severe maternal morbidity, neonatal intensive care unit admission, and fetal death were associated with greater risk of ideation and attempt. Major structural malformation was not associated with either outcome. Conclusions: The burden of postpartum suicidal behavior has increased over time and is unequally distributed across population subgroups. Adverse perinatal outcomes may help identify individuals that could benefit from additional care during the postpartum period.

Since the recognition of fetal alcohol syndrome, alcohol has been accepted as a human teratogen. However, little is known about the relation between prenatal alcohol exposure and the spectrum of associated major birth defects. The objective of this review was to summarize data on the association of major congenital abnormalities and prenatal alcohol exposure. We included all major birth defects according to ICD-10 classification. We found that the strongest evidence to date lies in the research examining herniation (gastroschisis and omphalocele), oral clefts (cleft lip with or without palate and cleft palate) and cardiac defects. There is less consistent evidence supporting the association between prenatal alcohol exposure and anomalies of gastrointestinal system, diaphragmatic hernia, genitourinary system and neural tube defects. We found no material support for PAE and choanal atresia, biliary atresia or clubfoot.

This article aimed to evaluate whether a substance-related diagnosis (SRD; i.e., alcohol, opioids, cannabis, stimulants, nicotine) predicts the likelihood and co-occurrence of preterm (20-37 weeks' gestation) and cesarean delivery.This study reviewed electronic health record data on women (aged 18-44 years) who delivered a single live or stillbirth at ≥ 20 weeks of gestation from 2012 to 2019. Women with and without an SRD were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios and 95% confidence intervals were calculated.Of the 19,346 deliveries, a matched cohort of 2,158 deliveries was identified. Of these, 1,079 (50%) had an SRD, 280 (13%) had a preterm delivery, 833 (39%) had a cesarean delivery, and 166 (8%) had a co-occurring preterm and cesarean delivery. An SRD was significantly associated with preterm and cesarean delivery (AOR = 1.84 [95% CI, 1.41-2.39], p-value=

IntroductionCare of young adults with SLE (YA-SLE, 18-24 years) is challenging due to major life transitions co-occurring with chronic healthcare needs. Studies have demonstrated poorer outcomes in the post-transition period. Epidemiological studies focused on serious infection-related hospitalisation (SIH) in YA-SLE are lacking.MethodsWe used National Inpatient Sample from 2010 to 2019 to study the epidemiology and outcomes of SIH for five common infections in SLE, namely sepsis, pneumonia, urinary tract infections, skin and soft tissue infections, and opportunistic infections. For time trends, we extended the dataset to cover 2000-2019. The primary outcome was the rate of SIH in YA-SLE compared with adults (25-44 years) with SLE and with young adults without SLE (YA-no SLE).ResultsFrom 2010 to 2019, we identified 1 720 883 hospital admissions with SLE in patients aged ≥18 years. Rates of SIH were similar in young adults and adults with SLE (15.0% vs 14.5%, p=0.12), but considerably higher than in the YA-no SLE group (4.2%, p

Background: Adverse childhood experiences (ACEs) are associated with substance use later in life, including marijuana use. It is unknown whether these behaviors extend to lactating women. Our objective was to examine the association between childhood ACE and marijuana use in lactating individuals and determine whether positive childhood experiences (PCEs) modified this association. Methods: This study included 617 lactating individuals from the UC San Diego Human Milk Research Biorepository enrolled from 2015 to 2020. ACE and PCE histories were assessed by the Positive and Adverse Childhood Experiences questionnaire. Past 2-week marijuana use was self-reported at enrollment. Multivariable log-linear regressions were used to calculate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for ACE history and marijuana use, and to assess modification by PCE. Results: Marijuana use during lactation was higher among individuals who reported three or more ACEs (aRR = 2.58, 95% CI = 1.23-5.44), household dysfunction (aRR = 3.08, 95% CI = 1.17-8.10), sexual abuse (aRR = 2.25, 95% CI = 1.08-4.68), or physical abuse (aRR = 2.10, 95% CI = 1.02-4.13). There was no association between emotional abuse and marijuana use during lactation. There was no effect modification by PCEs. Conclusion: Higher ACE frequency, and specifically history of household dysfunction, physical abuse, or sexual abuse increased risk for marijuana use during lactation. Because of marijuanas potential adverse effects on the infant through human milk, postpartum ACE screening is warranted.

