SARS-CoV-2 infection, inflammation and birth outcomes in a prospective NYC pregnancy cohort.

Associations between antenatal SARS-CoV-2 infection and pregnancy outcomes have been conflicting and the role of the immune system is currently unclear. This prospective cohort study investigated the interaction of antenatal SARS-CoV-2 infection, changes in cytokine and HS-CRP levels, birthweight and gestational age at birth. 2352 pregnant participants from New York City (2020-2022) were included. Plasma levels of interleukin (IL)-1ß, IL-6, IL-17A and high-sensitivity C-reactive protein (HS-CRP) were quantified in blood specimens obtained across pregnancy. Quantile and linear regression models were conducted to 1) assess the impact of antenatal SARS-CoV-2 infection, overall and by timing of detection of SARS-CoV-2 positivity (< 20 weeks versus ≥ 20 weeks), on birthweight and gestational age at delivery; 2) examine the relationship between SARS-CoV-2 infection and maternal immune changes during pregnancy. All models were adjusted for maternal demographic and obstetric factors and pandemic timing. Birthweight models were additionally adjusted for gestational age at delivery and fetal sex. Immune marker models were also adjusted for gestational age at specimen collection and multiplex assay batch. 371 (15.8%) participants were infected with SARS-CoV-2 during pregnancy, of which 98 (26.4%) were infected at < 20 weeks gestation. Neither SARS-CoV-2 infection in general nor in early or late pregnancy was associated with lower birthweight nor earlier gestational age at delivery. Further, we did not observe cytokine or HS-CRP changes in response to SARS-CoV-2 infection and thus found no evidence to support a potential association between immune dysregulation and the diversity in pregnancy outcomes following infection.

The effect of SARS-CoV-2 infection and vaccination on Th17 and regulatory T cells in a pregnancy cohort in NYC.

Disturbances in T-cells, specifically the Th17/Treg balance, have been implicated in adverse pregnancy outcomes. We investigated these two T-cell populations following pre-pregnancy and pregnancy SARS-CoV-2 infection and COVID-19 vaccination in 351 participants from a pregnancy cohort in New York City (Generation C; 2020-2022). SARS-CoV-2 infection status was determined via laboratory or medical diagnosis and COVID-19 vaccination status via survey and electronic medical records data. Peripheral blood mononuclear cells (PBMCs) were collected at routine prenatal visits throughout gestation (median 108 days; IQR 67-191 days) with repeated measures for 104 participants (29.6%). T-cell populations CD4+/CD3+, Th17/CD4+, Treg/CD4+ and the Th17/Treg ratio were quantified using flow cytometry. Results showed that inter-individual differences are a main influencing factor in Th17 and Treg variance, however total variance explained remained small (R2 = 15-39%). Overall, Th17 and Treg populations were not significantly affected by SARS-CoV-2 infection during pregnancy in adjusted linear mixed models (p>0.05), however comparison of repeated measures among SARS-CoV-2 infected participants and non-infected controls suggests a relative increase of the Th17/Treg ratio following infection. In addition, the Th17/Treg ratio was significantly higher after SARS-CoV-2 infection prior to pregnancy (10-138 weeks) compared to controls (ß=0.48, p=0.003). COVID-19 vaccination was not associated with Th17 and Treg cells. Our findings suggest an impact of SARS-CoV-2 infection on the Th17/Treg ratio, likely depending on severity of infection, yet the observed trends and their potential consequences for pregnancy outcomes require further investigation. Our study contributes to growing evidence that COVID-19 vaccination during pregnancy does not lead to an exacerbated immune response.

Increased postpartum anxiety symptoms after perinatal SARS-CoV-2 infection in a large, prospective pregnancy cohort in New York City.

