Concentrations of Fluoxetine Enantiomers Decline During Pregnancy and Increase After Birth.

RATIONALE: Few studies of the effect of the dynamic physiologic changes during pregnancy on plasma concentrations of fluoxetine (FLX) have been published. OBJECTIVES: We determined the change in concentration to dose (C/D) ratios of R- and S-FLX and R- and S-norfluoxetine monthly during pregnancy and postpartum, assessed their relationships to cytochrome P450 (CYP) 2D6 and CYP2C9 metabolizer phenotypes, and evaluated the course of their depressive and anxiety symptoms. METHODS: In this observational study, 10 FLX-treated pregnant individuals provided blood samples at steady state every 4 weeks during pregnancy and once postpartum for measurement of plasma FLX and norfluoxetine enantiomer concentrations. Participants were genotyped for variants in CYP2C9 and CYP2D6 using commercial assays with Taqman probes. At each assessment, depressive and anxiety symptoms were quantified. RESULTS: The C/D ratios of all FLX and norfluoxetine enantiomers, and the active moiety, decreased steadily through pregnancy and rose after birth. In the final trimester, the mean C/D ratio of the active moiety was 24.9% lower compared with the mean nonpregnant, 12-week postpartum C/D ratio. One individual with CYP2D6 ultrarapid metabolizer status was prescribed the highest FLX dose among participants. In these treated individuals, the mean depressive and anxiety symptoms remained in the mild range across the perinatal period. CONCLUSIONS: These data do not support a recommendation for routine plasma concentration monitoring or CYP2D6 pharmacogenetic testing for pregnant people treated with FLX; however, monitoring for symptom relapse is recommended because of declining plasma drug concentrations.

Factors Associated with Depressive and Anxiety Symptom Trajectories Across Pregnancy and Postpartum in Selective Serotonin Reuptake Inhibitor-Treated Individuals.

Objective: The primary purpose of this article is to identify factors that are associated with worsening mood and anxiety trajectories across the perinatal period among pregnant individuals receiving treatment with a selective-serotonin reupdate inhibitor. Methods: This secondary analysis of primary data from the original article, Trajectories of Depressive and Anxiety Symptoms Across Pregnancy and Postpartum in Selective Serotonin Reuptake Inhibitor-Treated Women, explores if number of lifetime episodes of depression as characterized in the Mini-International Neuropsychiatric Interview, elevated maternal adverse childhood experiences (ACE) score, or specific obstetric or neonatal factors from the Peripartum Events Scale (PES) were associated with membership in trajectory groups with the highest symptom burden. Results: No difference in ACE scores or obstetric or neonatal factors were associated with membership in the trajectory groups using Wilcoxon rank sum tests and bi-variable logistic regression. The trajectory group with the highest anxiety symptom burden experienced more lifetime episodes of depression compared to other groups (odds ratio = 1.17, 95% confidence intervals, 1.02-1.34, p = 0.03). Conclusions: Congruent with other studies, we found a high prevalence of co-occurring mood and anxiety symptoms and that past episodes of depression remain an important historical risk factor for perinatal symptom burden. This reinforces that past experiences of depression increase not only the risk of future symptoms but also higher symptom burden during antidepressant treatment.

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.

Design Considerations for Pharmacokinetic Studies During Pregnancy.

Most of the interventions performed by obstetric providers involve the administration of drugs. Pregnant patients are pharmacologically and physiologically different from nonpregnant young adults. Therefore, dosages that are effective and safe for the general public may be inadequate or unsafe for the pregnant patient and her fetus. Establishing dosing regimens appropriate for pregnancy requires evidence generated from pharmacokinetic studies performed in pregnant people. However, performing these studies during pregnancy often requires special design considerations, evaluations of both maternal and fetal exposures, and recognition that pregnancy is a dynamic process that changes as gestational age advances. In this article, we address design challenges unique to pregnancy and discuss options for investigators, including timing of drug sampling during pregnancy, appropriate selection of control groups, pros and cons of dedicated and nested pharmacokinetic studies, single-dose and multiple-dose analyses, dose selection strategies, and the importance of integrating pharmacodynamic changes into these protocols. Examples of completed pharmacokinetic studies in pregnancy are provided for illustration.