BACKGROUND: It is estimated that 1%-5% of children in the United States are affected by prenatal alcohol exposure while only a small percentage are so identified in clinical practice. One explanation for this discrepancy may be the way in which diagnostic criteria are operationalized. METHODS: To evaluate the extent to which three commonly used systems for the diagnosis of Fetal Alcohol Spectrum Disorder (FASD) consistently identified children in a community sample, data from the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (COFASP) study were re-analyzed. In the data set, there were 2325 children with variables necessary to allow diagnosis by three systems commonly used in North America. These systems were (1) that used by COFASP, which is a revised modification of the Institute of Medicines recommendations, (2) the 4-Digit Code, and (3) the most recent Canadian Guidelines. To determine the degree of association among these classifications, the Fleiss Multirater Kappa measure of agreement was applied. RESULTS: Among these three systems, 408 children were classified as FASD, 208 by the CoFASP system, 319 by the 4-Digit Code, and 28 by the Canadian Guidelines. Agreement among the findings from the three systems varied from slight to fair. CONCLUSIONS: These results indicate a lack of consistency in these approaches to FASD diagnosis. Discrepancies result from differences in specifying the criteria used to define the diagnosis, including growth, physical features, neurobehavior, and alcohol-use thresholds. The question of their relative accuracy cannot be resolved without reference to a measure of validity that does not currently exist, and this suggests the need for a more empirically based diagnostic schema.

ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, setting, and participantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main outcomes and measuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and relevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

OBJECTIVE: To determine whether maternal cannabis use disorder is associated with infant hospitalization or death in the first year of life. METHODS: We queried an administrative birth cohort derived from the hospital discharge database maintained by the California Office of Statewide Health Planning and Development and linked with vital statistics files. We included singleton, live-birth deliveries between 2011 and 2018. Pregnancies with cannabis use disorder were classified from International Classification of Disease codes. Outcomes included infant emergency department visits and hospital admissions identified from health records, and infant deaths identified from death records. Models were adjusted for sociodemographic variables, psychiatric comorbidities and other substance use disorders. RESULTS: There were 34,544 births (1.0 %) with a cannabis use disorder diagnosis in pregnancy, with increasing prevalence over the study period. The incidence of infant death in the first year of life was greater among those with a maternal cannabis use disorder diagnosis than those without (1.0 % vs 0.4 %; adjusted risk ratio 1.4 95 % CI: 1.2-1.6). When examining specific causes of death, the increased risk estimates were attributable to perinatal conditions and sudden unexpected infant death. After adjustment, there was no increased risk of infant hospitalizations or emergency department visits. CONCLUSIONS: These findings warrant further investigation into the underlying mechanisms of maternal prenatal CUD on infant outcomes, and add to a rapidly expanding body of literature supporting the need for effective treatment options for pregnant individuals with cannabis use disorders.

Introduction: Data on baseline rates of nonserious events in breastfed infants in the general population are sparse. This results in difficulty determining if there is an increase in infant nonserious events potentially due to prescription medication exposure through human milk. In this study, we determined the prevalence of nonserious events in infants consuming human milk whose mothers reported no exposure to any prescription medications, tobacco, or recreational drugs in the previous 14 days. Materials and Methods: Between August 2014 and December 2019, 487 breastfeeding mothers without any recent exposure to prescription medications, tobacco, or recreational drugs enrolled in the Human Milk Research Biorepository at the University of California, San Diego. Participants completed a semistructured telephone interview with trained research staff and provided information on maternal and child health, breastfeeding habits, recent medication, and lifestyle exposures, and completed a standard checklist of infant adverse reactions. Results: We found 131 (44.1%) participants reported one or more infant nonserious adverse events in the past 14 days at the time of their study interview. The most commonly reported nonserious events were rash (12.1%), irritability (9.4%), constipation (7.8%), poor sleep (7.1%), and fever (6.3%). Conclusions: These baseline frequencies provide a benchmark for rates of recent nonserious events in breastfed infants in the general population. These data can be used as a reference point for studies that examine adverse events in breastfed infants following maternal use of prescription medications or exposures due to other lifestyle habits such as tobacco or other substances. Clinical Trial Registration Number: NCT05553743.