Numerous studies reported an increase of postpartum mood symptoms during the COVID-19 pandemic. Yet, the link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and perinatal mental health is less well understood. We investigated the associations between prenatal SARS-CoV-2 infection and postpartum depressive and anxiety symptoms, including examinations of infection timing and pandemic timeline. We included 595 participants from Generation C, a prospective pregnancy cohort in New York City (2020-2022). Prenatal SARS-CoV-2 infection was determined via laboratory or medical diagnosis. Depression and anxiety symptoms were measured 4-12 weeks postpartum using the Edinburgh Postnatal Depression Scale (EPDS) and Generalized Anxiety Disorder questionnaire (GAD), respectively. Quantile regressions were conducted with prenatal SARS-CoV-2 infection as exposure and continuously measured EPDS and GAD scores as outcomes. We reran the analyses in those with COVID-19-like symptoms in the trimester during which infection occurred. 120 (20.1%) participants had prenatal SARS-CoV-2 infection. After adjusting for socio-demographic, obstetric and other maternal health factors, prenatal SARS-CoV-2 infection was associated with higher median postpartum anxiety scores (b = 0.55, 95% CI = 0.15; 0.96). Late gestation infection (b = 1.15, 95% CI = 0.22; 2.09) and symptomatic infection (b = 1.15, 95% CI = 0.12; 2.18) were also associated with higher median postpartum anxiety scores. No associations were found with depressive symptoms. The associations were not moderated by time since the start of the pandemic. This study suggests that prenatal SARS-CoV-2 infection increases the risk of postpartum anxiety symptoms among participants reporting median anxiety symptoms. Given that this association was not affected by pandemic timing and that SARS-CoV-2 transmission continues, individuals infected with SARS-CoV-2 during pregnancy should be monitored for postpartum anxiety symptoms.

Exposure to prenatal infection and the development of internalizing and externalizing problems in children: a longitudinal population-based study.

BACKGROUND: A large body of work has reported a link between prenatal exposure to infection and increased psychiatric risk in offspring. However, studies to date have focused primarily on exposure to severe prenatal infections and/or individual psychiatric diagnoses in clinical samples, typically measured at single time points, and without accounting for important genetic and environmental confounders. In this study, we investigated whether exposure to common infections during pregnancy is prospectively associated with repeatedly assessed child psychiatric symptoms in a large population-based study. METHODS: Our study was embedded in a prospective pregnancy cohort (Generation R; n = 3,598 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. Child total, internalizing, and externalizing problems were assessed repeatedly using the parent-rated Child Behavioral Checklist (average age: 1.5, 3, 6, 10, and 14 years). Linear mixed-effects models were run adjusting for a range of confounders, including child polygenic scores for psychopathology, maternal chronic illness, birth complications, and infections during childhood. We also investigated trimester-specific effects and child sex as a potential moderator. RESULTS: Prenatal exposure to infections was associated with higher child total, internalizing, and externalizing problems, showing temporally persistent effects, even after adjusting for important genetic and environmental confounders. We found no evidence that prenatal infections were associated with changes in child psychiatric symptoms over time. Moreover, in our trimester-specific analysis, we did not find evidence of significant timing effects of prenatal infection on child psychiatric symptoms. No interactions with child sex were identified. CONCLUSIONS: Our research adds to evidence that common prenatal infections may be a risk factor for psychiatric symptoms in children. We also extend previous findings by showing that these associations are present early on, and that rather than changing over time, they persist into adolescence. However, unmeasured confounding may still explain in part these associations. In the future, employing more advanced causal inference designs will be crucial to establishing the degree to which these effects are causal.

Prenatal antidepressant exposure and the risk of decreased gestational age and lower birthweight: A polygenic score approach to investigate confounding by indication.

INTRODUCTION: Prenatal antidepressant exposure has been associated with lower gestational age and birthweight. Yet, unmeasured residual confounding may inflate this association. We explored if maternal genetic liability for major depression explains part of the association of antidepressant use in pregnancy with lower gestational age and birthweight. MATERIAL AND METHODS: We employed the maternal polygenic score (PGS) for major depression as a measure of genetic liability. We used generalised linear models to estimate the differences in gestational age and birthweight at each PGS quintile between children whose mothers continued antidepressant use during pregnancy (continuation group), children whose mothers discontinued antidepressant use during pregnancy (discontinuation group) and unexposed children. RESULTS: After adjusting for confounders, we found significant differences in birthweight between PGS quintiles in the continuation and unexposed group. Yet, this relationship was not linear. Furthermore, at the lowest and highest PGS quintiles, the continuation group had significantly reduced mean gestational ages (adjusted ß ranges: 1.7-4.5 days, p < 0.001-0.008) and lower mean birthweights (adjusted ß ranges: 58.6-165.4 g, p = 0.001-0.008) than the discontinuation and unexposed groups. CONCLUSION: We confirmed that antidepressant use in pregnancy was associated with small reductions in gestational age and birthweight but found that genetic liability for depression was not linearly associated with this risk. The causality of the observed associations could not be established due to the observational nature of the study. Residual confounding linked to the underlying disease was likely still present.