Relationship between plasma concentration of 17-hydroxyprogesterone caproate and gestational age at preterm delivery.

BACKGROUND: The effectiveness of 17-hydroxyprogesterone caproate is unclear as trials have provided conflicting results. With the absence of fundamental pharmacologic studies addressing dosing or the relationship between drug concentration and gestational age at delivery, the effectiveness of the medication cannot be evaluated. OBJECTIVE: This study aimed to evaluate the relationship between plasma concentrations of 17-hydroxyprogesterone caproate and preterm birth rates and gestational age at preterm delivery and to assess the safety of the 500-mg dose. STUDY DESIGN: This study recruited 2 cohorts with previous spontaneous preterm birth; 1 cohort (n=143) was randomly assigned to either 250-mg or 500-mg 17-hydroxyprogesterone caproate, and the other cohort (n=16) was receiving the 250-mg dose for routine care. Steady-state trough plasma concentrations of 17-hydroxyprogesterone caproate obtained at 26 to 30 weeks of gestation were correlated to dose, spontaneous preterm birth rates, and measures of gestational length. Furthermore, maternal and neonatal safety outcomes were evaluated according to dose. RESULTS: There was a dose proportional increase in trough plasma concentrations with the 250-mg (median, 8.6 ng/m; n=66) and 500-mg (median, 16.2 ng/mL; n=55) doses. In 116 compliant participants with blood samples, drug concentration was not related to the spontaneous preterm birth rate (odds ratio, 1.00; 95% confidence interval, 0.93-1.08). However, there was a significant relationship between drug concentration and both the interval from the first administration to delivery (interval A: coefficient, 1.11; 95% confidence interval, 0.00-2.23; P=.05) and the interval from the 26- to 30-week blood draw to delivery (interval B: coefficient, 1.56; 95% confidence interval, 0.25-2.87; P=.02). The spontaneous preterm birth rate or measures of gestational length were not related to dose. Postenrollment cerclage adversely affected all pharmacodynamic assessments because it was a powerful predictor of spontaneous preterm birth (odds ratio, 4.03; 95% confidence interval, 1.24-13.19; P=.021) and both measures of gestational length (interval A [coefficient, -14.9; 95% confidence interval, -26.3 to -3.4; P=.011] and interval B [coefficient, -15.9; 95% confidence interval, -25.8 to -5.9; P=.002]). Initial cervical length was significantly related to the risk of postenrollment cerclage (odds ratio, 0.80; 95% confidence interval, 0.70-0.92; P=.001). Maternal and neonatal safety outcomes were similar in both dosing groups. CONCLUSION: In this pharmacodynamic study, trough plasma 17-hydroxyprogesterone caproate concentrations were significantly associated with gestational age at preterm birth but not with the preterm birth rate. Postenrollment cerclage was a powerful predictor of spontaneous preterm birth rate and gestational length. Initial cervical length predicted the risk of postenrollment cerclage. Adverse events were similar with the 500-mg and 250-mg doses of 17-hydroxyprogesterone caproate.

Temporal changes in the systemic concentrations of retinoids in pregnant and postpartum women.

