Impact of antidepressant use, discontinuation, and dosage modification on maternal depression during pregnancy.

Women tend to discontinue their antidepressants during pregnancy. This study compared the risk of depressive symptoms in the second-half of pregnancy in women who discontinue or continue with or without dosage modification their antidepressant during gestation. Women were eligible if they called MothertoBaby during 2006-2010 and within 14 completed weeks of pregnancy. A total of 367 pregnant women were included. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure depression during the first and second half of pregnancy. Presence of depressive symptoms was defined as EPDS ≥13. Among participants, 149 did not use antidepressants, 38 used antidepressants at the beginning of pregnancy but discontinued before the end of second-trimester, and 180 used antidepressants continuously throughout pregnancy. Among continued users, 46 modified antidepressant dosage before the end of the second trimester, and 134 did not modify dosage. The majority of antidepressant users (150/218, 68.8%) had mild to moderate depression. Thirteen percent (13%) of women who continued antidepressant use throughout pregnancy without dosage modification remained depressed. Adjusting for potential confounders including maternal depression/anxiety before pregnancy, and compared to non-users, discontinued users were 5.95 times (95%CI: 1.54-23.02), and continued users without dosage modification 4.59 times (95%CI: 1.44-14.64) more at risk of depression in the second-half of pregnancy. Those with dosage modifications were at a similar risk of depression during pregnancy than non-users (adjusted odds ratio 0.58, 95%CI: 0.06-5.52). In conclusion, in a cohort of mild to moderate depressive pregnant women, discontinuing or continuing antidepressant use without dosage modification during pregnancy were associated with an increased risk of depression during the remaining gestational period.

Association between CYP2D6 Genotypes and the Risk of Antidepressant Discontinuation, Dosage Modification and the Occurrence of Maternal Depression during Pregnancy.

Importance: Polymorphic expression of drug metabolizing enzymes affects the metabolism of antidepressants, and thus can contribute to drug response and/or adverse events. Pregnancy itself can affect CYP2D6 activity with profound variations determined by CYP2D6 genotype. Objective: To investigate the association between CYP2D6 genotype and the risk of antidepressant discontinuation, dosage modification, and the occurrence of maternal CYP2D6, Antidepressants, Depression during pregnancy. Setting: Data from the Organization of Teratology Information Specialists (OTIS) Antidepressants in Pregnancy Cohort, 2006-2010, were used. Women were eligible if they were within 14 completed weeks of pregnancy at recruitment and exposed to an antidepressant or having any exposures considered non-teratogenic. Main Outcomes and Measures: Gestational antidepressant usage was self-reported and defined as continuous/discontinued use, and non-use; dosage modification was further documented. Maternal depression and anxiety were measured every trimester using the telephone interviewer-administered Edinburgh Postnatal Depression Scale and the Beck Anxiety Inventory, respectively. Saliva samples were collected and used for CYP2D6 genotype analyses. Logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals. Results: A total of 246 pregnant women were included in the study. The majority were normal metabolizers (NM, n = 204, 83%); 3.3% (n = 8) were ultrarapid metabolizers (UM), 5.7% (n = 14) poor metabolizers (PM), and 8.1% (n = 20) intermediate metabolizers (IM). Among study subjects, 139 women were treated with antidepressants at the beginning of pregnancy, and 21 antidepressant users (15%) discontinued therapy during pregnancy. Adjusting for depressive symptoms, and other potential confounders, the risk of discontinuing antidepressants during pregnancy was nearly four times higher in slow metabolizers (poor or intermediate metabolizers) compared to those with a faster metabolism rate (normal or ultrarapid metabolizers), aOR = 3.57 (95% CI: 1.15-11.11). Predicted CYP2D6 metabolizer status did not impact dosage modifications. Compared with slow metabolizers, significantly higher proportion of women in the fast metabolizer group had depressive symptom in the first trimester (19.81 vs. 5.88%, P = 0.049). Almost 21% of treated women remained depressed during pregnancy (14.4% NM-UM; 6.1% PM-IM). Conclusions and Relevance: Prior knowledge of CYP2D6 genotype may help to identify pregnant women at greater risk of antidepressant discontinuation. Twenty percent of women exposed to antidepressants during pregnancy remained depressed, indicating an urgent need for personalized treatment of depression during pregnancy.

Impact of maternal prenatal and parental postnatal stress on 1-year-old child development: results from the OTIS antidepressants in pregnancy study.