Long-term effects of prenatal infection on the human brain: a prospective multimodal neuroimaging study.

There is convincing evidence from rodent studies suggesting that prenatal infections affect the offspring's brain, but evidence in humans is limited. Here, we assessed the occurrence of common infections during each trimester of pregnancy and examined associations with brain outcomes in adolescent offspring. Our study was embedded in the Generation R Study, a large-scale sociodemographically diverse prospective birth cohort. We included 1094 mother-child dyads and investigated brain morphology (structural MRI), white matter microstructure (DTI), and functional connectivity (functional MRI), as outcomes at the age of 14. We focused on both global and focal regions. To define prenatal infections, we composed a score based on the number and type of infections during each trimester of pregnancy. Models were adjusted for several confounders. We found that prenatal infection was negatively associated with cerebral white matter volume (B = -0.069, 95% CI -0.123 to -0.015, p = 0.011), and we found an association between higher prenatal infection scores and smaller volumes of several frontotemporal regions of the brain. After multiple testing correction, we only observed an association between prenatal infections and the caudal anterior cingulate volume (B = -0.104, 95% CI -0.164 to -0.045, p < 0.001). We did not observe effects of prenatal infection on other measures of adolescent brain morphology, white matter microstructure, or functional connectivity, which is reassuring. Our results show potential regions of interest in the brain for future studies; data on the effect of severe prenatal infections on the offspring's brain in humans are needed.

The Association Between Prenatal Infection and Adolescent Behavior: Investigating Multiple Prenatal, Perinatal, and Childhood Second Hits.

OBJECTIVE: Exposure to infections during pregnancy may be a potential risk factor for later psychopathology, but large-scale epidemiological studies investigating associations between prenatal infection and long-term offspring behavioral problems in the general population are scarce. In our study, we aimed to investigate the following: (1) the association between prenatal infection and adolescent behavior, (2) putative underlying pathways (mediation), and (3) "second hits" interacting with prenatal infection to increase the risk of adolescent behavior problems (moderation). METHOD: Our study was embedded in a prospective Dutch pregnancy cohort (Generation R; n = 2,213 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. At age 13 to 16 years, we assessed total, internalizing, and externalizing problems, and autistic traits using the Child Behavioral Checklist and the Social Responsiveness Scale, respectively. We investigated maternal lifestyle and nutrition, perinatal factors (placental health and delivery outcomes), and child health (lifestyle, traumatic events, infections) as mediators and moderators. RESULTS: We observed associations of prenatal infection with adolescent total behavioral, internalizing, and externalizing problems. The association between prenatal infection and internalizing problems was moderated by higher levels of maternal psychopathology, alcohol and tobacco use, and a higher number of traumatic childhood events. We found no association between prenatal infection and autistic traits. Yet, children exposed to prenatal infections and maternal substance use, and/or traumatic childhood events, had a higher risk of autistic traits in adolescence. CONCLUSION: Prenatal infection may be a risk factor for later psychiatric problems as well as a disease primer making individuals susceptible to other hits later in life. STUDY PREREGISTRATION INFORMATION: Prenatal maternal infection and adverse neurodevelopment: a structural equation modelling approach to downstream environmental hits; https://osf.io/cp85a; cp85a. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Titer Levels in Pregnant Individuals After Infection, Vaccination, or Both.

We examined differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody responses in pregnant individuals with natural, vaccine-induced, or combined immunity. Participants had live or nonlive births between 2020 and 2022, were seropositive (SARS-CoV-2 spike protein, anti-S), and had available mRNA vaccination and infection information (n=260). We compared titer levels among three immunity profiles: 1) natural immunity (n=191), 2) vaccine-induced immunity (n=37), and 3) combined immunity (ie, natural and vaccine-induced immunity; n=32). We applied linear regression to compare anti-S titers between the groups, controlling for age, race and ethnicity, and time between vaccination or infection (whichever came last) and sample collection. Anti-S titers were 57.3% and 94.4% lower among those with vaccine-induced and natural immunity, respectively, compared with those with combined immunity ( P <.001, P =.005).