Circulating miRNAs the in blood are promising biomarkers for predicting pregnancy complications and adverse birth outcomes. Previous work identified 11 gestationally elevated maternal circulating miRNAs (HEamiRNAs) that predicted infant growth deficits following prenatal alcohol exposure and regulated epithelial-mesenchymal transition in the placenta. Here we show that a single intravascular administration of pooled murine-conserved HEamiRNAs to pregnant mice on gestational day 10 (GD10) attenuates umbilical cord blood flow during gestation, explaining the observed intrauterine growth restriction (IUGR), specifically decreased fetal weight, and morphometric indices of cranial growth. Moreover, RNAseq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of members of the Notch pathway (Dll4, Rfng, Hey1), which is a pathway important for trophoblast migration and differentiation. Weighted gene co-expression network analysis also identified chemokine signaling, which is responsible for regulating immune cell-mediated angiogenesis in the placenta, as an important predictor of fetal growth and head size. Our data suggest that HEamiRNAs perturb the expression of placental genes relevant for angiogenesis, resulting in impaired umbilical cord blood flow and subsequently, IUGR.

Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies.

BACKGROUND: Cardinal and non-cardinal dysmorphic features are associated with prenatal alcohol exposure (PAE); however, their association with neurodevelopment is less clear. The objective of this study was to determine whether alcohol-related dysmorphic features predict neurodevelopmental delay in infants and toddlers. METHODS: We analyzed a prospective pregnancy cohort in western Ukraine enrolled between 2008 and 2014. A dysmorphology examination comprising body size and three cardinal and 14 non-cardinal dysmorphic features was performed at approximately 6 to 12 months of age. PAE was self-reported and operationalized as absolute ounces of alcohol per day around the time of conception. Neurodevelopment was assessed at 6 to 12 months with the Bayley Scales of Infant Development-II (BSID-II), and at 3.5 to 4.5 years of age with the Differential Ability Scales-II, the Child Behavior Checklist, and multiple measures that were used to create an executive functioning factor score. We performed logistic regression to predict childrens neurodevelopment from dysmorphic features, growth measures, sex, and PAE. RESULTS: From an analytic sample of 582 unique children, 566 had BSID-II scores in infancy, and 289 completed the preschool battery. Models with all cardinal and non-cardinal dysmorphic features, growth measures, sex, and PAE performed better than models with subsets of those inputs. In general, models had poor performance classifying delays in infancy (area under the curve (AUC)

