Reproductive Safety Research Articles

Tim-3+ decidual Mφs induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance via CD132

T-cell immunoglobulin mucin-3 (Tim-3) plays roles in the functional regulation of both adaptive and innate immune cells and is greatly involved in many diseases. However, the precise roles of Tim-3 on macrophages (Mφs) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3+ decidual Mφs (dMφs) in response to trophoblasts. The reduced abundance of Tim-3 on Mφs was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3+Mφs, but not Tim-3−Mφs, relieved murine embryo absorption induced by Mφ depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3+ and Tim-3−dMφs were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) Mφs. However, with higher CD132 expression, Tim-3+dMφs subset induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dMφ function and maintaining normal pregnancy, and suggested that Tim-3 on Mφs is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3−Mφs could rescue the fetal resorption induced by Mφ depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.

Guidance on the need for contraception related to use of pharmaceuticals: the Japan Agency for Medical Research and Development Study Group for providing information on the proper use of pharmaceuticals in patients with reproductive potential

BackgroundThe U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have published guidelines on the use of cancer treatments in young people of reproductive potential. However, no such guideline is available in Japan. Therefore, this project aimed to gather relevant data and draft a respective guidance paper.MethodsFrom April 2019 to March 2021, the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential at the Japan Agency for Medical Research and Development gathered opinions from experts in reproductive medicine, toxicology, and drug safety measures. The group considered these opinions, the FDA and EMA guidelines, and relevant Japanese guidelines and prepared a guidance paper, which they sent to 19 related organizations for comment.ResultsBy November 2020, the draft guidance paper was completed and sent to the related organizations, 17 of which provided a total of 156 comments. The study group finalized the guidance paper in March 2021.ConclusionsThe “Guidance on the Need for Contraception Related to Use of Pharmaceuticals” (The report of the Study Group for Providing Information on the Proper Use of Pharmaceuticals in Patients with Reproductive Potential, Research on Regulatory Science of Pharmaceuticals and Medical Devices, Japan Agency for Medical Research and Development: JP20mk0101139) is expected to help Japanese healthcare professionals provide fertility-related care and advice to adolescents, and young adults with cancer and their families.

Antibody-drug conjugates targeting CD248 inhibits liver fibrosis through specific killing on myofibroblasts

BackgroundChronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo.MethodsCD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo.ResultsCD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo.ConclusionsOur study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.Graphic

The neurodevelopmental morbidity of children born after assisted reproductive technology: a Nordic register study from the Committee of Nordic Assisted Reproductive Technology and Safety group

To assess the risk of neurodevelopmental disorders in singletons born after the use of assisted reproductive technology (ART) compared with singletons born without the use of ART. Nordic register-based study. Cross-linked data from Medical Birth Registers and National ART and Patient Registers; liveborn singletons in 1995-2014 in Denmark and Finland, 2005-2015 in Norway, and 1995-2015 in Sweden with follow-up to 2014 (Denmark and Finland) or 2015 (Norway and Sweden). A total of 5,076,444 singletons: 116,909 (2.3%) born with and 4,959,535 (97.7%) born without the use of ART (non-ART). Invitro fertilization, intracytoplasmic sperm injection, and fresh and frozen embryo transfer. The primary outcomes (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes) were learning and motor functioning disorders (F80-F83), autism spectrum disorder (F84), attention-deficit/hyperactivity disorder and conduct disorders (F90-F92), and tic disorders (F95). Crude hazard ratios (HRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals were calculated. Singletons in the ART cohort had a higher adjusted risk of learning and motor functioning disorders (HR, 1.01 [0.96-1.07]; aHR, 1.17 [1.11-1.24]) and a tendency toward a higher risk of autism spectrum disorder (HR, 1.12 [1.04-1.21]; aHR, 1.07 [0.98-1.16]) and attention-deficit/hyperactivity disorder and conduct disorders (HR, 0.82 [0.77-0.86]; aHR, 1.17 [0.99-1.12]) but not of tic disorders (HR, 1.21 [1.06-1.38]; aHR, 1.17 [0.96-1.27]). No differences in risk were found between children born after invitro fertilization and intracytoplasmic sperm injection or after fresh and frozen embryo transfer. Our findings of only small differences in neurodevelopment between ART and non-ART singletons are reassuring and in line with previous studies.

