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.

Timing and dosage of intrapartum prophylactic penicillin for preventing early-onset group B streptococcal disease: assessing maternal and umbilical cord blood concentration.

OBJECTIVE: Timing of administration of antibiotics and concentrations in maternal blood and the umbilical cord blood are important prerequisites for optimal intrapartum antibiotic prophylaxis (IAP) of neonatal early-onset group B streptococcus (GBS) disease. This cohort study aimed to explore penicillin concentrations in mothers and infants at birth in relation to time elapsed from administration to delivery and to the minimal inhibitory concentration (MIC) for GBS. MAIN OUTCOME MEASURES: Penicillin G concentrations in maternal and umbilical cord blood in relation to time and dose from administration to time of delivery. RESULTS: In 44 mother-infant dyads, median maternal penicillin G concentration was 0.2 mg/L (IQR 0-0.8 mg/L; range 0-1.6 mg/L). Median infant penicillin G concentration was 1.2 mg/L (IQR 0.5-5.0 mg/L; range 0-12.7 mg/L). In all infants (N=38) born less than 4 hours after the latest IAP administration, penicillin G concentrations far exceeded MIC (0.125 mg/L), even after short time intervals between IAP administration and birth. The highest plasma concentrations were reached in umbilical cord blood within 1 hour from IAP administration to birth.For 44 mother-infant dyads, maternal concentrations were very low compared with their infants'; particularly, very high concentrations were seen in the 20 infants with only one dose of IAP. CONCLUSION: High concentrations of penicillin G were found in umbilical cord blood of infants born less than 4 hours after IAP administration, well above the MIC for GBS.

Use of medication in pregnancy on the rise: Study on 1.4 million Danish pregnancies from 1998 to 2018.

INTRODUCTION: Maternal demographics have evolved, and more women than ever enter pregnancy with preexisting comorbidity and with potentially complex medication exposure, including polypharmacy (concomitant intake of multiple medications). This study aims to describe the evolution of medication use in pregnancy in Denmark from 1998 to 2018 with special focus on polypharmacy, patterns of use, and underlying demographics. MATERIAL AND METHODS: A Danish nationwide historical registry study based on all clinically recognized pregnancies with a gestation ≥10 weeks between 1998 and 2018. Medication use was estimated by redemption of prescriptions during pregnancy. RESULTS: Among a total of 1 402 327 clinically recognized pregnancies, redemption of at least one prescription medication during pregnancy increased from 56.9% in 1998 to 63.3% in 2018, coinciding with an increased use of polypharmacy (from 24.8% in 1998 to 35.2% in 2018). The prevalence of pregnant women who used medications for chronic conditions increased more than the prevalence of women treated for occasional or short-time conditions. Redemption of one or multiple prescription medications during pregnancy was mostly seen among pregnant women ≥35 years of age. However, pregnant women <25 years old exhibited the largest increase in medication use during the study period. CONCLUSIONS: Medication use in general, and polypharmacy in particular, increased from 1998 to 2008, possibly as the result of an increased prevalence of pregnant women with chronic conditions requiring pharmacological treatment. Notably, a marked maternal age-based discrepancy in usage pattern was observed, highlighting the need for further research in this area. The rise in the prevalence of polypharmacy during pregnancy underscores the need for pharmacovigilance to monitor adverse effects. Future studies should investigate the patterns of polypharmacy and the accompanying maternal and fetal risks.

Preterm Birth Following Active Surveillance vs Loop Excision for Cervical Intraepithelial Neoplasia Grade 2.