Perinatal psychological stress has been associated with unfavorable maternal and neonatal outcomes. We aimed to assess the impact of perinatal stress on infant development at 1 year of age. We recruited pregnant women calling North American Teratogen Information Services or attending outpatient clinics at CHU Sainte Justine (Montreal) between 2008 and 2010 and their spouses. To be part of our study, women had to be (1) >18 years of age, (2) <15 weeks of gestational age at recruitment, (3) living within 250-km radius of Montreal, and (4) taking antidepressants or non-teratogenic drugs. Stress was assessed using the telephone-administered four-item perceived stress scale during pregnancy in mothers and at 2 months postpartum in both parents. Child development at 1 year of age was evaluated with the Bayley III scales. Socio-demographic and potential confounders were collected through telephone interviews. Multivariable linear regression models were built to assess the association between perinatal parental stress and child development. Overall, 71 couples and their infants were included. When adjusted for potential confounders, maternal prenatal stress was positively associated with motor development (adjusted ß = 1.85, CI 95 % (0.01, 3.70)). Postpartum maternal and paternal stresses were negatively associated with motor and socio-emotional development, respectively (adjusted ß = -1.54, CI 95 % (-3.07, -0.01) and adjusted ß = -1.67, CI 95 % (-3.25, -0.10), respectively). Maternal and paternal postnatal stress seems to be harmful for the motor and socio-emotional development in 1-year-old children. No association was demonstrated between parental stress and cognitive, language, and adaptive behavioral development. However, prenatal maternal stress appears to improve motor skills.

Proteomic analyses of Urine Exosomes reveal New Biomarkers of Diabetes in Pregnancy.

OBJECTIVE: To evaluate 24 hour urine exosome protein content changes among pregnant US subjects with diabetes and obesity during early pregnancy. METHODS: The exosome proteome content from 24 hour urine samples of pregnant subjects with gestational diabetes mellitus (GDM, N=8) and pre-gestational Type 2 diabetes (PGD, N = 10) were compared with control samples (CTRL, N = 10) obtained at week 20 of pregnancy. Differences in exosome protein load between groups was identified by liquid chromatography/mass spectrometry, analyzed by linear regression in negative binomial distribution, visualized in MetaboAnalyst (version 3.0), and validated by western immunoblotting. RESULTS: At the 20th week of pregnancy, we identified 646, 734 and 856 proteins in exosomes from 24 hour urine samples of patients from the CTRL, GDM and PGD groups, respectively. S100 calcium binding protein A9, damage associated molecular pattern (DAMP) signal, was found to be significantly increased in both GDM and PGD subjects. In GDM subjects the peptide counts for S100A9 protein independently correlated with maternal obesity and macrosomia of the newborn infants. Early to late pregnancy developmental changes in the GDM group were shown to utilize pathways and protein expression levels differently from those in PGD or CTRL groups. CONCLUSIONS: Urinary exosome proteomic analysis non-invasively provides insights into maternal changes during diabetic pregnancy. Exosome biomarkers early in pregnancy can be potentially used to better understand pathophysiologic mechanisms of diabetes at a cellular level, and to distinguish between gestational and pre-gestational diabetes at the pathway level. This information can aid intervention efforts to improve pregnancy outcomes in women with diabetes.

Using the electronic medical record to refer women taking category D or X medications for teratogen and contraceptive counseling.

BACKGROUND: Women taking teratogens may not receive teratogen and contraceptive counseling. The objective of this study is to explore the feasibility of an electronic medical record (EMR) alert and referral system to improve teratogen and contraceptive counseling. METHODS: We conducted a descriptive study in an academic outpatient setting to evaluate the feasibility of an EMR alert and referral system. Reproductive age women taking category D or X medications seen in family medicine clinics were referred by means of an EMR alert for teratogen and contraceptive counseling. A subset of these women consented to follow-up surveys assessing contraceptive usage before counseling, intended contraceptive method after counseling and satisfaction with the counseling. Participants were contacted at 1 and 3 months to assess contraceptive usage. RESULTS: A total of 354 women were prescribed category D or X medications by clinicians who received the EMR alert, 170 women were referred, 59 women received counseling, and 33 participants enrolled in the study. One participant did not use any contraception. Among the 32 participants using contraception, 12 (37.5%) used oral contraceptives, 11 (34.4%) used condoms, 3 (9.4%) used withdrawal, 3 (9.4%) used intrauterine devices, 2 (6.3%) used contraceptive rings, and 1 (3.1%) used the diaphragm. After counseling, one-third of participants were considering more effective contraception. Almost all participants strongly agreed or agreed that the counseling was helpful. CONCLUSION: Creating an EMR alert and referral system for women prescribed category X or D medications is feasible. Counseling on teratogen exposure and contraception may improve the acceptability of more effective contraception.