OBJECTIVES: Many studies of sudden unexpected infant death (SUID) have focused on individual domains of risk factors (maternal, infant, and environmental), resulting in limited capture of this multifactorial outcome. The objective of this study was to examine the geographic distribution of SUID in San Diego County, and assess maternal, infant, and environmental risk factors from a large, administrative research platform. STUDY DESIGN: Births in California between 2005 and 2017 were linked to hospital discharge summaries and death files. From this retrospective birth cohort, cases of SUID were identified from infant death files in San Diego County. We estimated adjusted hazard ratios (aHRs) for infant, maternal, and environmental factors and SUID in multivariable Cox regression analysis. Models were adjusted for maternal sociodemographic characteristics and prenatal nicotine exposure. RESULTS: There were 211 (44/100,000 live births; absolute risk 0.04%) infants with a SUID among 484,905 live births. There was heterogeneity in geographic distribution of cases. Multiparity (0.05%; aHR 1.4, 95% confidence interval (CI) 1.1, 1.9), maternal depression (0.11%; aHR 1.8, 95% CI 1.0, 3.4), substance-related diagnoses (0.27%; aHR 2.3, 95% CI 1.3, 3.8), cannabis-related diagnosis (0.35%; aHR 2.7, 95% CI 1.5, 5.0), prenatal nicotine use (0.23%; aHR 2.5, 95% CI 1.5, 4.2), preexisting hypertension (0.11%; aHR 2.3, 95% CI 1.2, 4.3), preterm delivery (0.09%; aHR 2.1, 95% CI 1.5, 3.0), infant with a major malformation (0.09%; aHR 2.0, 95% CI 1.1, 3.6), respiratory distress syndrome (0.12%; aHR 2.6, 95% CI 1.5, 4.6), and select environmental factors were all associated with SUID. CONCLUSIONS: Multiple risk factors were confirmed and expanded upon, and the geographic distribution for SUID in San Diego County was identified. Through this approach, prevention efforts can be targeted to geographies that would benefit the most.

Rationale: There is little information regarding the allergen content of milk feeds in the preterm population. Previous studies have not performed a broad analysis of the allergenic peptide content and protease activity of milk feeds in this population. Methods: To evaluate feasibility, we initially performed mass spectrometry on 4 human milk (HM) samples (2 term and 2 preterm) from the Mommys Milk Human Milk Biorepository (HMB) and analyzed the results against the University of Nebraska FASTA database and UniProt for a total of 2,211 protein sequences. We then further analyzed five samples from the Microbiome, Atopy, and Prematurity (MAP) study including peptidomic and protease activity analysis. Results: Each HMB sample had between 806 and 1,007 proteins, with 37-44 nonhuman proteins/sample encompassing 26 plant and animal species. In the preterm MAP samples, 784 digested nonhuman proteins were identified, 30 were nonbovine in origin. Proteins from 23 different species including aeroallergens, food, and contact allergens were identified. Protease activity was highest in HM samples without human milk fortifier and lowest in preterm formula. Conclusions: These findings represent the first preterm milk feed mass spectrometry and protease analysis with identification of known allergenic proteins to food, contact, and aeroallergens. These results raise questions of whether the composition of milk feeds in the neonatal intensive care unit impact the development of atopic disease in the preterm population and whether the complex interaction between allergens, proteases, and other HM components can serve to induce sensitization or tolerance to allergens in infants. Clinical Trial Registration Number: NCT04835935.

Human milk is the optimal infant nutrition. However, although human-derived metabolites (such as lipids and oligosaccharides) in human milk are regularly reported, the presence of exogenous chemicals (such as drugs, food, and synthetic compounds) are often not addressed. To understand the types of exogenous compounds that might be present, human milk (n = 996) was analyzed by untargeted metabolomics. This analysis revealed that lifestyle molecules, such as medications and their metabolites, and industrial sources, such as plasticizers, cosmetics, and other personal care products, are found in human milk. We provide further evidence that some of these lifestyle molecules are also detectable in the newborn's stool. Thus, this study gives important insight into the types of exposures infants receiving human milk might ingest due to the lifestyle choices, exposure, or medical status of the lactating parent.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are developmental disabilities that are estimated to occur in 2-5% of elementary school children and that negatively impact a childs ability to function without support. Timely diagnosis-informed interventions are crucial to optimizing the developmental trajectory of children with FASD. The true prevalence of FASD among children receiving services for developmental disabilities is unknown. METHODS: An FASD prevalence study was carried out between 2011 and 2014 among a sample of 5- to 7-year-old children who were receiving services provided by the California State Regional Center for Developmental Disabilities in San Diego County. Children whose parent or caregiver consented were evaluated using the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence study assessment protocol and classification criteria. RESULTS: Among 216 eligible caregiver-child dyads, 44 completed assessments that were sufficient to obtain a classification for FASD, including fetal alcohol syndrome (FAS), partial FAS, alcohol-related neurodevelopmental disorder, or no fetal alcohol spectrum disorder. Fifteen children were classified as meeting the criteria for an FASD. A minimum FASD prevalence rate of 69.4 per 1000 (6.9%) among all eligible children was estimated. None of the children classified as FASD were receiving services because of an FASD diagnosis, and none had previously been diagnosed with FASD. Autism was the most common qualifying diagnosis for which children classified as FASD were receiving services. CONCLUSIONS: The 6.9% prevalence estimate among Regional Center clients was higher than the prevalence estimate of 2.3% in the same community among 5- to 7-year-old children in the general population, though the estimate was based on only 20% of eligible dyads. All children in the sample were receiving Regional Center services for another diagnosis. Barriers to eligibility for services for children with FASD may lead to less than optimum care for these children. Study findings support the facilitation of access to developmental services for children with FASD.