Psychotropic drug utilization patterns in pregnant women with bipolar disorder: A 16-year population-based cohort study

Despite growing concern about reproductive safety of psychotropic drugs, there is a paucity of research assessing prenatal prescribing practices for bipolar disorder (BD). This population-based cohort study identified women aged 15–50 years with BD diagnosis, who delivered their first and singleton child between 2003 and 2018 in Hong Kong, with an aim to examine temporal trends and predictors of prenatal psychotropic drug use as well as drug utilization patterns before and during pregnancy were evaluated. Data were retrieved from territory-wide medical-record database of public healthcare services. Of 302 identified women, 202 (66.9%) and 180 (59.6%) redeemed at least 1 prescription for psychotropic drugs in 12 months pre-pregnancy and during pregnancy, respectively. Psychotropic drug treatment (OR = 16.14 [95% CI: 8.79–29.65]) and psychiatric admission (OR = 4.12 [95% CI: 1.66–10.24]) within 12 months pre-pregnancy were associated with prenatal drug use. Second-generation antipsychotic use during pregnancy increased over time, while prenatal use of lithium, anti-epileptics and first-generation-antipsychotics showed declining trend. Use of psychotropic drugs progressively decreased across pre-pregnancy and trimesters of pregnancy. Forty-two (23.3%) women received polypharmacy during pregnancy. Antidepressant use accounted for 17% of all monotherapy episodes. A significant proportion of women exposed to valproate in 12 months pre-pregnancy (27.2%) and first-trimester (16%). In conclusion, our results generally indicate trajectories of reduced psychotropic drug use across pregnancy. Deviations between real-world prescribing patterns and treatment guidelines underscore the need for comprehensive review of current clinical practices. Further research clarifying relationships of prenatal psychotropic drug exposure with maternal and fetal outcomes is warranted.

Reproductive and developmental safety of nirmatrelvir (PF-07321332), an oral SARS-CoV-2 Mpro inhibitor in animal models

Nirmatrelvir (PF-07321332; NMV) the antiviral component of PAXLOVID™ is a potent and selective inhibitor of the SARS-CoV-2 main protease (Mpro), which plays a critical role in viral replication. PAXLOVID, comprised of nirmatrelvir and ritonavir (used as a pharmacokinetic enhancer), is an oral therapy currently in development as a therapeutic option for those infected with SARS-CoV-2 to prevent progression to severe disease, hospitalization, and death. PAXLOVID has been shown to be efficacious against hospitalization and death in two Phase 2/3 clinical studies that evaluated non hospitalized patients both with and without high risk factors for progression to severe illness. Given that males and females of reproductive age are included in the intended patient population, we assessed the potential effects of NMV up to the limit dose of 1000 mg/kg/day in ICH guideline embryo-fetal development studies in rats and rabbits, and a fertility and early embryonic development study in rats. There were no effects on male and female fertility or early embryonic development in rats, and no severe manifestations of developmental toxicity in rats or rabbits. The lack of adverse findings reported here in nonclinical species is consistent with the intended therapeutic target of NMV (a virus specific protein not present in mammalian cells), the favorable off-target selectivity profile, and lack of genetic toxicity. The results of these nonclinical studies with NMV along with existing ritonavir safety information indicate that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and in males and females of reproductive age.