The ASQ and R-PDQ telephone-administered validation within the OTIS antidepressant in pregnancy study.

This study aimed to assess the telephone administration of the 12-month Ages and Stages Questionnaire (ASQ) and the 9- to 24-month Revised Prescreening Denver Questionnaire (R-PDQ) using the Antidepressants in Pregnancy Study cohort from the Organization of Teratology Information Specialists. The ASQ includes five domains (communication, gross motor, fine motor, problem-solving, and personal-social). The R-PDQ tests four areas of development (gross motor, fine motor, personal-social, and language). Both instruments were self and telephone-administered to mothers at 12 months postpartum. Concordance between the telephone and self-administration was assessed with intraclass correlation coefficients (ICCs) with 95% CIs. For the ASQ, concordance between test scores was substantial for the communication scale (ICC = 0.76, 95% CI [0.63, 0.85]), almost perfect for the gross motor scale (ICC = 0.83, 95% CI [0.73, 0.89]), and moderate for the fine motor, problem-solving, and personal-social scales (ICC = 0.43, 95% CI [0.19, 0.61]; ICC = 0.42, 95% CI [0.19, 0.61]; and ICC = 0.50, 95% CI [0.29, 0.67], respectively). Regarding the R-PDQ, concordance between test scores was as follows: gross motor (ICC = 0.90, 95% CI [0.83, 0.94]), language (ICC = 0.57, 95% CI [0.36, 0.73]), and personal-social scales (ICC = 0.26, 95% CI [0.00, 0.49]). For the fine motor scale, the correlation between both modes was 100%. The 12-month ASQ telephone administration could be an alternative for children developmental screening. Except the personal-social scale, the 9- to 24-month R-PDQ could be telephone-administered for prescreening development.

Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study.

OBJECTIVE: High-dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX. METHODS: Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX). RESULTS: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points. CONCLUSION: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort.

The CTIS Womb to Classroom Screening Program for the detection of agents with adverse effects on neuropsychological development.

Over the last several decades, federal agencies engaged in the screening of environmental or pharmaceutical agents have recognized the need to conduct research in animal models to identify agents that have classic teratogenic effects as well as effects on neural and behavioral development. Many questions typically addressed in rodent models can be further addressed using real-world, everyday human exposures. Although some postmarketing surveillance programs have been put in place to examine the influences on birth characteristics, it is now urgent that programs be launched to examine the long-term risks associated with exposure to the many medications, drugs, and environmental chemicals for which data are currently unavailable and unexplored. The California Teratogen Information Service (CTIS), established in 1983, and its corresponding Clinical Research Program represent the oldest national program directed at identifying pregnancy risk factors and exposures associated with adverse pregnancy outcome, including behavioral dysfunction. In recognition of the rising rates of developmental disorders involving compromised mental ability, in 2007, CTIS committed to the development of a more comprehensive screening program designed to detect relationships between adverse prenatal exposures and compromised human neurobehavioral development. The "CTIS Womb to Classroom Screening Program for the Detection of Agents with Adverse Effects on Neuropsychological Development" is the first program designed to identify agents not yet known to be of concern.

Reliability and validity of the 4-item perceived stress scale among pregnant women: results from the OTIS antidepressants study.

We aimed to estimate the reliability of the 4-item Perceived Stress Scale (PSS) and its validity in predicting maternal depression and quality of life (QoL). Data regarding stress, depression and QoL were collected during pregnancy among a sub-sample from the Organization of Teratology Information Specialists Antidepressants in Pregnancy Cohort. The 4-item PSS demonstrated acceptable internal consistency (Cronbach's alpha coefficient = .79), alternate forms stability reliability with the 10-item PSS (Pearson correlation coefficient r = .63; p < .001), convergent validity with the Edinburgh Postnatal Depression Scale (r = .67; p < .001), and concurrent validity with the mental health component of the Short-Form-12 (r = -.62; p < .001) as a measure of QoL. The 4-item PSS is a valid and useful tool for assessing maternal stress during pregnancy.

