Mirtazapine in pregnancy and lactation: A systematic review of adverse outcomes.

INTRODUCTION: Peripartum depression is common and treatment with mirtazapine may be indicated. However, evidence on its safety in pregnancy and lactation is fragmented. The objective of this systematic review was to evaluate the literature on the safety of mirtazapine in pregnancy and lactation. METHODS: PubMed, Embase, Medline, PsycInfo, and clinicaltrials.gov were searched for 'antidepressants' or 'mirtazapine' in combination with 'pregnancy', 'lactation' or 'offspring'. No restrictions on type of study were applied and selection was performed by two independent reviewers using Covidence. Two reviewers extracted data and performed risk of bias assessment and evidence synthesis was performed for each outcome individually. The protocol was registered at PROSPERO (registration number CRD42021275127). RESULTS: The initial search yielded 15,380 articles after removal of duplicates. After screening based on title and abstract, 431 articles remained for full text review. Of these, 41 studies were included (15 cohort studies, one case-control study, 11 case series, and 14 case reports). In most studies, the outcomes in mirtazapine-exposed pregnancies were comparable to controls. However, results on congenital malformations and spontaneous abortion were conflicting. Neonatal adaptation syndrome was reported after mirtazapine exposure in late pregnancy. Data on mirtazapine exposure during lactation were scarce. CONCLUSIONS: We identified no substantial evidence indicating that mirtazapine exposure is associated with adverse outcomes in pregnancy or in offspring, other than neonatal adaptation syndrome. However, overall quality of evidence was low, and results on congenital malformations and spontaneous abortions were conflicting. Data on mirtazapine exposure through breastfeeding were limited and did not allow for conclusions.

Antiseizure medication use during pregnancy and neonatal growth outcomes: A systematic review and meta-analysis.

AIMS: We aimed to systematically synthesize the current published literature on neonatal growth outcomes associated with antiseizure medication (ASM) use during pregnancy. METHODS: We searched seven databases, from inception to 23 March 2022. We investigated small for gestational age (SGA) and low birth weight (LBW) as primary outcomes and birth weight, birth height, cephalization index and head circumference as secondary outcomes. The primary analysis included pregnant people exposed to any ASM compared with unexposed pregnant people. Subgroup analysis included ASM class analysis, within epilepsy group analysis and polytherapy compared to monotherapy. RESULTS: We screened 15 720 citations and included 65 studies in the review. Exposed pregnant people had a significantly increased risk of SGA relative risk (RR) 1.33 (95% CI 1.18 to 1.50, I2 74%), LBW RR 1.54 (95% CI 1.33 to 1.77, I2 67%), and decreased birth weight with a mean difference (MD) of -118.87 (95% CI -161.03 to -76.71, I2 42%) g. A non-significant risk change in birth height and head circumference was observed. In subgroup analysis, ASM polytherapy, within epilepsy and ASM class analysis were also associated with an increased risk of SGA and LBW. CONCLUSIONS: This meta-analysis demonstrates that pregnant people exposed to ASMs have a significantly increased risk of adverse fetal growth outcomes including SGA and LBW and decreased birth weight compared to unexposed pregnant people. Polytherapy was associated with higher risks compared to monotherapy. Additional studies are warranted on specific ASM risks.

Fetal safety of chloroquine and hydroxychloroquine use during pregnancy: a nationwide cohort study.