Retinoids and vitamin A are essential for multiple biological functions, including vision and immune responses, as well as the development of an embryo during pregnancy. Despite its importance, alterations in retinoid homeostasis during normal human pregnancy are incompletely understood. We aimed to characterize the temporal changes in the systemic retinoid concentrations across pregnancy and postpartum period. Monthly blood samples were collected from twenty healthy pregnant women, and plasma concentrations of retinol, all-trans-retinoic acid (atRA), 13-cis-retinoic acid (13cisRA), and 4-oxo-retinoic acids were measured using liquid chromatography-tandem mass spectrometry. Significant decreases in 13cisRA concentrations over the pregnancy were observed, with rebound increases in retinol and 13cisRA levels after delivery. Of note, atRA concentrations exhibited a unique temporal pattern with levels peaking at mid-pregnancy. While the 4-oxo-atRA concentration was below the limit of quantification, 4-oxo-13cisRA was readily detectable, and its temporal change mimicked that of 13cisRA. The time profiles of atRA and 13cisRA remained similar after correction by albumin levels for plasma volume expansion adjustment. Together, the comprehensive profiling of systemic retinoid concentrations over the course of pregnancy provides insights into pregnancy-mediated changes in retinoid disposition to maintain its homeostasis.

Principles of Obstetric Pharmacology: Maternal Physiologic and Hepatic Metabolism Changes.

Since the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigations have expanded our understanding of obstetric pharmacology. Many of the basic physiologic changes that occur during pregnancy impact on drug absorption, distribution, or clearance. Activities of hepatic metabolizing enzymes are variably altered by pregnancy, resulting in concentrations sufficiently different for some drugs that efficacy or toxicity may be affected. Understanding these unique pharmacologic changes will better inform our use of medications for our pregnant patients.

Use of Obstetric and Gynecologic Hospitalists Is Associated With Decreased Severe Maternal Morbidity in the United States.

OBJECTIVES: This study aimed to evaluate the prevalence of obstetric and gynecologic (Ob/Gyn) hospitalists and determine if an association exists between the presence of Ob/Gyn hospitalists and severe maternal morbidity (SMM). METHODS: This observational study included data from hospitals listed in the USA TODAY 's 2019 article titled, "Deadly deliveries: Childbirth complication rates at maternity hospitals." Telephone and email surveys of staff in these hospitals identified the presence or absence of continuous providers in the hospital 24 hours, 7 days a week (24/7 coverage) and the types of providers who are employed, then compared these responses with the SMM cited by USA TODAY . RESULTS: Eight hundred ten hospitals were contacted, with participation from 614 labor and delivery units for a response rate of 75.8%. Fifty-seven percent of units were staffed with 24/7 coverage, with 46% of hospitals' coverage primarily provided by an Ob/Gyn hospitalist and 54% primarily by a nonhospitalist OB/Gyn provider. The SMM and presence of 24/7 coverage increased with the level of neonatal care and delivery volume. Of hospitals with 24/7 coverage, those that primarily used Ob/Gyn hospitalists had a lower SMM for all mothers (1.7 versus 2.0, P = 0.014) and for low-income mothers (1.9 versus 2.30, P = 0.007) than those who primarily used nonhospitalist OB/Gyn providers. CONCLUSIONS: Severe maternal morbidity increases with delivery volume, level of neonatal care, and 24/7 coverage. Of hospitals with 24/7 coverage, units that staff with Ob/Gyn hospitalists have lower levels of SMM than those that use nonhospitalist Ob/Gyn providers.

Trajectories of Depressive and Anxiety Symptoms Across Pregnancy and Postpartum in Selective Serotonin Reuptake Inhibitor-Treated Women.