Breastfeeding among women exposed to antidepressants during pregnancy.

This prospective cohort study compares the breastfeeding outcomes of women exposed to selective serotonin reuptake inhibitor (SSRI) antidepressants at the time of delivery, those who discontinued use prior to delivery, and those not exposed. Participants include 466 pregnant women who enrolled in the California Teratogen Information Service Clinical Research Program (CTIS) over 10 years. In bivariate analyses, breastfeeding rates were significantly different across SSRI exposure groups, with unexposed women having the highest rates. We used logistic regression to examine the relationship between SSRI exposure and breastfeeding outcomes. After adjustment for potential confounders, those exposed to an SSRI both prior to delivery (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.20-0.94) and at the time of delivery (OR, 0.34; 95% CI, 0.16-0.72) were significantly less likely to initiate breastfeeding as compared to unexposed women. Women exposed to an SSRI during pregnancy appear to be at risk for poorer breastfeeding outcomes and may benefit from additional education and support.

Prenatal alcohol exposure patterns and alcohol-related birth defects and growth deficiencies: a prospective study.

BACKGROUND: The physical features of fetal alcohol syndrome include smooth philtrum, thin vermillion border, short palpebral fissures, microcephaly, and growth deficiencies on weight and height. However, little is known about the specific quantities of alcohol exposure, pattern of drinking, timing of exposure, and magnitude of risk for each of these features. METHODS: Using data on 992 subjects collected prospectively in California between 1978 and 2005, we examined the patterns and timing of alcohol exposure in relation to these features. Structural features were assessed by a dysmorphologist who performed a blinded physical examination of all infants. Patterns of drinking were evaluated by drinks per day, number of binge episodes, and maximum number of drinks. Timing of exposure was evaluated 0 to 6 weeks postconception, 6 to 12 weeks postconception, first trimester, second trimester, and third trimester. RESULTS: Higher prenatal alcohol exposure in every pattern was significantly associated with the incidence of smooth philtrum but not with short palpebral fissures. The strongest associations were with timing of exposure in the second half of the first trimester (RR 1.25, 95% CI 1.14 to 1.36 for average number of drinks per day; RR 1.17, 95% CI 1.09 to 1.26 for maximum number of drinks in 1 episode). Similarly, thin vermillion border was most strongly associated with exposure in the second half of the first trimester. Findings with respect to timing of exposure were similar for microcephaly and reduced birth weight. However, reduced birth length was increased with exposure in any trimester. These associations were linear, and there was no evidence of a threshold. CONCLUSIONS: Reduced birth length and weight, microcephaly, smooth philtrum, and thin vermillion border are associated with specific gestational timing of prenatal alcohol exposure and are dose-related without evidence of a threshold. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy.

Patterns of prenatal alcohol exposure and associated non-characteristic minor structural malformations: a prospective study.

The characteristic facial features of the more severe end of Fetal Alcohol Spectrum Disorders (FASD) include smooth philtrum, thin vermillion of the upper lip, and short palpebral fissures. A systematic evaluation of a comprehensive list of minor structural defects in association with varying patterns of prenatal exposure to alcohol has not been performed. We examined the patterns and timing of prenatal alcohol exposure to minor structural malformations occurring in at least 5% of the sample. Patterns of drinking were evaluated by drinks per day, number of binge episodes, and maximum number of drinks. Timing of exposure was evaluated 0-6 weeks post-conception, 6-12 weeks post-conception, first trimester, second trimester, and third trimester. Naevus flammeus neonatorum is significantly associated with various patterns of drinking during the second half of the first trimester (RR 1.14, 95% CI 1.04, 1.24 for average number of drinks per day; RR 1.04, 95% CI 1.02, 1.07 for number of binge episodes; RR 1.08, 95% CI 1.01, 1.15 for maximum number of drinks in one episode) and similar for number of binge episodes in all categories of timing of exposure and in the second trimester for average number of drinks per day. Other minor malformations occurring in at least 5% of the sample were not found to be significantly associated with prenatal alcohol exposure. Expected minor malformations were not found to be significantly associated with prenatal alcohol exposure. Naevus flammeus neonatorum appears to be part of the spectrum of features associated with prenatal alcohol exposure.