Importance: Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) is being implemented in many high-income countries due to the association of excisional treatment with preterm birth. However, it is unknown whether active surveillance results in lower risk of preterm birth given that cervical dysplasia itself is associated with higher risk of preterm birth. Objective: To compare the preterm birth risk between women with CIN2 undergoing active surveillance or immediate loop electrosurgical excision procedure (LEEP). Design, Setting, and Participants: This historical population-based cohort study included women with a first-time diagnosis of CIN2 and a subsequent singleton birth from 1998 to 2018 in Denmark. Women with prior CIN grade 3 or greater or LEEP were excluded. Data were collected from 4 Danish health care registries. Analyses were conducted from October 2022 to June 2023. Exposure: Women were categorized into active surveillance (cervical biopsy and/or cytology) or immediate LEEP based on their first cervical sample after CIN2 diagnosis. The active surveillance group was further subdivided based on whether a delayed LEEP was performed within 28 months from CIN2 diagnosis. Main Outcomes and Measures: Risk of preterm birth (<37 + 0 weeks) was assessed and relative risks (RRs) were calculated using modified Poisson regression. Analyses used inverse probability treatment weighting of the propensity scores to adjust for age, parity, calendar year, index cytology, and smoking. Results: A total of 10 537 women with CIN2 and a singleton birth were identified; 4430 (42%) underwent active surveillance and 6107 (58%) were treated with immediate LEEP. For both groups, most were aged 23 to 29 years at CIN2 diagnosis (3125 [70%] and 3907 [64%], respectively). Overall, 869 births (8.2%) were preterm. The risk of preterm birth was comparable between active surveillance and immediate LEEP (RR, 1.03; 95% CI, 0.90-1.18). However, for women undergoing delayed LEEP after active surveillance (1539 of the active surveillance group [35%]), the risk of preterm birth was higher than for women treated with immediate LEEP (RR, 1.29; 95% CI, 1.08-1.55). Conclusions and relevance: In this cohort study of women with CIN2, the risk of preterm birth was comparable between active surveillance and immediate LEEP. However, delayed LEEP was associated with 30% higher risk of preterm birth than immediate LEEP. Thus, risk stratification at CIN2 diagnosis is important to identify women with increased risk of delayed LEEP.

Obesity in pregnancy-Long-term effects on offspring hypothalamic-pituitary-adrenal axis and associations with placental cortisol metabolism: A systematic review.

Obesity, affecting one in three pregnant women worldwide, is not only a major obstetric risk factor. The resulting low-grade inflammation may have a long-term impact on the offspring's HPA axis through dysregulation of maternal, placental and fetal corticosteroid metabolism, and children born of obese mothers have increased risk of diabetes and cardiovascular disease. The long-term effects of maternal obesity on offspring neurodevelopment are, however, undetermined and could depend on the specific effects on placental and fetal cortisol metabolism. This systematic review evaluates how maternal obesity affects placental cortisol metabolism and the offspring's HPA axis. Pubmed, Embase and Scopus were searched for original studies on maternal BMI, obesity, and cortisol metabolism and transfer. Fifteen studies were included after the screening of 4556 identified records. Studies were small with heterogeneous exposures and outcomes. Two studies found that maternal obesity reduced placental HSD11ß2 activity. In one study, umbilical cord blood cortisol levels were affected by maternal BMI. In three studies, an altered cortisol response was consistently seen among offspring in childhood (n = 2) or adulthood (n = 1). Maternal BMI was not associated with placental HSD11ß1 or HSD11ß2 mRNA expression, or placental HSD11ß2 methylation. In conclusion, high maternal BMI is associated with reduced placental HSD11ß2 activity and a dampened cortisol level among offspring, but the data is sparse. Further investigations are needed to clarify whether the HPA axis is affected by prenatal factors including maternal obesity and investigate if adverse effects can be ameliorated by optimising the intrauterine environment.

Clinical interpretation of cell-based non-invasive prenatal testing for monogenic disorders including repeat expansion disorders: potentials and pitfalls.

Introduction: Circulating fetal cells isolated from maternal blood can be used for prenatal testing, representing a safe alternative to invasive testing. The present study investigated the potential of cell-based noninvasive prenatal testing (NIPT) for diagnosing monogenic disorders dependent on the mode of inheritance. Methods: Maternal blood samples were collected from women opting for prenatal diagnostics for specific monogenic disorders (N = 7). Fetal trophoblasts were enriched and stained using magnetic activated cell sorting and isolated by fluorescens activated single-cell sorting. Individual cells were subject to whole genome amplification, and cells of fetal origin were identified by DNA-profiling using short tandem repeat markers. The amplified fetal DNA was input for genetic testing for autosomal dominant-, autosomal recessive-, X-linked and repeat expansion disorders by direct variant analysis and haplotyping. The cell-based NIPT results were compared with those of invasive testing. Results: In two cases at risk of skeletal dysplasia, caused by variants in the FGFR3 gene (autosomal dominant disorders), cell-based NIPT correctly stated an affected fetus, but allelic dropout of the normal alleles were observed in both cases. Cell-based NIPT gave an accurate result in two cases at risk of autosomal recessive disorders, where the parents carried either different diastrophic dysplasia causing variants in the SLC26A2 gene or the same cystic fibrosis disease-causing variant in the CFTR gene. Cell-based NIPT accurately identified an affected male fetus in a pregnancy at risk of Duchenne muscular dystrophy (DMD gene, X-linked recessive disorders). In two cases at risk of the myotonic dystrophy type 1 (DMPK gene, repeat expansion disorder), cell-based NIPT correctly detected an affected and an unaffected fetus, respectively. Discussion: Circulating fetal cells can be used to detect both maternally- and paternally inherited monogenic disorders irrespective of the type of variant, however, the risk of allelic dropout must be considered. We conclude that the clinical interpretation of the cell-based NIPT result thus varies depending on the disorders' mode of inheritance.