Antibacterial effects of nano-decoction iron polysulfide in epididymitis and the systematic evaluation of its toxicity on the reproductive health of male mice

Ferrous iron and polysulfide (Fe(II)Sn aq) is a nano‐decoction. It is usually prepared from the suspension of iron sulfide nanomaterial, using autoclave and centrifugation. A previous study conducted in our laboratory revealed that Fe(II)Sn aq was highly antibacterial, and it could efficiently kill more than 90% population of Escherichia coli and Staphylococcus aureus, within 5 min of the treatment. Our study reported that the intravenous administration of Fe(II)Sn aq provided effective treatment against epididymis infection, caused by S. aureus. The results of the study further highlighted its potential for clinical application. However, its effects on the reproductive system and overall health of mammals have not been investigated earlier. The present study assessed the impacts of Fe(II)Sn aq on reproductive health and other aspects of male mice. Briefly, male mice were exposed to Fe(II)Sn aq, either intravenously at the dose of 0.7 mM, 1.4 mM, and 2.8 mM of Fe2+or orally at the dose of 1.4 mM, 2.8 mM, and 5.6 mM of Fe2+. Following this, body weight, organs index, quality of sperm, blood biochemical markers, histopathology of organs, oxidative stress and apoptosis were evaluated, after 1 day and 30 days of exposure. In addition, male reproductivity was evaluated in terms of mating with female mice, and the body weight of the resulting offspring was recorded. Our results showed that the mice processed with Fe(II)Sn aq exhibited normal physiological status and reproductive capability. The present study illustrated the short‐ and long‐term influences of Fe(II)Sn aq on the fertility of male mice for the first time. The findings of the study provided a valuable reference for the application of Fe(II)Sn aq, particularly in terms of reproductive safety.

64.2 TEACHING ADULT PSYCHIATRY RESIDENTS ABOUT PERINATAL MENTAL HEALTH

The objective of this presentation is to address the knowledge gap in perinatal mental health (MH) in adult psychiatry training. Psychiatric residency programs rarely include formal training in women’s mental health issues across the life span, including during pregnancy and the postpartum period. Pregnant women frequently discontinue their mental health medications when learning they are pregnant—often at the suggestion of their psychiatrist or obstetrician, unfamiliar with the reproductive safety profile of commonly prescribed medications. This can lead to poorer outcomes of morbidity and mortality and higher rates of suicide and infanticide. Current robust evidence shows that exposing the developing fetus to untreated psychopathology may result in long-term adverse consequences for the child and the mother-baby dyad. These interconnections between perinatal MH and infant mental health can get lost in the “silos” of medical specialty training. This knowledge gap can result in critical errors in assessment, diagnosis, and intervention, and can contribute to poor outcomes for the mother, her child, and society in general. The presenters, a perinatal expert and a psychiatry trainee, use media-based educational content to demonstrate how an expert trains an adult psychiatry resident in important perinatal MH topics. The trainee explores the gaps in their understanding of perinatal MH, and the expert addresses these knowledge gaps through a lecture and videos following 2 pregnant women’s mental health experiences in a “telenovela” format. These dialogues offer compelling and relatable narratives that place didactic content in the social and cultural context of learners. This demonstration of media-based adult psychiatry training in perinatal MH and the related effects on infant development begins to fill an important knowledge gap for adult psychiatrists caring for pregnant women and their infants. The method of using interactive dialogue and video offers critical knowledge to clinicians treating this important population. There remains a significant knowledge gap in perinatal MH and infant mental health in adult psychiatrists. This gap can be recognized, understood, and filled by the development of innovative didactic and videotaped content that can be widely distributed across adult psychiatry residency programs.

The Effect of Spiritual Guidance of Reproductive Health by Booklets on The Changes of Adolescent's sAttitudes: Dating Status In Premarital Sexual Behavior