Association Between Mental Health and Reproductive System Disorders in Women: A Systematic Review and Meta-analysis.

Importance: Reproductive system and mental health disorders are commonly comorbid in women. Although the causes of this overlap remain elusive, evidence suggests potential shared environmental and genetic factors associated with risk. Objective: To investigate the comorbidity between psychiatric and reproductive system disorders, both as broad diagnostic categories and among specific pairs of diagnoses. Data Source: PubMed. Study Selection: Observational studies published between January 1980 and December 2019 assessing prevalence of psychiatric disorders in women with reproductive system disorders and prevalence of reproductive system disorders in women with psychiatric disorders were included. The study did not include psychiatric and reproductive disorders triggered by life events (eg, trauma, infection, surgery) to address potential confounding. Data Extraction and Synthesis: A search yielded 1197 records, of which 50 met the inclusion criteria for the qualitative and 31 for the quantitative synthesis in our study. A random-effects model was used for data synthesis and Egger test and I2 to assess study bias and heterogeneity. Data were analyzed from January to December 2022. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures: Psychiatric and reproductive system disorders. Results: A total of 1197 records were identified, of which 50 met the inclusion criteria for qualitative and 31 for quantitative synthesis. Diagnosis of a reproductive system disorder was associated with a 2- to 3-fold increased odds of having a psychiatric disorder (lower bound odds ratio [OR], 2.00; 95% CI, 1.41-2.83; upper bound OR; 2.88; 95% CI, 2.21-3.76). The analysis focused on specific diagnoses described in the literature and found that polycystic ovary syndrome was associated with increased odds of depression (population-based studies OR, 1.71; 95% CI, 1.19-2.45; clinical studies OR, 2.58; 95% CI, 1.57-4.23) and anxiety (population-based studies OR, 1.69; 95% CI, 1.36-2.10; clinical studies OR, 2.85; 95% CI, 1.98-4.09). Chronic pelvic pain was also associated with both depression (OR, 3.91; 95% CI, 1.81-8.46) and anxiety (OR, 2.33; 95% CI, 1.33-4.08). Few studies investigated risk of other reproductive system disorders in women with psychiatric disorders, or reverse associations (risk of reproductive system disorder among women with a psychiatric diagnosis). Conclusions and Relevance: In this systematic review and meta-analysis, a high rate of reported co-occurrence between psychiatric and reproductive disorders overall was observed. However, data for many disorder pairs were limited. The available literature focused overwhelmingly on affective disorders in polycystic ovary syndrome, overlooking a substantial portion of disease overlap. As such, the associations between the majority of mental health outcomes and conditions of the female reproductive system are largely unknown.

Impact of prenatal COVID-19 vaccination on delivery and neonatal outcomes: Results from a New York City cohort.

Research suggest prenatal vaccination against coronavirus disease-19 (COVID-19) is safe. However, previous studies utilized retrospectively collected data or examined late pregnancy vaccinations. We investigated the associations of COVID-19 vaccination throughout pregnancy with delivery and neonatal outcomes. We included 1,794 mother-neonate dyads enrolled in the Generation C Study with known prenatal COVID-19 vaccination status and complete covariate and outcome data. We used multivariable quantile regressions to estimate the effect of prenatal COVID-19 vaccination on birthweight, delivery gestational age, and blood loss at delivery; and Poisson generalized linear models for Caesarean delivery (CD) and Neonatal Intensive Care Unit (NICU) admission. Using the above methods, we estimated effects of trimester of vaccine initiation on these outcomes. In our sample, 13.7% (n = 250) received at least one prenatal dose of any COVID-19 vaccine. Vaccination was not associated with birthweight (ß = 12.42 g [-90.5, 114.8]), gestational age (ß = 0.2 days [-1.1, 1.5]), blood loss (ß = -50.6 ml [-107.0, 5.8]), the risks of CD (RR = 0.8; [0.6, 1.1]) or NICU admission (RR = 0.9 [0.5, 1.7]). Trimester of vaccine initiation was also not associated with these outcomes. Our findings suggest that there is no associated risk between prenatal COVID-19 vaccination and adverse delivery and neonatal outcomes in a cohort sample from NYC.