A decade of change - lessons learned from prenatal diagnostics in Central Denmark region in 2008-2018.

INTRODUCTION: In 2011, it was decided to implement chromosomal microarray in prenatal testing in the Central Denmark Region, mainly due to the expected higher diagnostic yield. Chromosomal microarray was introduced gradually for an increasing number of pregnancies and without a transition period where both karyotyping and chromosomal microarray were performed: first malformations (2011), then large nuchal translucency (2013), then high risk at combined first trimester risk screening (2016) and finally for all indications (2018). This retrospective study summarizes 11 years of using chromosomal microarray in invasive prenatal testing and presents the effect on diagnostic yield and turnaround time. Furthermore, the concerns when introducing chromosomal microarray are presented and discussed. MATERIAL AND METHODS: Registry data from the Danish Fetal Medicine Database, the regional fetal medicine database, the Danish Cytogenetic Central Register and the local laboratory database at Department of Clinical Genetics were all combined, and a cohort of 147 158 singleton pregnancies with at least one ultrasound examination was established RESULTS: Of the 147 158 pregnancies, invasive sampling was performed (chorionic villi or amniocytes) in 8456, corresponding to an overall invasive rate of 5.8%. Between 2016 and 2018, 3.4% (95% confidence interval [CI] 2.8-4.2%; n = 86) of the invasive samples (n = 2533) had a disease causing copy number variant and 5.3% (95% CI 4.4-6.2%; n = 133) had trisomies and other aneuploidies. The turnaround time more than halved from 14 days to an average of 5.5 days for chorionic villus sampling. CONCLUSIONS: Chromosomal microarray identified 5.3% trisomies and 3.4% copy number variants, thereby increased the diagnostic yield by more than 64% compared with karyotype only and it also more than halved the turnaround time. Some preliminary concerns proved real, eg prenatal counseling complexity, but these have been resolved over time in a clinical path with expert consultations.

Comparatively low rates of COVID-19 in women admitted in labor and their newborns prior to routine vaccination of pregnant women: insights from Denmark.

Background: In a country with a high-test frequency, societal lockdown, and pregnancy leave granted from 28 gestational weeks, we investigated SARS-CoV-2 infection in women admitted in labor and their newborn in the pre-vaccine period.Material and methods: A total of 1042 women admitted for delivery in two Danish hospitals agreed to a plasma sample and nasopharyngeal, vaginal, and rectal swabs and to sampling of umbilical cord blood and a nasopharyngeal swab from their newborn at delivery. Plasma samples from women were examined for SARS-CoV-2 antibodies. If antibodies were detected, or the woman had a positive nasopharyngeal swab upon admission or had a household contact with symptoms consistent with COVID-19, SARS-CoV-2 PCR was performed on plasma and swab samples from mother and child.Results: Seventeen women (1.6%) were seropositive. Half the newborn (n = 9 (53%)) of seropositive mothers were also seropositive. None of the seropositive women or newborns had clinical signs of COVID-19 and all had SARS-CoV-2 PCR negative plasma and swab samples.Conclusion: Adherence to specific national guidelines pertaining to testing, self-imposed isolation, and cautious behaviors among pregnant women likely contributed to the exceptionally low prevalence of both prior and current COVID-19 infections detected at the time of childbirth preceding the routine vaccination of pregnant women in Denmark.

Fetal cardiac safety of sertraline use during pregnancy.

INTRODUCTION: Fetal cardiac safety of sertraline is controversial even though it is among the most frequently used antidepressants in pregnancy. Sertraline could theoretically affect the fetal heart resulting in malformations or more subtle changes, but studies evaluating fetal cardiac safety are prone to a number of systematic and random errors. AREAS COVERED: The objective of this review is to evaluate the fetal cardiac safety profile of sertraline in pregnancy. A literature review included articles until November 2022 in Medline with no time or language limitations. EXPERT OPINION: Sertraline is associated with septal heart malformations, but not with more severe heart malformations. The association may be causal or at least partly related to systematic errors, including confounding by indication. Regardless of the causal mechanism, the association should not limit well-indicated treatments of maternal depression. The few available studies on fetal heart function is reassuring. There are no human data on the long-term effects on offspring cardiac function, but the teratogenic and fetal heart function studies do not imply risks of any major cardiac problems later in life. Interactions with other medication may, however, alter the risks associated with any medication in pregnancy, and information and surveilence systems taking this into account is much needed.