Objective: Tracking perinatal mood and anxiety disorders is championed by the American Psychiatric Association and the International Marcé Society for Perinatal Mental Health. We conducted this study to examine trajectories of monthly depressive and anxiety symptoms through pregnancy and postpartum. Methods: This is a prospective longitudinal observational cohort study of pregnant women interviewed at baseline (≤18th gestational week), every four weeks through delivery and at 6 and 14 weeks postpartum at three urban academic medical centers (N = 85) and a single rural health center (N = 3) from 2016 to 2020. Pregnant women had at least one prior episode of major depressive disorder, were not in a current episode, and were treated with sertraline, fluoxetine, citalopram, or escitalopram. Of 192 women screened, 88 (46%) women enrolled, and 77 (88%) women completed the postpartum follow-up. Symptom trajectories were generated with scores from the Edinburgh Postnatal Depression Scale, the Quick Inventory of Depressive Symptoms, the Generalized Anxiety Disorder Scale, 7-item, and the Patient-Reported Outcomes Measurement Information System Global Health measure. A semi-parametric, group-based mixture model (trajectory analysis) was applied. Results: Three relatively stable depression trajectories emerged, described as Minimal, Mild, and Subthreshold, in each group across pregnancy. Two of the four anxiety trajectories were stable, including Asymptomatic and Minimal, while the third, termed Breakthrough, was ascending with increasing symptoms and the fourth trajectory, described as Mild, had descending symptoms. Conclusions: Screening for anxiety with depression for pregnant women will yield a comprehensive view of psychiatric symptoms and treatment targets in perinatal women.

Changes in Sertraline Plasma Concentrations Across Pregnancy and Postpartum.

Major depressive disorder (MDD) is a common disorder in pregnancy. Although sertraline is the most frequently prescribed antidepressant for pregnant people in the United States, limited information about its pharmacokinetics in pregnancy is available. Our objectives were to characterize plasma sertraline concentration to dose (C/D) ratios across pregnancy and postpartum and investigate the effect of pharmacogenetic variability on sertraline elimination. We performed a prospective observational cohort study in people with a singleton pregnancy ≤ 18 weeks gestation and a lifetime diagnosis of MDD at the 3 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-funded Obstetrical-Fetal Pharmacology Research Center sites. Subjects (N = 47) were receiving maintenance sertraline therapy and chose to continue it during pregnancy. Blood samples were obtained 24-hours postdose every 4 weeks across pregnancy and twice postpartum for measurement of plasma concentrations of sertraline and desmethylsertraline. Overall mean sertraline C/D ratios were decreased at study onset and remained consistently low until after delivery. During the last 4 weeks of pregnancy the mean sertraline C/D ratio (95% confidence interval (CI)), 0.25 (95% CI, 0.19, 0.3) ng/mL/dose (mg/day), was smaller than the mean ratio at ≥ 8 weeks after delivery, 0.32 (95% CI, 0.27, 0.37) ng/mL/dose (mg/day), a 22% difference. Mean sertraline/desmethylsertraline ratios were highest after birth, which confirmed increased sertraline elimination during pregnancy. Sertraline C/D ratios in participants with functional CYP2C19 activity did not change significantly during pregnancy, whereas ratios in participants with poor or intermediate CYP2C19 activity decreased by 51%. Exploratory pharmacogenomic analysis indicated that pregnant people with poor or intermediate CYP2C19 activity are at risk for subtherapeutic sertraline concentrations during pregnancy.

A randomized pilot clinical trial of pravastatin versus placebo in pregnant patients at high risk of preeclampsia.

BACKGROUND: Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia. OBJECTIVE: We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin. STUDY DESIGN: This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight. RESULTS: Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects. CONCLUSION: This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.

Contraception for Women With Psychiatric Disorders.

OBJECTIVE: Mental health care for women includes decision support to prepare for major life events, including preconception planning for treatment during pregnancy and the postpartum period. The authors discuss contraceptive choices and their effectiveness, side effects, and impact on psychiatric symptoms. The Centers for Disease Control and Prevention's recommendations, Medical Eligibility Criteria for Contraceptive Use, provided the structure for review of contraceptive choices. METHODS: A search of PsycINFO, PubMed, Embase, and Scopus was conducted for publications on the management of contraception for women with mental illness. Publications were selected if they included, based on the authors' consensus, data supporting evidence-based care important for psychiatrists who treat women desiring contraceptives. RESULTS: The majority of women choose combined oral contraceptives. Although long-acting reversible contraceptives (implants, intrauterine devices) are associated with low failure rates, favorable safety profiles, rapid return to fertility after removal, and few contraindications, they are chosen by only 14% of women. All methods are acceptable for women with depression, although medical comorbidities may dictate a specific type. The impact of hormonal contraceptives on the risk for depression is controversial; however, clinical studies and randomized placebo-controlled trials of women with psychiatric disorders have generally reported similar or lower rates of mood symptoms in hormonal contraceptive users compared with nonusers. Although interactions between psychotropic drugs and contraceptives are rare, clozapine, anticonvulsants, and St. John's Wort are exceptions. CONCLUSIONS: Proactive management of mental illness, contraception, and pregnancy improves a woman's capacity to function and optimizes her mental and reproductive health.