The spiritual guidance of reproductive health and safety is oriented towards strengthening moral ​​and religious values ​​in addressing adolescent reproductive health problems with an approach on several aspects, such as preventive, curative, rehabilitative, and developmental. The booklet is a medium of guidance/learning that can attract interest and help teenagers understand the guidance material. This study aimed to determine the effect of the spiritual guidance of reproductive health care professionals by booklets on changes in adolescent attitudes towards dating status in premarital sexual behavior. A combination of qualitative and quantitative experimental research with a pre-experimental design, one group pretest-posttest, with a total sample of 26 adolescents, selected a purposive sampling technique. The spiritual guidance intervention used booklets for six meetings with 60-90 minutes each meeting within 2 months. Data were collected through pre-test and post-tests using interview sheets and Likert scale questionnaires. Data were analyzed qualitatively and statistically tests using the Wilcoxon test. The results showed that the sexual behavior of adolescents in dating was including holding hands, embracing the arms/shoulders and waist, hugging, kissing cheeks and lips, stroking the head, laying on the partner's thighs, and having sex with condoms. Then, from the statistical test, the negative ranks between the pre-test and post-test values were 0. Meanwhile, the positive ranks between the pre-test and post-test values indicated that 24 respondents with a positive value and a mean rank value of 13.00, and 2 respondents with a pre-post value remain the same. The Wilcoxon test shows the p-value (sig) 0.000 <0.05. Thus, the spiritual guidance of reproductive health care professionals using booklets significantly affected changes in adolescent attitudes towards dating status in premarital sexual behavior.

A Call for Increased Focus on Reproductive Health within Lab Safety Culture.

The approach to reproductive health and safety in academic laboratories requires increased focus and a shift in paradigm. Our analysis of the current guidance from more than 100 academic institutions' Chemical Hygiene Plans (CHPs) indicates that the burden to implement laboratory reproductive health and safety practices is often placed on those already pregnant or planning conception. We also found inconsistencies in the classification of potential reproductive toxins by resources generally considered to be authoritative, adding further confusion. In the interest of human health and safe laboratory practice, we suggest straightforward changes that institutions and individual laboratories can make to address these present deficiencies: Provide consistent and clear information to laboratory researchers about reproductive health and normalize the discussion of reproductive health among all researchers. Doing so will promote safer and more inclusive laboratory environments.

Reproductive Safety of Second-Generation Antipsychotics: Updated Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Objective: Second-generation antipsychotics (SGAs) are prescribed for a wide range of indications in women of reproductive age. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established to determine the risk of major malformations among infants exposed to these medications during the first trimester relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity. Methods: Women, aged 18-45 years, with histories of psychiatric illness were prospectively followed through pregnancy and during the postpartum period. Pediatric and maternal medical records were obtained and screened for evidence of major malformations. Potential cases were adjudicated by a dysmorphologist who was blinded to drug exposure.. Recruitment to the Registry, which is based at the Ammon-Pinizzotto Center for Women's Mental Health at Massachusetts General Hospital (MGH), includes nationwide provider referral, self-referral, and advertisement through the MGH Center for Women's Mental Health website. Results: As of April 9, 2020, 1,906 women had enrolled, including 889 in the exposure group and 1,017 controls. A total of 1,311 women completed the study and were eligible for inclusion in the analysis. Medical records were obtained for 81.3% of participants. Among 640 live births in the exposure group, 16 (2.50%) had confirmed major malformations reported, and among 704 live births in the control group, 14 (1.99%) had confirmed major malformations reported. The estimated odds ratio for major malformations comparing exposed and unexposed infants was 1.48 (95% CI, 0.625-3.517). Conclusions: Data from the Registry assessing SGAs as a class indicate that they are unlikely to have a major teratogenic effect. These findings provide pertinent information for women and their health care providers regarding decisions about atypical antipsychotic use during pregnancy. Trial Registration: ClinicalTrails.gov identifier: NCT01246765.

Machine learning analysis of non-marital sexual violence in India.