OBJECTIVE: The antimalaria 4-aminoquinoline drugs chloroquine and HCQ are used in the treatment of a wide range of CTDs. Data to inform on the safety of their use in pregnancy are limited. METHODS: In a Danish nationwide cohort study from 1996 through 2016, we identified 4-aminoquinoline-exposed pregnancies from a cohort of 1 240 875 pregnancies to investigate the associated risks of major birth defects, preterm birth, and small size for gestational age (SGA). Distinct study cohorts of propensity-score-matched 4-aminoquinoline-exposed and unexposed pregnancies (in a 1:1 ratio) were established for each outcome analysis. The association with the outcomes was assessed by prevalence odds ratios (ORs) estimated through logistic regression. The associated risks for chloroquine and HCQ were individually assessed through additional analyses. RESULTS: A total of 1487 pregnancies exposed to 4-aminoquinolines (1184 chloroquine- and 303 HCQ-exposed) were identified. Among the 983 pregnancies exposed to 4-aminoquinolines in the first trimester, 34 infants (3.5%) were diagnosed with major birth defects as compared with 36 (3.7%) among the matched unexposed pregnancies (prevalence OR, 0.94; 95% CI: 0.59, 1.52). Exposure to 4-aminoquinolines in pregnancy was neither associated with an increased risk of preterm birth (prevalence OR, 0.97; 95% CI: 0.73, 1.28) or SGA (prevalence OR, 1.18; 95% CI: 0.93, 1.50), compared with unexposed pregnancies. No significant associations between exposure to chloroquine or HCQ individually and risk of the outcomes were identified. CONCLUSION: Among pregnancies exposed to 4-aminoquinolines (chloroquine and HCQ), no increased risk of major birth defects, preterm birth, or SGA was identified.

Analysis of the susceptibility to COVID-19 in pregnancy and recommendations on potential drug screening.

To analyze the susceptibility of SARS-CoV-2 in pregnancy and the drugs that can be used to treat pregnancy with COVID-19, so as to provide evidence for drug selection in clinic. By reviewing the existing literature, this paper analyzes the susceptibility of pregnant women to virus, especially to SARS-CoV-2, from the aspects of anatomical, reproductive endocrine and immune changes during pregnancy and screens effective and fetal-safe treatments from the existing drugs. The anatomical structure of the respiratory system is changed during pregnancy, and the virus transmitted by droplets and aerosols is more easily inhaled by pregnant women and is difficult to remove. Furthermore, the prognosis is worse after infection when compared with non-pregnancy women. And changes in reproductive hormones and immune systems during pregnancy collectively make them more susceptible to certain infections. More importantly, angiotensin-converting enzyme (ACE)-2, the SARS-CoV-2 receptor, has been proven highly increased during pregnancy, which may contribute to the susceptibility to SARS-CoV-2. When it comes to treatment, specific drugs for COVID-19 have not been found at present, and taking old drugs for new use in treating COVID-19 has become an emergency method for the pandemic. Particularly, drugs that show superior maternal and fetal safety are worthy of consideration for pregnant women with COVID-19, such as chloroquine, metformin, statins, lobinavir/ritonavir, glycyrrhizic acid, and nanoparticle-mediated drug delivery (NMDD), etc. Pregnant women are susceptible to COVID-19, and special attention should be paid to the selection of drugs that are both effective for maternal diseases and friendly to the fetus. However, there are still many deficiencies in the study of drug safety during pregnancy, and broad-spectrum, effective and fetal-safe drugs for pregnant women need to be developed so as to cope with more infectious diseases in the future.

Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study.

BACKGROUND: Safety data on first-trimester natalizumab exposure are scarce, as natalizumab is usually withdrawn three months before pregnancy. OBJECTIVE: The objective of this paper is to investigate the fetal safety of exposure to natalizumab (Tysabri(®)) during the first trimester of pregnancy using disease-matched (DM) and healthy control (HC) comparison groups. METHODS: A total of 101 German women with RRMS exposed to natalizumab during the first trimester of pregnancy were identified. Birth outcomes in the exposed group were compared to a DM group (N = 78) with or without exposure to other disease-modifying drugs, and an HC group (N = 97). RESULTS: A total of 77, 69 and 92 live births occurred in the Exposed, DM and HC groups, respectively. The rates of major malformations (p = 0.67), low birth weight (<2500 grams) (p = 1.0) and premature birth (p = 0.37) did not differ among groups. Higher miscarriage rates (p = 0.002) and lower birth weights (p = 0.001) occurred among the Exposed and DM groups, as compared to the HC; however, there was no significant difference between the Exposed and DM groups. CONCLUSION: Exposure to natalizumab in early pregnancy does not appear to increase the risk of adverse pregnancy outcomes in comparison to a DM group not exposed to natalizumab.