Drugs in pregnancy: Pharmacologic and physiologic changes that affect clinical care.

Pharmacologic interventions play a major role in obstetrical care throughout pregnancy, labor and delivery and the postpartum. Traditionally, obstetrical providers have utilized standard dosing regimens developed for non-obstetrical indications based on pharmacokinetic knowledge from studies in men or non-pregnant women. With the recognition of pregnancy as a special pharmacokinetic population in the late 1990s, investigators have begun to study drug disposition in this unique patient dyad. Many of the basic physiologic changes that occur during pregnancy have significant impact on drug absorption, distribution and clearance. Activity of Phase I and Phase II drug metabolizing enzymes are differentially altered by pregnancy, resulting in drug concentrations sufficiently different for some medications that efficacy or toxicity is affected. Placental transporters play a major dynamic role in determining fetal drug exposure. In the past two decades, we have begun to expand our understanding of obstetrical pharmacology; however, to truly optimize pharmacologic care of our pregnant patients and their developing fetus, additional research is critically needed.

Methods to study mechanisms underlying altered hepatic drug elimination during pregnancy.

Hepatic drug metabolism is a major route of drug elimination, mediated by multiple drug-metabolizing enzymes. Any changes in the rate and extent of hepatic drug metabolism can lead to altered drug efficacy or toxicity. Accumulating clinical evidence indicates that pregnancy is accompanied by changes in hepatic drug metabolism. In this article, we discuss in vitro and in vivo tools used to study the mechanisms underlying the altered drug metabolism during pregnancy, focusing on primary hepatocyte culture, transgenic animal models, and use of probe drugs to assess change in enzymatic activity. The information obtained from these studies has enabled prediction of clinical PK changes for a given drug in pregnant women.

Transdermal Estradiol Treatment for Postpartum Depression: A Pilot, Randomized Trial.

Postpartum depression occurs in 14.5% of women in the first 3 months after birth. This study was an 8-week acute phase randomized trial with 3 cells (transdermal estradiol [E2], sertraline [SERT], and placebo [PL]) for the treatment of postpartum major depressive disorder. However, the study was stopped after batch analysis revealed that the E2 serum concentrations were lower than prestudy projections. This paper explores our experiences that will inform future investigations of therapeutic E2 use. Explanations for the low E2 concentrations were as follows: (1) study patch nonadhesion, which did not explain the low concentrations across the entire sample. (2) Ineffective transdermal patch preparations, although 2 different patch preparations were used and no significant main effect of patch type on E2 concentrations was found. (3) Obesity, at study entry, E2-treated women had body mass index of 32.9 (7.4) (mean [SD]). No pharmacokinetic data comparing E2 concentrations from transdermal patches in obese women versus normal weight controls are available. (4) Induction of cytochrome P450 (CYP450) 3A4 and other E2 elimination pathways in pregnancy. CYP4503A4 is induced in pregnancy and is a pathway for the metabolism of E2. Conversion to estrone and phase II metabolism via glucuronidation and sulfation, which also increase in pregnancy, are routes of E2 elimination. The time required for these pathways to normalize after delivery has not been elucidated. The observation that transdermal E2 doses greater than 100 µg/d did not increase serum concentrations was unexpected. Another hypothesis consistent with this observation is suppression of endogenous E2 secretion with increasing exogenous E2 dosing.