BackgroundGenomic RNA of severe acute respiratory syndrome-associated coronavirus type 2 (SARS-CoV-2) has been detected in the breast milk of lactating women, but its pathological significance has remained uncertain due to the small size of prior studies.MethodsBreast milk from 110 lactating women was analyzed by reverse transcription-polymerase chain reaction (285 samples) and viral culture (160 samples). Those containing SARS-CoV-2 viral RNA (vRNA) were examined for the presence of subgenomic RNA (sgRNA), a putative marker of infectivity.ResultsSixty-five women had a positive SARS-CoV-2 diagnostic test, 9 had symptoms but negative diagnostic tests, and 36 symptomatic women were not tested. SARS-CoV-2 vRNA was detected in the milk of 7 (6%) women with either a confirmed infection or symptomatic illness, including 6 of 65 (9%) women with a positive SARS-CoV-2 diagnostic test. Infectious virus was not detected in any culture and none had detectable sgRNA. In control experiments, infectious SARS-CoV-2 could be cultured after addition to breastmilk despite several freeze-thaw cycles, as it occurs in the storage and usage of human milk.ConclusionsSARS-CoV-2 RNA can be found infrequently in the breastmilk after recent infection, but we found no evidence that breastmilk contains an infectious virus or that breastfeeding represents a risk factor for transmission of infection to infants.ImpactThis article goes beyond prior small studies to provide evidence that infectious SARS-CoV-2 is not present in the milk of lactating women with recent infection, even when SARS-CoV-2 RNA is detected. Recent SARS-CoV-2 infection or detection of its RNA in human milk is not a contraindication to breastfeeding.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

OBJECTIVE: To investigate causes of discrepancies in the association between early pregnancy oral glucocorticoid (OGC) use and preterm birth risk among women with rheumatoid arthritis (RA) in health care utilization data from California Medicaid (Medi-Cal) and the prospective cohort MotherToBaby Pregnancy Studies. METHODS: Separately, we estimated risk ratios (RRs) between OGC exposure before gestational day 140 and preterm birth risk in data from Medi-Cal (2007-2013; n = 844) and MotherToBaby (2003-2014; n = 528). We explored differences in socioeconomic status, OGC dose distribution, exposure misclassification, and confounding by RA severity across the data sources. RESULTS: Preterm birth risk in women without OGC was 17.3% in Medi-Cal and was 9.7% in MotherToBaby. There was no association between OGC and preterm birth in Medi-Cal (adjusted RR 1.00 [95% confidence interval (95% CI) 0.71, 1.42]), and a 1.85-fold (95% CI 1.20, 2.84) increased preterm birth risk in MotherToBaby. When restricting each sample to women with a high-school diploma or less, preterm birth risk following no OGC exposure was 15.9% in Medi-Cal and 16.7% in MotherToBaby; adjusted RRs were 1.16 (95% CI 0.74, 1.80) in Medi-Cal and 0.81 (95% CI 0.25, 2.64) in MotherToBaby. Cumulative OGC dose was higher in MotherToBaby (median 684 mg) than in Medi-Cal (median 300 mg). An OGC dose of ≤300 mg was not associated with increased preterm birth risk. Exposure misclassification and confounding by RA severity were unlikely explanations of differences. CONCLUSION: Higher baseline preterm birth risk and lower OGC dose distribution in Medi-Cal may explain the discrepancies. Studies are needed to understand the effects of autoimmune disease severity and undertreatment on preterm birth risk in low-income populations.