Impact of a prenatal screening program on the Down syndrome phenotype: An interrupted time series analysis.

INTRODUCTION: We hypothesized that children with Down syndrome who were born after the implementation of first-trimester combined screening for trisomy 13, 18, and 21 and a second-trimester ultrasound scan in Denmark would show a milder syndrome phenotype. We investigated the birth biometry, prevalence of congenital malformations, and early childhood morbidity of children with Down syndrome before and after implementation of this screening program. MATERIAL AND METHODS: A nationwide register-based study of all live born singletons with Down syndrome in Denmark from 1995 to 2018. In interrupted time series analyses, we studied the temporal developments in birth biometry, prevalence of congenital malformations, and early childhood morbidity related to the implementation of a national prenatal screening program. RESULTS: We included 602 singletons with Down syndrome born before and 308 after implementation of the screening program. Z-scores of birthweight and head circumference increased over time before screening, but this temporal development changed after implementation by -0.05 (95% confidence interval [CI]: -0.11 to 0.01) and -0.05 (95% CI -0.12 to 0.02), respectively. Just after implementation, the prevalence of non-severe congenital heart disease decreased (relative change in odds 0.48 [95% CI: 0.24-0.94]). For severe congenital heart disease, atrioventricular septal defect, and non-heart malformations, this change was 1.16 (95% CI: 0.56-2.41), 0.95 (95% CI: 0.43-2.03), and 0.98 (95% CI: 0.33-2.76), respectively. For all malformations, pre-existing temporal developments did not change following implementation of screening. The implementation was associated with higher odds of admission to a neonatal intensive care unit (relative change 1.98 [95% CI: 0.76-5.26]) and an increased risk of hearing impairment (risk difference 3.4% [95% CI: -0.4% to 7.1%]). In contrast, the implementation was not associated with the incidence of hospital admissions by 2 years of age or with the probability of a thyroid disorder. CONCLUSIONS: After implementation of a national prenatal screening program, we did not observe a milder Down syndrome phenotype apart from an apparent reduction in the proportion of children with non-severe congenital heart disease; this result is, however, limited by small numbers.

Maternal antipsychotic use during pregnancy and congenital malformations.

BACKGROUND: Existing data may underestimate the potential teratogenic effects of prenatal antipsychotic exposure because of lacking data on miscarriages and induced abortions. OBJECTIVE: This study aimed to present a comprehensive analysis based on information on pregnancies ending in termination, miscarriage, stillbirth, and live birth. STUDY DESIGN: We conducted a population-based cohort study in Denmark of clinically recognized singleton pregnancies with the first-trimester scan performed from 2008 to 2017. We compared the risk of major malformations between pregnancies exposed to antipsychotics in the first trimester and unexposed pregnancies. In secondary analyses, the comparison was made with pregnancies of women who used antipsychotics before but not during pregnancy (discontinuers). We used weighted log-binomial regression to estimate adjusted prevalence ratios and propensity score fine stratifications for confounding control. We performed 4 sensitivity analyses, including a sibling-controlled analysis. RESULTS: Of the 503,158 pregnancies, 1252 (0.2%) were of women who filled an antipsychotic prescription in the first trimester. Major malformations were present in 7.3% of antipsychotic-exposed pregnancies, 5.1% of unexposed pregnancies, and 6.0% of discontinuers' pregnancies. The adjusted prevalence ratio was 1.23 (95% confidence interval, 1.01-1.50) among exposed pregnancies compared with unexposed pregnancies. The prevalence ratio was attenuated to 1.14 (95% confidence interval, 0.88-1.48) compared with discontinuers and 1.08 (95% confidence interval, 0.47-2.49) in the sibling analysis. Similar findings were observed with cardiac malformations. Results were consistent for classes and individual antipsychotics, and remained robust across the 4 sensitivity analyses. CONCLUSION: Our findings suggest limited or no overall teratogenic effect of first-trimester antipsychotic exposure. For individual antipsychotics, with estimations based on very few cases, further studies with sufficient sample sizes are warranted.

Is the first-trimester combined screening result associated with the phenotype of Down syndrome? A population-based cohort study.