The incidence of depressive episodes is different before, during, and after pregnancy: A population-based study.

BACKGROUND: Depressive episodes during pregnancy are widely investigated but it is still unknown whether pregnancy is a high-risk period compared to the pre-pregnancy period. Therefore, we aimed to investigate the incidence and recurrence of depressive episodes before, during, and after pregnancy. METHODS: In the current population-based registry study, we calculated monthly incidence and recurrence of psychiatric inpatient admissions and outpatient psychiatric contact for depressive episodes. We identified a population consisting of all first childbirths in Denmark from 1999 through 2015 (N = 392,287). RESULTS: Incidence of inpatient admission during pregnancy was lower than before pregnancy. After childbirth, a significant increase in first-time and recurrent psychiatric inpatient admissions was observed, especially in the first months. In contrast, outpatient psychiatric treatment incidence and recurrence were increased both during pregnancy as well as in the postpartum period, as compared to pre-pregnancy. LIMITATIONS: Analyses were performed on depressive episodes representing the severe end of the spectrum, questioning generalizability to milder forms of depression treated outside psychiatric specialist treatment facilities. CONCLUSION: We found a different pattern of severe episodes of depression compared to moderate episodes before, during, and after pregnancy. In light of our findings and those of others, we suggest distinguishing between timing of onset in the classification of depression in the perinatal period: Depression with pregnancy onset OR with postpartum onset (instead of the current DSM classifier "with perinatal onset"), as well as severity of depression, which is important for both clinical and future research endeavors.

Cross-sectional associations of maternal PFAS exposure on SARS-CoV-2 IgG antibody levels during pregnancy.

BACKGROUND: Perfluoroalkylated substances (PFAS) are man-made, persistent organic compounds with immune-modulating potentials. Given that pregnancy itself represents an altered state of immunity, PFAS exposure-related immunotoxicity is an important environmental factor to consider in SARS-CoV-2 infection during pregnancy as it may further affect humoral immune responses. AIM: To investigate the relationship between maternal plasma PFAS concentrations and SARS-CoV-2 antibody levels in a NYC-based pregnancy cohort. METHODS: Maternal plasma was collected from 72 SARS-CoV-2 IgG + participants of the Generation C Study, a birth cohort established at the beginning of the COVID-19 pandemic in New York City. Maternal SARS-CoV-2 anti-spike IgG antibody levels were measured using ELISA. A panel of 16 PFAS congeners were measured in maternal plasma using a targeted UHPLC-MS/MS-based assay. Spearman correlations and linear regressions were employed to explore associations between maternal IgG antibody levels and plasma PFAS concentrations. Weighted quantile sum (WQS) regression was also used to evaluate mixture effects of PFAS. Models were adjusted for maternal age, gestational age at which SARS-CoV-2 IgG titer was measured, COVID-19 vaccination status prior to IgG titer measurement, maternal race/ethnicity, parity, type of insurance and pre-pregnancy BMI. RESULTS: Our study population is ethnically diverse with an average maternal age of 32 years. Of the 16 PFAS congeners measured, nine were detected in more than 60% samples. Importantly, all nine congeners were negatively correlated with SARS-CoV-2 anti-spike IgG antibody levels; n-PFOA and PFHxS, PFHpS, and PFHxA reached statistical significance (p < 0.05) in multivariable analyses. When we examined the mixture effects using WQS, a quartile increase in the PFAS mixture-index was significantly associated with lower maternal IgG antibody titers (beta [95% CI] = -0.35 [-0.52, -0.17]). PFHxA was the top contributor to the overall mixture effect. CONCLUSIONS: Our study results support the notion that PFAS, including short-chain emerging PFAS, act as immunosuppressants during pregnancy. Whether such compromised immune activity leads to downstream health effects, such as the severity of COVID-19 symptoms, adverse obstetric outcomes or neonatal immune responses remains to be investigated.