Case report: A pregnant woman accidental treated with spironolactone in mid-gestation.

Spironolactone, a potassium-sparing diuretic, is used to treat hypertension, heart failure, and certain hyperandrogenic disorders. Its use during pregnancy is not recommended due to the risk of feminizing male fetuses, primarily because of its antiandrogenic activity. However, human data remain scarce and largely inconclusive. Here, we present the first case of a 25-year-old pregnant woman, at 16 weeks of gestation, who was inadvertently exposed to spironolactone (240 mg/day) for 1 week due to a pharmacy dispensing error. The patient subsequently delivered a healthy male infant with normal genitalia at 38 weeks of gestation following vaginal delivery. Current follow-up shows that the infant is healthy and developing normally. This article summarizes the potential causes of spironolactone-induced anomalous genital development and explores the safety of new-generation mineralocorticoid receptor antagonists (MRAs) during pregnancy. The mechanisms behind spironolactone-induced anomalous genital development in male fetuses have not been fully elucidated. Spironolactone competes with dihydrotestosterone for binding to androgen receptors and inhibits enzymes involved in androgen biosynthesis, which may partly explain its antiandrogenic effects. Recent advancements in MRAs have led to the development of compounds with higher selectivity for the mineralocorticoid receptor, thereby reducing the incidence of antiandrogen side effects. These new-generation MRAs may be effective alternatives during pregnancy, but more data are needed to establish their safety in pregnant women. This case contributes to the limited but growing body of literature on the safety profile of spironolactone in pregnancy, providing insights into its effects during a critical period of fetal development.

Challenges in Conducting Therapeutic Trials in Pregnancy: Emphasizing Recent Lessons Learned.

Pregnant people have traditionally been excluded from therapeutic research by restrictions intended for fetal protection. Despite a movement toward inclusion, concerns for the feasibility and safety of including pregnant people in studies continue to limit this research. This article reviews the history of research guidelines in pregnancy and illustrates ongoing challenges, as seen in the development of vaccines and therapies during the coronavirus disease 2019 pandemic and investigation of statins for preeclampsia prevention. It explores new approaches that may be used to improve therapeutic research in pregnancy. A major cultural shift is needed to balance potential maternal and/or fetal risks with potential benefits from participation in research, as well as harm from withholding treatment or providing one that is not evidence-based. Finally, it is important to honor maternal autonomy in decision-making regarding participation in clinical trials.

Management of breast cancer diagnosed during pregnancy: global perspectives.

INTRODUCTION: Pregnancy-associated breast cancer (PABC) encompasses breast cancer diagnosed during pregnancy (BCP) or postpartum (PPBC). BCP is especially challenging with concerns regarding maternal and fetal safety synchronously. This review provides a comprehensive global view to optimize care of this unique entity. Areas covered Published literature and practices across the globe including real world published data from the first Indian registry are thoroughly reviewed to derive inferences. Diagnostic delays are common with resultant upstaging and inferior outcomes. Sonography-mammography and a biopsy with immunohistochemistry for estrogen, progesterone and HER-2neu receptors is mandatory. Multidisciplinary specialist teams are critical for trimester dependent management. Stage-wise surgical and systemic treatment remains largely similar to that of the nonpregnant women. Anthracyclines- and taxane-based chemotherapy is found to be safe after the 1st trimester. Frequent fetal and maternal monitoring is required to minimize complications. Chemotherapy should stop three weeks prior to the delivery to prevent peripartum infection/bleeding. Anti- Her-2 targeted therapy, endocrine therapy and radiation therapy are administered post-delivery. Iatrogenic premature delivery leads to poor neurocognition and should be avoided. Expert opinion Stage-wise outcomes are similar to that of non-pregnant patients with breast cancer, and underscores the importance of early detection especially in low- and middle-income countries. Global collaborations are warranted. AREAS COVERED: Published literature and practices across the globe including real world published data from the first Indian registry are thoroughly reviewed to derive inferences. Diagnostic delays are common with resultant upstaging and inferior outcomes. Sonography-mammography and a biopsy with immunohistochemistry for estrogen, progesterone and HER-2neu receptors is mandatory. Multidisciplinary specialist teams are critical for trimester dependent management. Stage-wise surgical and systemic treatment remains largely similar to that of the nonpregnant women. Anthracyclines- and taxane-based chemotherapy is found to be safe after the 1st trimester. Frequent fetal and maternal monitoring is required to minimize complications. Chemotherapy should stop three weeks prior to the delivery to prevent peripartum infection/bleeding. Anti- Her-2 targeted therapy, endocrine therapy and radiation therapy are administered post-delivery. Iatrogenic premature delivery leads to poor neurocognition and should be avoided. EXPERT OPINION: Stage-wise outcomes are similar to that of non-pregnant patients with breast cancer, and underscores the importance of early detection especially in low- and middle-income countries. Global collaborations are warranted.