OBJECTIVE: To investigate if the Down syndrome phenotype differs according to the result of first-trimester combined screening (FTS). METHOD: We included all Down syndrome cases diagnosed by karyotype in pregnancy or after birth in Denmark during 2005-2018. We compared screen positive (odds ≥1:300) and screen negative (odds <1:300) cases as well as screen result subgroups with respect to anthropometrics, congenital malformations, childhood diseases, and hospitalization. RESULTS: Absolute measures of fetal and birth anthropometrics were comparable between groups. A prenatal malformation diagnosis was more prevalent among screen positive than screen negative cases. Analyses suggested that this could reflect a detection bias. Cases with a screen result of 1:2-1:10 had a higher probability of being diagnosed with a malformation prenatally and with severe congenital heart disease (CHD) postnatally compared with a result of 1:11-1:300. Screen positive cases more often had non-severe CHD but less often a non-heart malformation compared with screen negative cases, while proportions of severe CHD were similar in these groups. Data on hospitalizations showed inconsistent results. CONCLUSION: The 1:300 screening threshold had limited or no value in predicting Down syndrome phenotype severity. In contrast, cases with a screen result between 1:2 and 1:10 may represent a more severe phenotype.

[Screening, diagnostics, and treatment of cervical cancer in pregnancy].

Cervical cancer is one of the most common cancers in pregnancy. Early diagnosis is of utmost importance for the outcome of the woman and her child. Vaginal bleeding in pregnancy should prompt gynaecological examination, and further diagnostic is needed in women with persistent symptoms. A decision on preservation of the pregnancy in women who are diagnosed with early-stage cervical cancer depends on stage and gestational age, as argued in this review.

Current controversies: Null hypothesis significance testing.

Traditional null hypothesis significance testing (NHST) incorporating the critical level of significance of 0.05 has become the cornerstone of decision-making in health care, and nowhere less so than in obstetric and gynecological research. However, such practice is controversial. In particular, it was never intended for clinical significance to be inferred from statistical significance. The inference of clinical importance based on statistical significance (p < 0.05), and lack of clinical significance otherwise (p ≥ 0.05) represents misunderstanding of the original purpose of NHST. Furthermore, the limitations of NHST-sensitivity to sample size, plus type I and II errors-are frequently ignored. Therefore, decision-making based on NHST has the potential for recurrent false claims about the effectiveness of interventions or importance of exposure to risk factors, or dismissal of important ones. This commentary presents the history behind NHST along with the limitations that modern-day NHST presents, and suggests that a statistics reform regarding NHST be considered.

Mirtazapine exposure in pregnancy and fetal safety: A nationwide cohort study.

OBJECTIVE: To investigate the association between mirtazapine exposure in pregnancy and risk of specific adverse pregnancy outcomes. METHODS: A register-based nationwide cohort study was conducted including all registered pregnancies in Denmark from 1997 to 2016. Mirtazapine-exposed pregnancies were compared with mirtazapine unexposed pregnancies in a 1:4 ratio matched according to propensity scores. Outcomes were major congenital malformations analyzed using log binomial models, and spontaneous abortion, stillbirth and neonatal death analyzed using Cox proportional hazard regression. RESULTS: From a source population of 1,650,649 pregnancies, the propensity score-matched cohort included 4475 pregnancies (895 mirtazapine exposed) in the analysis of major congenital malformations. The analyses of spontaneous abortion included 9 500 pregnancies (1900 mirtazapine exposed), and for the analyses of stillbirths and neonatal deaths 9725 (1 945 mirtazapine-exposed) and 4485 pregnancies (897 mirtazapine-exposed) were included, respectively. Thirty-one (3.5%) children were diagnosed with major congenital malformation among the mirtazapine exposed compared with 152 (4.3%) among the unexposed pregnancies (OR=0.81, 95% CI 0.55-1.20). Spontaneous abortion occurred in 237 (12.5%) of the mirtazapine exposed compared with 931 (12.3%) of the unexposed pregnancies (HR = 1.04%, 95% CI 0.91-1.20). The analyses revealed no increased risk of stillbirth (HR = 0.88%, 95% CI 0.34-2.29) or neonatal death (HR = 0.60%, 95% CI 0.18-2.02). CONCLUSIONS: In this nationwide Danish register study, mirtazapine exposure in pregnancy was not associated with major congenital malformations, spontaneous abortion, stillbirth, or neonatal death. Clinicians and patients can be reassured that mirtazapine is safe in pregnancy.