Gestational SARS-CoV-2 infection is associated with placental expression of immune and trophoblast genes.

INTRODUCTION: Maternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy. METHODS: We performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City. We compared histologic features and the expression of 48 immune and trophoblast genes in placentas delivered from 15 SARS-CoV-2 IgG antibody positive and 30 IgG SARS-CoV-2 antibody negative mothers. Statistical analyses were performed using Fisher's exact tests, Spearman correlations and linear regression models. RESULTS: The median gestational age at the time of SARS-CoV-2 IgG serology test was 35 weeks. Two of the IgG positive participants also had a positive RT-PCR nasal swab at delivery. 82.2% of the infants were delivered at term (≥37 weeks), and gestational age at delivery did not differ between the SARS-CoV-2 antibody positive and negative groups. No significant differences were detected between the groups in placental histopathology features. Differential expression analyses revealed decreased expression of two trophoblast genes (PSG3 and CGB3) and increased expression of three immune genes (CXCL10, TLR3 and DDX58) in placentas delivered from SARS-CoV-2 IgG positive participants. DISCUSSION: SARS-CoV-2 infection during pregnancy is associated with gene expression changes of immune and trophoblast genes in the placenta at birth which could potentially contribute to long-term health effects in the offspring.

Temperament Dimensions and Awakening Cortisol Levels in Attention-Deficit/Hyperactivity Disorder.

Objective: To investigate whether temperament dimensions, Effortful Control (EC), Surgency-Extraversion (SE), and Negative Affectivity (NA), are associated with attention-deficit/hyperactivity disorder (ADHD) and how they relate to awakening cortisol levels, as a proxy measure of peripheral arousal. Methods: Parent-rated temperament and saliva samples were collected from 55 children with ADHD and 65 age-matched controls. Results: Compared to controls, youths with ADHD showed lower EC, higher NA, and lower awakening cortisol levels but did not differ in SE. Similar findings emerged in dimensional analyses linking temperament traits to inattention and hyperactivity-impulsivity symptoms. The results remained unchanged when controlling for the presence of co-occurring opposition-defiance and anxiety traits, as well as medication status. Temperament dimensions were not associated with cortisol levels. Conclusions: Poor temperamental emotional and cognitive self-regulation showed significant associations with ADHD but did not appear to be linked to the under-arousal typically seen in ADHD.

The influence of structural racism, pandemic stress, and SARS-CoV-2 infection during pregnancy with adverse birth outcomes.