The effects of a physical exercise program on fetal well-being and intrauterine safety.

OBJECTIVES: The aim of this study was to evaluate the effects of a supervised physical exercise program on fetal well-being and intrauterine safety. Physical activity is recommended for healthy pregnant women. However, constant evaluation of fetal condition and development is recommended to ensure the safety of the exercise program. MATERIAL AND METHODS: Randomized control trial study design. Sixty-six healthy pregnant women (age 24-35) with singleton gestation were randomly assigned to either an exercise group (EG, n = 34) or a non-active control group (CG, n = 32). The exercise program included 81 sessions (moderate intensity, 3 times per week, 50-60 min/session from weeks 13 to weeks 40/41 of pregnancy). Fetal well-being was assessed in weeks 32 and 37 of pregnancy. The cerebroplacental ratio (CPR) was calculated to evaluate the safety of the exercise program for the fetus. RESULTS: The differences in the CPR ratio measurements between EG and CG groups in week 37 (p < 0.05) were observed. The increase in the CPR ratio was also shown in week 37 of pregnancy in comparison to week 32 (p < 0.01). Moreover, maternal heart rate was significantly lower in the exercise group as measured at 37 weeks (p < 0.05). CONCLUSIONS: The results of this study confirm that regular and supervised exercise program throughout pregnancy does not affect fetal well-being and is safe for the fetus. Additionally, regular physical activity improves maternal physical fitness and cardiac efficiency which might aid at preparing pregnant women for natural labor.

COVID-19 pandemic's effects on the quality of pregnant women's emergency treatment: Review of two cases from a medical center in northern Taiwan.

The spread of COVID-19 has resulted in a high risk of infection in hospitals worldwide. The medical staff in emergency rooms, in particular, have borne the brunt of the pandemic, and strict protection measures are needed to avoid infection in these units. Taiwan as a whole has performed extremely well in this epidemic, an achievement that has been acknowledged internationally. This success can be attributed to the Taiwan Epidemic Prevention Management Center's extensive experience and courageous strategy. The emergency department professionals of all hospitals, in conjunction with the outstanding performance of the center's policy, have also done much to control the infection's spread. However, excessive protection can also negatively affect patients' safety and the quality of medical care, especially for pregnant and parturient women. This article uses two actual cases from a medical center in northern Taiwan to discuss the impact of COVID-19 on pregnant women. This case study serves to highlight that, to ensure more effective coordination during severe epidemics, a comprehensive infection prevention plan should be formulated. In addition, pregnant women's human rights must be safeguarded so that various protective mechanisms can be effectively used to achieve win-win solutions. Hospitals need to plan their production methods and timing in advance for when pregnant patients are in critical condition. The findings include that obstetricians recommend caesarean sections as a safer method in during epidemics. Emergency room physicians and obstetricians should also actively assist mothers prepare for birth to enhance maternal and fetal safety.

Pregnancy Outcomes in Patients With Multiple Sclerosis Exposed to Natalizumab-A Retrospective Analysis From the Austrian Multiple Sclerosis Treatment Registry.