BackgroundMachine learning techniques can explore low prevalence data to offer insight into identification of factors associated with non-marital sexual violence (NMSV). NMSV in India is a health and human rights concern that disproportionately affects adolescents, is under-reported, and not well understood or addressed in the country.MethodsWe applied machine learning methods to retrospective cross-sectional data from India's nationally-representative National Family Health Survey 4, a demographic and health study conducted in 2015–16, which offers 4000+ variables as potential independent variables. We used Least Absolute Shrinkage and Selection Operator (lasso) or L-1 regularized logistic regression models as well as L-2 regularized logistic regression or ridge models; we conducted an iterative thematic analysis (ITA) of variables generated from a series of regularized models.FindingsThematic analysis of regularized models highlight that past exposure to violence was most predictive of NMSV, followed by geography, sexual behavior, and poor sexual and reproductive health knowledge. After these, indicators largely related to resources and autonomy (e.g., access to health services, and income generating) were associated with NMSV. Exploratory analysis with the subsample of never married adolescents 15–19 years old, a population with higher representation of recent NMSV, further emphasized the role of wealth and mobility as key correlates of NMSV, along with poor HIV knowledge, tobacco use, higher fertility preferences, and attitudes accepting of marital violence.InterpretationFindings indicate the validity of machine learning with iterative theme analysis (ITA) to identify factors associated with violence. Findings were consistent with prior work demonstrating associations between NMSV and other violence experiences, but also showed novel correlates such as lower SRH knowledge and service utilization and, for girls, norms and preferences suggesting more restrictive gender norms. Sexual and reproductive health, gender equity and safety focused interventions are important for addressing NMSV in India, particularly for adolescents.

Developmental and reproductive safety of AZD1222 (ChAdOx1 nCoV-19) in mice

AZD1222 (ChAdOx1 nCoV-19) is a COVID-19 vaccine that is not yet licensed for use during pregnancy. To support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies, a non-clinical developmental and reproductive toxicity study was performed to evaluate its effects on fertility and reproductive processes of female CD-1 mice during the embryofetal development phase, and postnatal outcomes during the littering phase. Immunogenicity assessments were also made in dams, fetuses, and pups. There were no vaccine-related unscheduled deaths throughout the study. Furthermore, there were no vaccine-related effects on female reproduction, fetal or pup survival, fetal external, visceral, or skeletal findings, pup physical development, and no abnormal gross pathology findings in pups or dams. Antibody responses raised in dams were maintained throughout gestation and postnatal periods, and seroconversion in fetuses and pups indicate placental and lactational transfer of immunoglobulins. Together with clinical data from non-pregnant people, these results support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies.

Tim-3/CTLA-4 pathways regulate decidual immune cells-extravillous trophoblasts interaction by IL-4 and IL-10.

To obtain a successful pregnancy, the establishment of maternal-fetal tolerance and successful placentation are required to be established. Disruption of this immune balance and/or inadequate placental perfusion is believed to be associated with a lot of pregnancy-related complications, such as recurrent spontaneous abortion, pre-eclampsia, and fetal intrauterine growth restriction. Extravillous trophoblasts (EVTs) have the unique ability to instruct decidual immune cells (DICs) to develop a regulatory phenotype for fetal tolerance. Utilizing immortalized human first trimester extravillous trophoblast cells and primary EVTs, we found that DICs promote EVT function and placental development. We have previously shown that checkpoints T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are important for DIC function. In the present study, we showed that blockade of Tim-3 and CTLA-4 pathways leaded to the abnormal DICs-EVTs interaction, poor placental development, and increased fetal loss. Treatment with IL-4 and IL-10 could rescue the adverse effects of targeting Tim-3 and CTLA-4 on the pregnancy outcome. Hence, the reproductive safety must be a criterion considered in the assessment of immuno-therapeutic agents. In addition, IL-4 and IL-10 may represent novel therapeutic strategies to prevent pregnancy loss induced by checkpoint inhibition.

Reproductive healthcare in prison: A qualitative study of women's experiences and perspectives in Ontario, Canada.