BACKGROUND: Structural racism and pandemic-related stress from the COVID-19 pandemic may increase the risk of adverse birth outcomes. OBJECTIVE: Our objective was to examine associations between neighborhood measures of structural racism and pandemic stress with 3 outcomes: SARS-CoV-2 infection, preterm birth, and delivering small-for-gestational-age newborns. Our secondary objective was to investigate the joint association of SARS-CoV-2 infection during pregnancy and neighborhood measures with preterm birth and delivering small-for-gestational-age newborns. STUDY DESIGN: We analyzed data of 967 patients from a prospective cohort of pregnant persons in New York City, comprising 367 White (38%), 169 Black (17%), 293 Latina (30%), and 87 Asian persons (9%), 41 persons of other race or ethnicity (4%), and 10 of unknown race or ethnicity (1%). We evaluated structural racism (social/built structural disadvantage, racial-economic segregation) and pandemic-related stress (community COVID-19 mortality, community unemployment rate increase) in quartiles by zone improvement plan code. SARS-CoV-2 serologic enzyme-linked immunosorbent assay was performed on blood samples from pregnant persons. We obtained data on preterm birth and small-for-gestational-age newborns from an electronic medical record database. We used log-binomial regression with robust standard error for clustering by zone improvement plan code to estimate associations of each neighborhood measure separately with 3 outcomes: SARS-CoV-2 infection, preterm birth, and small-for-gestational-age newborns. Covariates included maternal age, parity, insurance status, and body mass index. Models with preterm birth and small-for-gestational-age newborns as the dependent variables additionally adjusted for SARS-CoV-2 infection. RESULTS: A total of 193 (20%) persons were SARS-CoV-2-seropositive, and the overall risks of preterm birth and small-for-gestational-age newborns were 8.4% and 9.8%, respectively. Among birthing persons in neighborhoods in the highest quartile of structural disadvantage (n=190), 94% were non-White, 50% had public insurance, 41% were obese, 32% were seropositive, 11% delivered preterm, and 12% delivered a small-for-gestational-age infant. Among birthing persons in neighborhoods in the lowest quartile of structural disadvantage (n=360), 39% were non-White, 17% had public insurance, 15% were obese, 9% were seropositive, 6% delivered preterm, and 10% delivered a small-for-gestational-age infant. In adjusted analyses, structural racism measures and community unemployment were associated with both SARS-CoV-2 infection and preterm birth, but not small-for-gestational-age infants. High vs low structural disadvantage was associated with an adjusted relative risk of 2.6 for infection (95% confidence interval, 1.7-3.9) and 1.7 for preterm birth (95% confidence interval, 1.0-2.9); high vs low racial-economic segregation was associated with adjusted relative risk of 1.9 (95% confidence interval, 1.3-2.8) for infection and 2.0 (95% confidence interval, 1.3-3.2) for preterm birth; high vs low community unemployment increase was associated with adjusted relative risk of 1.7 (95% confidence interval, 1.2-1.5) for infection and 1.6 (95% confidence interval, 1.0-2.8) for preterm birth. COVID-19 mortality rate was associated with SARS-CoV-2 infection but not preterm birth or small-for-gestational-age infants. SARS-CoV-2 infection was not independently associated with birth outcomes. We found no interaction between SARS-CoV-2 infection and neighborhood measures on preterm birth or small-for-gestational-age infants. CONCLUSION: Neighborhood measures of structural racism were associated with both SARS-CoV-2 infection and preterm birth, but these associations were independent and did not have a synergistic effect. Community unemployment rate increases were also associated with an increased risk of preterm birth independently of SARS-CoV-2 infection. Mitigating these factors might reduce the impact of the pandemic on pregnant people.

The long-term impact of elevated C-reactive protein levels during pregnancy on brain morphology in late childhood.

IMPORTANCE: Animal studies show that Maternal Immune Activation (MIA) may have detrimental effects on fetal brain development. Clinical studies provide evidence for structural brain abnormalities in human neonates following MIA, but no study has investigated the long-term effects of MIA (as measured with biomarkers) on human brain morphology ten years after the exposure. OBJECTIVE: Our aim was to evaluate the long-term impact of MIA on brain morphology in 10-year-old children, including the possible mediating role of gestational age at birth. DESIGN: We leveraged data from Generation R, a large-scale prospective pregnancy cohort study. Pregnant women were included between 2002 and 2006, and their children were invited to participate in the MRI study between 2013 and 2015. To be included, mother-child dyads had to have data on maternal C-reactive protein levels during gestation and a good quality MRI-scan of the child's brain at age 10 years. Of the 3,992 children scanned, a total of 2,053 10-year-old children were included in this study. EXPOSURE: Maternal C-reactive protein was measured in the first 18 weeks of gestation. For the analyses we used both a continuous approach as well as a categorical approach based on clinical cut-offs to determine if there was a dose-response relationship. MAIN OUTCOMES AND MEASURES: High-resolution MRI brain morphology measures were used as the primary outcome. Gestational age at birth, established using ultrasound, was included as a mediator using a causal mediation analysis. Corrections were made for relevant confounders and multiple comparisons. Biological sex was investigated as moderator. RESULTS: We found a direct association between continuous MIA and lower cerebellar volume. In girls, we demonstrated a negative indirect association between continuous MIA and total brain volume, through the mediator gestational age at birth. We observed no associations with categorical MIA after multiple testing correction. CONCLUSION AND RELEVANCE: Our results suggest sex-specific long-term effects in brain morphology after MIA. Categorical analyses suggest that this association might be driven by acute infections or other sources of severe inflammation, which is of clinical relevance given that the COVID-19 pandemic is currently affecting millions of pregnant women worldwide.

Antidepressant use during pregnancy and risk of adverse neonatal outcomes: A comprehensive investigation of previously identified associations.