BackgroundPrenatal alcohol exposure (PAE) has been shown to alter fetal blood flow in utero and is also associated with placental insufficiency and intrauterine growth restriction (IUGR), suggesting an underlying connection between perturbed circulation and pregnancy outcomes.MethodsTimed-pregnant C57/BL6NHsd mice, bred in-house, were exposed by gavage on gestational day 10 (GD10) to ethanol (3 g/kg) or purified water, as a control. Pulse-wave Doppler ultrasound measurements for umbilical arteries and ascending aorta were obtained post-gavage (GD12, GD14, GD18) on 2 fetuses/litter. RNA from the non-decidual (labyrinthine and junctional zone) portion of placentas was isolated and processed for RNA-seq and subsequent bioinformatic analyses, and the association between transcriptomic changes and fetal phenotypes assessed.ResultsExposure to ethanol in pregnant mice on GD10 attenuates umbilical cord blood flow transiently during gestation, and is associated with indices of IUGR, specifically decreased fetal weight and morphometric indices of cranial growth. Moreover, RNA-seq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of Tet3, which is associated with spontaneous abortion. Weighted gene co-expression network analysis (WGCNA) identified erythrocyte differentiation and homeostasis as important pathways associated with improved umbilical cord blood flow as gestation progresses. WGCNA also identified sensory perception of chemical stimulus/odorant and receptor activity as important pathways associated with cranial growth.ConclusionOur data suggest that PAE perturbs the expression of placental genes relevant for placental hematopoiesis and environmental sensing, resulting in transient impairment of umbilical cord blood flow and, subsequently, IUGR.

ObjectivesMost women may have temporary pain for which they use analgesics, but those with autoimmune disorders have chronic pain that may be exacerbated for some during pregnancy. This study aimed to determine whether prenatal acetaminophen use was associated with an increased risk of adverse pregnancy and birth outcomes in women with autoimmune disorders.MethodsParticipants were enrolled between 2004 and 2018 in the MotherToBaby cohort study and limited to women with an autoimmune disorder (n = 1821). Self-reported acetaminophen use was characterized over gestation for indication, timing of use and duration. Cumulative acetaminophen use through 20 and 32 weeks was categorized into quintiles, with no acetaminophen use as the reference category. The association between acetaminophen quintile and preeclampsia or pregnancy-induced hypertension, small for gestational age and preterm birth was examined using adjusted multiple log-linear regression.ResultsOverall, 74% of women reported acetaminophen use during pregnancy. The most often reported indication for using acetaminophen was headache/migraines, followed by pain and injury. Risk of preeclampsia was 1.62 (95% CI: 1.10, 2.40) times greater for those in the fifth quintile of cumulative acetaminophen use through 20 weeks compared with those with no acetaminophen use. There were no associations with lower use quintiles, nor for the other outcomes.ConclusionThe highest quintile of cumulative acetaminophen was associated with a modestly increased risk for preeclampsia. Some women with autoimmune conditions have pain throughout pregnancy; clinicians and patients should discuss approaches to best avoid high levels of acetaminophen in their pain management strategies.