To explore women's experiences and perspectives of reproductive healthcare in prison. We conducted a qualitative study using semi-structured focus groups in 2018 with women in a provincial prison in Ontario, Canada. We asked participants about their experiences and perspectives of pregnancy and contraception related to healthcare in prison. We used a combination of deductive and inductive content analysis to categorize data. A concept map was generated using a reproductive justice framework. The data reflected three components of a reproductive justice framework: 1) women have limited access to healthcare in prison, 2) reproductive safety and dignity influence attitudes toward pregnancy and contraception, and 3) women in prison want better reproductive healthcare. Discrimination and stigma were commonly invoked throughout women's experiences in seeking reproductive healthcare. Improving reproductive healthcare for women in prison is crucial to promoting reproductive justice in this population. Efforts to increase access to comprehensive, responsive, and timely reproductive healthcare should be informed by the needs and desires of women in prison and should actively seek to reduce their experience of discrimination and stigma in this context.

Decreased level of Eomes+dCD8+ T cells with altered function might be associated with miscarriage.

The T-box transcription factor protein eomesodermin (Eomes) is known for both homeostasis and function of effector and memory CD8+T cells. However, much less is known about the functional regulation of Eomes on CD8+ T cells during pregnancy. In the present study, we concluded the higher Eomes expression dCD8+T cells during normal early pregnancy. The number of Eomes+dCD8+T cells decreased in miscarriage. This Eomes+dCD8+T cell subset also expressed less growth-promoting factors, shifted toward pro-inflammatory phenotype in miscarriage. Primary Trophoblasts and HTR8/SVneo cell line could increase Eomes expression of dCD8+T cells from both normal early pregnancy and miscarriage, which might provide a new strategy for therapy to promote maternal-fetal tolerance and prevent pregnancy loss. These findings indicated that Eomes might be promising early warming targets of miscarriage. In addition, this study suggested that the reproductive safety must be a criterion considered in modulating the dose and function of Eomes in CD8+T cells to reverse T cell exhaustion.

Reproductive safety of aripiprazole: data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Aripiprazole has become one of the most commonly prescribed psychotropics, making a more comprehensive understanding of its reproductive safety profile a priority. The goal of the current analysis was to determine the risk of major malformations in infants exposed during the first trimester of pregnancy to aripiprazole compared to infants whose mothers had psychiatric diagnoses but did not use an atypical antipsychotic during pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Medical records are assessed to confirm presence or absence of major malformations. Pregnant women ages 18-45 with psychiatric diagnoses are enrolled. As of April 2020, N = 848 women who had delivered infants were eligible for analyses. A total of 158 women with first trimester exposure to aripiprazole were compared to 690 controls. For 163 infants born to women in the exposed group, seven major malformations were confirmed (4.29%), compared to fourteen of the 690 unexposed infants (1.99%). The unadjusted odds ratio for major malformations between aripiprazole-exposed and unexposed infants was 2.21 (95% confidence interval [CI] = (0.88, 5.57) The adjusted odds ratio for major malformations was 1.35 (95% confidence interval [CI] = (0.43, 4.20). After adjustment for confounding variables, the risk of major malformations after first trimester exposure to aripiprazole was not significant compared to controls. While these results are reassuring, they are limited by relatively small numbers of participants. Future analyses with larger numbers are expected to provide more of a complete and precise reproductive safety profile regarding aripiprazole use during pregnancy. Trial registration: clinicaltrials.gov NCT01246765.

PRODUCTIVE AND REPRODUCTIVE PERFORMANCE OF FIRST CALVING CROSSBRED COWS

The article presents the results of studies of reproductive performance, safety and average daily milk yield of first-calf cows of the Ukrainian Red-and-White dairy breed, obtained from the Montbeliard and Holstein sire bulls in the SE "Gontarivka", Kharkiv region. It was found that the weight at the first fertilization in heifers obtained from bulls of different breeds did not practically differ, and averaged 470 kg. At the same time, the age of the first insemination and calving of the daughters obtained from the Montbeliard bulls was significantly less than of the daughters obtained from the Holstein bulls, which indicates a greater intensity of growth of crossbred heifers. The average daily milk yield of daughters of Montbeliard breed bulls for the first two months of lactation was 1.6 kg and 0.5 kg less than that of their counterparts. In the third month of lactation, the average daily milk yield of first calving cows obtained from Holstein bulls became 0.2 kg less than that of crossbred ones, and later this trend of the advantage in daily milk yield of the daughters of Holstein bulls continued. For 8 months of lactation, the milk yield of the daughters of the Montbeliard bulls was slightly less by 201.4 kg than their peers. There were no significant differences in the content of fat, protein and the somatic cells count.

