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.

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.

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.

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.

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.

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.

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.

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.

Parenting a child with Down syndrome: A qualitative study of everyday practices in Danish families.

Genetic counseling about Down syndrome is suggested to include information on a future family life. However, there is an insufficient knowledge on the potential impact of parenting a child with Down syndrome on parents' everyday practices. We aimed to address this gap by exploring the experienced everyday practices of parents in families where a child has Down syndrome. Taking a qualitative approach, we conducted semi-structured interviews with 25 parents of children with Down syndrome aged 4-12 years. Using reflexive thematic analysis, we identified two themes concerned with the parents' practice. The first, 'Supporting our child', describes how the parents perceived their child as a valuable human being and how this perception founded parents' support of the child's development and social interactions. The second, 'Managing our family life', demonstrates how the parents acted to manage a family life that had become the 'new normal' including being alert toward the child, shaping the practical and logistical framework of daily life, and balancing between being at home and away from home. Overall, the analysis presents an everyday practice aimed at a desirable future for the child with Down syndrome and at a management of everyday life on the family's own terms. In conclusion, this study provides specific knowledge on parents' everyday practice, which may inform genetic counseling about Down syndrome and be of value to service providers.

Antidepressant use during pregnancy and risk of congenital heart defects: A case-time-control study.

PURPOSE: We estimated the association between maternal antidepressant (AD) use in early pregnancy and risk of congenital heart defects. METHODS: We applied a case-time-control design with the aim of controlling for confounding from time-invariant factors and compared the results of the design to results from a cohort design in a population of 792 685 singletons born alive in Denmark during 1995-2008. In the case-time-control design, we identified children diagnosed with a congenital heart defect in the first 5 years of life (cases) and compared maternal AD use in the risk period (the first 3 months of pregnancy) and the reference period (gestational months 5-7). A nondiseased control group was included to adjust for time trends of exposure. In the cohort design, we identified children whose mothers redeemed at least one AD prescription in the first 3 months of pregnancy (the exposed) and two other groups including the unexposed children with maternal AD prescriptions in the 12 months before pregnancy. We applied conditional logistic regression and logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The case-time-control OR for any congenital heart defect was 1.03 (95% CI, 0.61-1.73), which was similar to the OR (1.09, 95% CI, 0.88-1.35) from the cohort design when we compared the exposed children with the unexposed children with maternal AD use before pregnancy. CONCLUSIONS: The case-time-control design provided results similar to the cohort design when the cohort design had a better confounder control strategy. We discussed the strengths and drawbacks of case-time-control design.

Prenatal exposure to ß2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring.

PURPOSE: We aimed to examine the risk of autism spectrum disorders (ASDs) in the offspring who were exposed to maternal use of ß2-adrenoreceptor agonist (ß2AA) during pregnancy. METHODS: This is a population-based cohort study including all live singleton births in Denmark from 1 January 1997 to 31 December 2008. Children born to mothers who used ß2AA during pregnancy were categorized as exposed, and all other children were included in the unexposed group. Cases of ASDs were identified from the Danish Psychiatric Central Register and the Danish Patient Register. Incidence rate ratio (IRR) and 95% confidence interval were estimated by Poisson regression models. RESULTS: Among 751 888 children in the cohort, 9098 (1.21%) received a diagnosis of ASDs. We observed an increased risk of ASDs in the exposed children (IRR = 1.28, 1.11-1.47), especially for those who were exposed during the second trimester period (IRR = 1.38, 1.14-1.67). However, when extending the exposure time window to 1 year prior to pregnancy, we observed a similar association in children born to women who received ß2AA treatment during pregnancy (IRR = 1.33, 1.11-1.59) to that in children born to women who received ß2AA treatment 1 year prior to pregnancy (IRR = 1.35, 1.17-1.56). CONCLUSION: Our finding suggested that children born to women who used ß2AA during pregnancy have an increased risk of ASDs in later life, which is more likely due to underlying maternal diseases rather than the exposure to ß2AA itself. However, further study, which would better differentiate the effects between indication and medicine, is needed to corroborate the finding. Copyright © 2017 John Wiley & Sons, Ltd.

Prenatal exposure to antidepressants and risk of epilepsy in childhood.