OBJECTIVE: Prenatal antidepressant use is widespread. Observational studies have investigated the neonatal effects of prenatal antidepressant exposure with inconclusive results. We aimed to comprehensively investigate the associations between prenatal antidepressant exposure and the most commonly studied adverse neonatal outcomes: preterm birth, birthweight, poor neonatal adaptation, persistent pulmonary hypertension of the neonate (PPHN), neonatal admission and congenital malformations. METHODS: We included 45,590 singletons (born 1997-2015) whose mothers used antidepressants within one year before pregnancy. Children were categorised into two groups: continuation (antidepressant use before and during pregnancy) or discontinuation (antidepressant use before but not during pregnancy). We applied random-effects logistic and linear regressions, adjusting for covariates. RESULTS: After adjusting for confounders, prenatal antidepressant exposure was associated with a 2.3 day (95% CI -2.9; -2.0) decrease in gestational age and a 51 g (95% CI -62g; -41 g) decrease in birthweight. The continuation group was at increased risk for moderate-to-late preterm birth (32-37 weeks) (aOR = 1.43; 95%CI 1.33; 1.55), moderately low birthweight (1500-2499 g) (aOR = 1.28; 95%CI 1.17; 1.41), postnatal adaptation syndrome (aOR = 2.59; 95%CI 1.87; 3.59) and neonatal admission (aOR = 1.52; 95%CI 1.44; 1.60) compared to the discontinuation group. CONCLUSION: Prenatal antidepressant exposure was associated with small decreases in gestational age and birthweight, as well as higher risk for moderate-to-late preterm birth, moderately low birthweight, neonatal admission and postnatal adaptation syndrome. No differences in risk were found for PPHN, or congenital malformations. The causality of the observed associations cannot be established due to the potential for unmeasured residual confounding linked to the underlying disease.

Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency in Denmark: A population-based propensity score-matched cohort study.

BACKGROUND: Women prescribed antidepressants face the dilemma of whether or not to continue their treatment during pregnancy. Currently, limited evidence is available on the efficacy of continuing versus discontinuing antidepressant treatment during pregnancy to aid their decision. We aimed to estimate whether antidepressant discontinuation before or during pregnancy was associated with an increased risk of psychiatric emergency (ascertained by psychiatric admission or emergency room visit), a proxy measure of severe exacerbation of symptoms/mental health crisis. METHODS AND FINDINGS: We carried out a propensity score-matched cohort study of women who gave birth to live-born singletons between January 1, 1997 and June 30, 2016 in Denmark and who redeemed an antidepressant prescription in the 90 days before the pregnancy, identified by Anatomical Therapeutic Chemical (ATC) code N06A. We constructed 2 matched cohorts, matching each woman who discontinued antidepressants before pregnancy (N = 2,669) or during pregnancy (N = 5,467) to one who continued antidepressants based on propensity scores. Maternal characteristics and variables related to disease severity were used to generate the propensity scores in logistic regression models. We estimated hazard ratios (HRs) of psychiatric emergency in the perinatal period (pregnancy and 6 months postpartum) using stratified Cox regression. Psychiatric emergencies were observed in 76 women who discontinued antidepressants before pregnancy and 91 women who continued. There was no evidence of higher risk of psychiatric emergency among women who discontinued antidepressants before pregnancy (cumulative incidence: 2.9%, 95% confidence interval [CI]: 2.3% to 3.6% for discontinuation versus 3.4%, 95% CI: 2.8% to 4.2% for continuation; HR = 0.84, 95% CI: 0.61 to 1.16, p = 0.298). Overall, 202 women who discontinued antidepressants during pregnancy and 156 who continued had psychiatric emergencies (cumulative incidence: 5.0%, 95% CI: 4.2% to 5.9% versus 3.7%, 95% CI: 3.1% to 4.5%). Antidepressant discontinuation during pregnancy was associated with increased risk of psychiatric emergency (HR = 1.25, 95% CI: 1.00 to 1.55, p = 0.048). Study limitations include lack of information on indications for antidepressant treatment and reasons for discontinuing antidepressants. CONCLUSIONS: In this study, we found that discontinuing antidepressant medication during pregnancy (but not before) is associated with an apparent increased risk of psychiatric emergency compared to continuing treatment throughout pregnancy.

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.