ObjectiveThe objective was to investigate maternal and pregnancy characteristics associated with neonatal encephalopathy (NE).Study designWe queried an administrative birth cohort from California between 2011 and 2017 to determine the association between each factor and NE with and without hypothermia treatment.ResultsFrom 3 million infants born at 35 or more weeks of gestation, 6,857 cases of NE were identified (2.3 per 1000 births), 888 (13%) received therapeutic hypothermia. Risk factors for NE were stronger among cases receiving hypothermia therapy. Substance-related diagnosis, preexisting diabetes, preeclampsia, and any maternal infection were associated with a two-fold increase in risk. Maternal overweight/obesity, nulliparity, advanced maternal age, depression, gestational diabetes or hypertension, and short or long gestations also predicted NE. Young maternal age, Asian race and Hispanic ethnicity, and cannabis-related diagnosis lowered risk of NE.ConclusionsBy disseminating these results, we encourage further interrogation of these perinatal factors.

We studied the T cell response to SARS-CoV-2 spike and non-spike peptide epitopes in eight convalescent pregnant women together with the immune monitoring that included innate tolerogenic dendritic cell populations important to maintain the immunological mother/fetus interface to address a potential risk for the antiviral cellular response in the outcome of pregnancy. Four subjects had pre-existing chronic inflammatory conditions that could have potentially affected the SARS-CoV-2-specific T cell response. Seven of eight subjects responded to SARS-CoV-2 peptides with differences within CD4+ T helper (Th) and CD8+ cytotoxic T cells (CTL). SARS-CoV-2-specific inducible regulatory T cells (iTreg) were numerous in circulation. CD4+ T cell memory included central memory T cells (TCM) and effector memory (TEM). As far as the CD8+ memory repertoire, TCM and TEM were very low or absent in eight of eight subjects and only effector cells that revert to CD45RA+, defined as TEMRA were measurable in circulation. T cells were in the normal range in all subjects regardless of pre-existing inflammatory conditions. The immune phenotype indicated the expansion and activation of tolerogenic myeloid dendritic cells including CD14+ cDC2 and CD4+ ILT-4+ tmDC. In summary, SARS-CoV-2 infection induced a physiological anti-viral T cell response in pregnant women that included SARS-CoV-2-specific iTreg with no negative effects on the tolerogenic innate dendritic cell repertoire relevant to the immune homeostasis of the maternal-fetal interface. All eight subjects studied delivered full-term, healthy infants.

Background The pathogenesis of congenital heart disease (CHD) remains largely unknown, with only a small percentage explained solely by genetic causes. Modifiable environmental risk factors, such as alcohol, are suggested to play an important role in CHD pathogenesis. We sought to evaluate the association between prenatal alcohol exposure and CHD to gain insight into which components of cardiac development may be most vulnerable to the teratogenic effects of alcohol. Methods and Results This was a retrospective analysis of hospital discharge records from the California Office of Statewide Health Planning and Development and linked birth certificate records restricted to singleton, live-born infants from 2005 to 2017. Of the 5 820 961 births included, 16 953 had an alcohol-related International Classification of Diseases, Ninth and Tenth Revisions (ICD-9; ICD-10) code during pregnancy. Log linear regression was used to calculate risk ratios (RR) for CHD among individuals with an alcohol-related ICD-9 and ICD10 code during pregnancy versus those without. Three models were created: (1) unadjusted, (2) adjusted for maternal demographic factors, and (3) adjusted for maternal demographic factors and comorbidities. Maternal alcohol-related code was associated with an increased risk for CHD in all models (RR, 1.33 to 1.84); conotruncal (RR, 1.62 to 2.11) and endocardial cushion (RR, 2.71 to 3.59) defects were individually associated with elevated risk in all models. Conclusions Alcohol-related diagnostic codes in pregnancy were associated with an increased risk of an offspring with a CHD, with a particular risk for endocardial cushion and conotruncal defects. The mechanistic basis for this phenotypic enrichment requires further investigation.