PURPOSE: This study aimed to estimate the association between prenatal exposure to antidepressants and risk of epilepsy in childhood, taking maternal depression into account. METHODS: We conducted a population-based cohort study including all Danish singletons born alive between 1997 and 2008 (n = 734 237). Information on antidepressant medication and diagnosis of depression and epilepsy was obtained from Danish National Registers. The exposed group comprised children of mothers who used antidepressants from 30 days before pregnancy until the date of birth. The reference group comprised children of mothers who used no antidepressants from 6 months before pregnancy to birth. We estimated the hazard ratios (HR) of epilepsy and 95% confidence intervals (CI) using Cox proportional hazard models. RESULTS: We identified 12 438 (1.7%) children exposed to antidepressants during pregnancy (including 30 days before pregnancy) and 5829 (0.8%) children diagnosed with epilepsy in the follow-up time (mean: 6.7 years). Children exposed to antidepressants during pregnancy had a 27% higher risk of epilepsy (aHR: 1.27; 95%CI: 1.05-1.54) than children in the reference group. The estimate of this association was 1.71 (95%CI: 1.10-2.66) if their mothers also had a registry-based hospital diagnosis of depression in the 6 months before pregnancy or during pregnancy and 1.14 (95%CI: 0.91-1.43) if their mothers had no registry-based hospital diagnosis of depression. Children of mothers who used antidepressants from 2 to 6 months before pregnancy (but not during pregnancy) had an increased risk of epilepsy (aHR: 1.36; 95%CI: 1.07-1.73). CONCLUSIONS: Antidepressant use during pregnancy was associated with a higher risk of epilepsy among children whose mothers had also a registry-based hospital diagnosis of depression during pregnancy. Copyright © 2016 John Wiley & Sons, Ltd.

Association of prenatal exposure to acetaminophen and coffee with childhood asthma.

PURPOSE: Some studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma, and whether such a potential association could be modified by maternal coffee consumption. METHODS: We included 63,652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards regression model. RESULTS: After adjusting for potential confounders, acetaminophen use during pregnancy was associated with an increased risk of offspring asthma (HR = 1.16, 95% confidence interval (CI): 1.11-1.22). Coffee drinking during pregnancy was associated with a slightly decreased risk (HR = 0.94, 95%CI: 0.90-0.99). But there was no strong evidence of effect measure modification of acetaminophen use on offspring asthma by coffee consumption. CONCLUSIONS: Acetaminophen use during pregnancy was associated with a modest increased risk for offspring asthma, which was not modified by coffee consumption.

No association between prenatal exposure to psychotropics and intelligence at age five.

OBJECTIVE: To examine associations between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs)/anxiolytics and intelligence assessed with a standard clinical intelligence test at age 5 years. DESIGN: Longitudinal follow-up study. SETTING: Denmark, 2003-2008. POPULATION/SAMPLE: A total of 1780 women and their children sampled from the Danish National Birth Cohort. METHODS: Self-reported information on use of SSRI and anxiolytics was obtained from the Danish National Birth Cohort at the time of consent and from two prenatal interviews. Intelligence was assessed at age 5 years, and parental education, maternal intelligence quotient (IQ), maternal smoking and alcohol consumption in pregnancy, the child's age at testing, sex, and tester were included in the full model. The IQ of 13 medication-exposed children was compared with the IQ of 19 children whose mothers had untreated depression and 1748 control children. MAIN OUTCOME MEASURE: Wechsler Preschool and Primary Scale of Intelligence - Revised. RESULTS: In unadjusted analyses, children of mothers who used antidepressants or anxiolytics during pregnancy had higher verbal IQ; this association, however, was insignificant after adjustment for potentially confounding maternal and child factors. CONCLUSION: No consistent associations between IQ and fetal exposure to antidepressants and anxiolytics were observed, but the study had low statistical power, and there is an obvious need to conduct long-term follow-up studies with comprehensive cognitive assessment and sufficiently large samples of adolescent or adult offspring.

Birth outcomes after prenatal exposure to antiepileptic drugs--a population-based study.

OBJECTIVE: We studied the potential impact of antiepileptic drugs (AEDs) on fetal growth and gestational age at birth. METHODS: In the Danish Medical Birth Registry, we identified all pregnancies with birth outcomes from 1997 to 2008 and linked with data from the Danish National Prescription Register. We used binomial regression to study preterm birth (<37 weeks), low birth weight (<2,500 g), and small for gestational age (SGA), adjusted for potential confounding factors including maternal age, smoking, substance abuse, cohabitation, income, education, and parity. RESULTS: We identified 679,762 singletons, and 2,928 (0.4%) of these had been exposed to AEDs. Exposure to AEDs was associated with a risk of preterm birth (adjusted risk ratio (aRR) 1.32; 95% confidence interval [CI] 1.16-1.50) when compared to unexposed children. However, when stratifying on maternal epilepsy, there was no association between AED exposure and preterm birth in offspring of women with epilepsy (aRR 1.00; 95% CI 0.82-1.21), whereas there was a risk associated with AED exposure in offspring of women without epilepsy (aRR 1.56; 95% CI 1.27-1.92). AED exposure was associated with a risk of being born with low birth weight (aRR 1.40; 95% CI 1.22-1.60) both for children born of women with epilepsy (aRR 1.32; 95% CI 1.06-1.63) and children born of women without epilepsy (aRR 1.61; 95% CI 1.28-2.02). The risk of being born SGA associated with AED exposure (aRR 1.21; 95% CI 1.10-1.34) was found both in offspring of women with epilepsy (aRR 1.19; 95% CI 1.02-1.37) and without epilepsy (aRR 1.21; 95% CI 1.01-1.45). SIGNIFICANCE: Prenatal AED exposure was associated with low birth weight and risk of being born SGA, but only with preterm birth among women without epilepsy.

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.