Objectives: To analyze safety and impact of natalizumab (NTZ) exposure on the disease course, pregnancy, and newborn outcomes of relapsing-remitting multiple sclerosis (RRMS) patients from the Austrian Multiple Sclerosis Treatment Registry (AMSTR). Materials and Methods: Twelve pregnancies of 11 women with RRMS exposed to treatment with NTZ were identified from the AMSTR. Exposure to NTZ was defined as treatment with NTZ from 8 weeks prior to the start of the last menstrual period and onward. All patients completed a standardized questionnaire regarding pregnancy and newborn outcomes until the postpartum period for up to 12 months. Results: NTZ was stopped on average 46 days after the last menstrual period. There were 11 live births and one elective termination due to ectopic pregnancy. Mean gestational age of live born individuals was 39.0 weeks [standard deviation (SD) ± 1.1]. Mean birth weight and length were 3,426 g (SD ± 348) and 51.9 cm (SD ± 1.9), respectively. Apgar scores 1 min after birth were normal, with 9.2 points on average. One child displayed hip dysplasia as the only congenital malformation documented in this cohort. Three patients experienced relapses during pregnancy and three patients in the postpartum period, resulting in confirmed Expanded Disability Status Scale (EDSS) progression in four of them. Conclusion: In this cohort, there was no increased risk concerning pregnancy and newborn outcomes due to NTZ exposure. However, relapses occurring during pregnancy and postpartum period resulted in confirmed disability.

A Preliminary Study on the Safety of Elastography during Pregnancy: Hypoacusia, Anthropometry, and Apgar Score in Newborns.

Transient or acoustic radiation force elastography (ARFE) is becoming the most extended technology to assess cervical effacement, additionally to the Bishop test and conventional ultrasound. However, a debate on the fetal safety has been opened due to the high intensity focused beam emitted to produce shear waves. This work is aimed at providing preliminary data to assess clinical effects of fetal exposure. A follow-up study in newborns of 42 women exposed to ARFE during pregnancy was carried out to explore neonatal hypoacusia, Apgar test, and anthropometry. No hypoacusia cases attributable to ARFE were observed. The Apgar test at five minutes scored normally in all the newborns. Comparisons between anthropometric measurements showed no significant statistically differences. The results preclude to state the harmfulness nor the safety of ARFE. However, given the concern on the high level of energy and the potential risk of harmful bioeffects, larger studies are recommended.

Fetal safety of medications used in treating infertility.

INTRODUCTION: The medications used in assisted reproduction are given before and during early pregnancy, and hence, they may potentially result in adverse fetal effects. In this review we present an updated account of their fetal safety and discuss methodological challenges in interpretation of existing data. AREAS COVERED: The fetal safety/risks of clomiphene citrate, aromatase inhibitors, metformin, gonadotropins and progestins are discussed. We searched PubMed, EMBASE, Cochrane, Google, and Google Scholar from inception to 30 April 2020 for publications pertinent to our topic. EXPERT OPINION: There are several major challenges in studying fetal safety of medications used in assisted reproduction. The fact is that the rates of congenital malformations among infertile women giving birth spontaneously is higher than the rates among healthy women conceiving spontaneously. In most clinical studies of assisted reproduction, the primary endpoint is the success in inducing pregnancy, neglecting to report pregnancy outcome and adverse neonatal event. As an example for this reality, it has been estimated that between 1977 and 2005 around 10 million pregnancies were treated with dydrogesterone (DYD), yet till 2019 only very few studies, with a total sample size of less than 600 were reported with regards to fetal safety.

Interdisciplinary Team Huddles for Fetal Heart Rate Tracing Review.

To address an increase in unexpected poor outcomes in term neonates, our team developed a goal of high reliability and improved fetal safety in the culture of the Labor and Delivery nursing department. We implemented interdisciplinary reviews of fetal heart rate, along with a Category II fetal heart rate management algorithm and a fetal heart rate assessment rapid response alert to call for unscheduled reviews when needed. Enhanced communication between nurses and other clinicians supported an interdisciplinary approach to fetal safety, and we observed an improvement in health outcomes for term neonates. We share our experience with the intention of making our methods available to any labor and delivery unit team committed to safe, high-quality care and service excellence.