Association of Medicaid Expansion With Access to Abortion Services for Women With Low Incomes in Oregon.

The Affordable Care Act allowed states to expand Medicaid eligibility for women with low incomes before pregnancy. Women who experience an unintended pregnancy may encounter fewer delays in accessing abortion services if they are already enrolled in Medicaid. In states where the Medicaid program includes coverage for abortion services, Medicaid expansion may increase timely access to abortion services. Oregon has expanded Medicaid and is 1 of 16 states in which the Medicaid program covers abortion services. We explored how Medicaid expansion in Oregon was associated with Medicaid-financed abortion rates and receipt of medication abortion relative to surgical abortion. Using Medicaid claims and eligibility data we identified women ages 19 to 43 (n=30,367) who had abortions before the expansion period (2008-2013) and after the expansion period (2014-2016). We used American Community Survey data to estimate the annual number of Oregon women aged 19 to 43 with incomes below 185% of the federal poverty level who would be eligible for a Medicaid-financed abortion. We conducted interrupted time series analyses using negative binomial and logistic regression models. Incidence of Medicaid-financed abortion increased from 13.4 in 1,000 women in 2008 to 16.3 in 2016. Medication abortion receipt increased from 11.5% of abortions in 2008 to 31.7% in 2016. For both outcomes, we identified an increasing time trend after Medicaid expansion, followed by a subsequent leveling off of the trend. By the end of 2016, incidence of Medicaid-financed abortion was 4.5 abortions per 1,000 women-years (95% confidence interval, 3.3-5.7) higher than it would have been without expansion and medication abortions comprised a 7.4 percentage point (95% confidence interval, 4.4-10.4) greater share of all abortions. Medicaid expansion was associated with increased receipt of Medicaid-financed abortions and may have reduced out-of-pocket payment among women with low incomes. Increased receipt of medication abortion may indicate that expansion enhanced earlier access to services, possibly as a result of increased prepregnancy Medicaid enrollment, and this earlier access may increase reproductive autonomy and safety.

Risk of congenital malformations in offspring of women using β-blockers during early pregnancy: An updated meta-analysis of observational studies.

Beta-blockers are commonly used to treat hypertension that arises during pregnancy. However, reproductive safety concerns have been expressed. Here, we investigated whether the use of β-blockers during early pregnancy increased the risk of congenital malformations. A systematic literature search was performed in PubMed, Embase and Cochrane Library to identify relevant studies published from database inception until February 2020. Observational studies evaluating associations between maternal β-blocker use and congenital malformations were included in this meta-analysis. Two reviewers independently extracted data and assessed study quality. Meta-analysis of outcomes was performed and a summary odds ratio (OR) was calculated with consideration of heterogeneity. Twenty observational studies were identified. Beta-blocker use during early pregnancy was not associated with an increased risk of congenital malformations (OR = 1.01, 95% confidence interval [CI] = 0.93-1.09). Subgroup analysis of organ-specific malformations revealed that β-blocker use was associated with an increased risk of heart malformations (OR = 1.29, 95% CI = 1.02-1.63) and an increased risk of cleft lip or palate (OR = 1.5, 95% CI = 1.18-1.91); however, these associations (OR = 1.11, 95% CI = 0.94-1.32 for heart malformations; OR = 1.34, 95% CI = 0.98-1.85 for cleft lip or palate) disappeared when the adjusted data were pooled. Beta-blocker use was not associated with increased risks of central nervous system malformations, neural tube defects or hypospadias. Exposure to β-blockers during early pregnancy does not appear to be associated with congenital malformations or heart malformations in offspring. Other organ-specific congenital malformations should be evaluated in further studies.