In many perinatal pharmacoepidemiologic studies, exposure to a medication is classified as "ever exposed" versus "never exposed" within each trimester or even over the entire pregnancy. This approach is often far from real-world exposure patterns, may lead to exposure misclassification, and does not to incorporate important aspects such as dosage, timing of exposure, and treatment duration. Alternative exposure modeling methods can better summarize complex, individual-level medication use trajectories or time-varying exposures from information on medication dosage, gestational timing of use, and frequency of use. We provide an overview of commonly used methods for more refined definitions of real-world exposure to medication use during pregnancy, focusing on the major strengths and limitations of the techniques, including the potential for method-specific biases. Unsupervised clustering methods, including k-means clustering, group-based trajectory models, and hierarchical cluster analysis, are of interest because they enable visual examination of medication use trajectories over time in pregnancy and complex individual-level exposures, as well as providing insight into comedication and drug-switching patterns. Analytical techniques for time-varying exposure methods, such as extended Cox models and Robins' generalized methods, are useful tools when medication exposure is not static during pregnancy. We propose that where appropriate, combining unsupervised clustering techniques with causal modeling approaches may be a powerful approach to understanding medication safety in pregnancy, and this framework can also be applied in other areas of epidemiology.

OBJECTIVE: To investigate the trends of 1-year mortality and neonatal morbidities in preterm infants with serious congenital heart disease (CHD). STUDY DESIGN: This cohort study used a population-based administrative dataset of all liveborn infants of 26-36 weeks gestational age with serious CHD born in California between 2011 and 2017. We assessed 1-year mortality and major neonatal morbidities (ie, retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage grade >2, and periventricular leukomalacia) across the study period and compared these outcomes with those in infants without CHD. RESULTS: We identified 1921 preterm infants with serious CHD. The relative risk (RR) of death decreased by 10.6% for each year of the study period (RR, 0.89; 95% CI, 0.84-0.95), and the RR of major neonatal morbidity increased by 8.3% for each year (RR, 1.08; 95% CI, 1.02-1.15). Compared with preterm neonates without any CHD (n = 234 522), the adjusted risk difference (ARD) for mortality was highest at 32 weeks of gestational age (9.7%; 95% CI, 8.3%-11.2%), that for major neonatal morbidity was highest at 28 weeks (21.9%; 95% CI, 17.0%-26.9%), and that for the combined outcome was highest at 30 weeks (26.7%; 95% CI, 23.3%-30.1%). CONCLUSIONS: Mortality in preterm neonates with serious CHD decreased over the last decade, whereas major neonatal morbidities increased. Preterm infants with a gestational age of 28-32 weeks have the highest mortality or morbidity compared with their peers without CHD. These results support the need for specialized and focused medical neonatal care in preterm neonates with serious CHD.

Effects of prenatal alcohol exposure (PAE) are rarely measured in preschool children due to relative insensitivity of assessment methods at this age. To examine the potential of a nonverbal battery in early identification of cognitive problems in alcohol-exposed children, 291 prospectively identified Ukrainian children were evaluated using a test battery focusing on early executive functioning (EF) and visuospatial skills, areas of cognitive development particularly sensitive to PAE in older children. Tests included the Differential Ability Scales, 2nd Edition (DAS-2) and several NEPSY/NEPSY-II subtests, standardized in the United States. Others were adapted from commonly used non-standardized neuropsychological measures of EF (Preschool Spatial Span, Imitation Hand Game, A not B, Delayed Attention, Subject Ordered Pointing). Children in two sites in Ukraine, Rivne and Khmelnitsky, were tested at 3 ½-4 ½ years to identify effects of PAE. Although most children performed within the average range, Alcohol-Exposed preschoolers had lower scores on DAS-II Summary Scores as well as on specific subtests. To evaluate the effects of alcohol dose during the pre-pregnancy recognition period and during mid-gestation of pregnancy, generalized linear regression models were used controlling for demographic and individual variables. In addition to DAS-II variables, measures reflecting sustained attention, working memory and ability to shift cognitive set were impacted by alcohol dose. Early executive function appears to subsume these performance differences. In conclusion, findings indicate that the effects of PAE can be identified in the preschool period and reliably measured using tests assessing nonverbal and spatial skills supported by executive functioning.