Prenatal exposure to mycophenolate mofetil: an updated estimate.

Mycophenolate mofetil (MMF) has become a major therapeutic option in the management of patients undergoing transplantation, as well as in the treatment of autoimmune conditions. Case reports have suggested that MMF use during pregnancy is associated with a specific pattern of congenital malformations. Because many pregnancies are unplanned, it is imperative to assess the teratogenic risk of MMF. Using the Organization of Teratology Information Specialists network, we prospectively identified and followed pregnant women exposed to MMF during pregnancy to update this teratogenic potential. Ten cases were identified and all received the drug during embryogenesis at the recommended doses (500 to 1500 mg daily). There were four miscarriages and one elective abortion due to fear of teratogenesis. None of the five live births had malformations. It is possible that, similar to other human teratogens discovered first by case reports, the absolute risk from MMF may be smaller than originally calculated based on case reports. Because the major malformations phenotypic of MMF may be visualized in utero (e.g., microtia, cleft palate, congenital diaphragmatic hernia, and cardiac malformation), diagnostic imaging should be performed.

Prevalence of periconceptional folic acid use and perceived barriers to the postgestation continuance of supplemental folic acid: survey results from a Teratogen Information Service.

BACKGROUND: Fewer than 40% of U.S. women are taking folic acid supplements periconceptionally at a time when the risk of neural tube defects (NTDs) can be reduced by supplementation. A better understanding of the vitamin-taking habits of childbearing-age women and effective methods for improving periconceptional supplement use are needed. METHODS: A telephone survey conducted through the California Teratogen Information Service (TIS) between August 2003 and January 2004 assessed the prevalence and characteristics of pregnant callers who did not use folic acid supplements in the periconceptional period, and explored attitudes toward advice to continue vitamin use following pregnancy in order to be protected in a future pregnancy. RESULTS: A total of 327 pregnant women who called the TIS for information agreed to participate in the survey. More than half (53.2%) were not taking folic acid-containing supplements in the periconceptional period. Predictors of lack of use included a higher prepregnancy body mass index, younger maternal age, non-white race/ethnicity, lower education level, and unplanned pregnancy. One-quarter of the women said they would be willing to continue taking vitamins after the pregnancy if advised to do so by a physician. The remainder identified obstacles to following that advice--notably, not planning to become pregnant again and the belief that enough folate is derived from diet alone. CONCLUSIONS: More than half of the callers to the TIS were not compliant with recommendations regarding periconceptional folic acid supplementation. This represents an opportunity for TIS specialists and physicians to intervene in a current pregnancy to encourage maintenance of supplement use in the subsequent interpregnancy interval.

Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy.

Topical tretinoin (Retin-A) is used to treat acne and photodamaged skin. Its teratogenic potential is of concern due to its similarity to isotretinoin (Accutane), a recognized human teratogen. Through the California Teratogen Information Service and Clinical Research Program, between 1983 and 2003, 106 pregnant women with first-trimester exposure to topical tretinoin were prospectively ascertained and followed. Birth outcomes, including pregnancy loss, major structural defects, and pre- and postnatal growth were compared to 389 similarly and prospectively ascertained women with no topical tretinoin exposure during pregnancy. Because a distinct pattern of malformation had already been described for isotretinoin, we also compared exposed (n = 62) and unexposed (n = 191) infants on the prevalence of a specific subset of minor malformations selected to represent the spectrum of defects comprising the retinoic acid embyopathy. There were no significant differences between groups in the proportion of pregnancies ending in spontaneous abortion (6.6% in exposed vs. 8.5% in unexposed; P = 0.53), or infants with major structural defects (2.2% in exposed vs. 1.2% in unexposed; P = 0.62). In addition, the groups were similar in birth weight, length and head circumference, and there were no significant differences between groups in length of gestation. Furthermore, the prevalence of one or more retinoic acid-specific minor malformations did not differ significantly between groups (12.9% in exposed vs. 9.9% in unexposed; P = 0.51). First-trimester topical tretinoin exposure in this study was not associated with an increased risk of any adverse pregnancy outcome evaluated. Specifically, there was no indication that topical tretinoin is associated with an increased risk for minor malformations that are consistent with the retinoic acid embryopathy. Although it is impossible to exclude the possibility that some women/infants may be uniquely susceptible to topical tretinoin exposure, this study provides further reassurance for women who are inadvertently exposed early in pregnancy.

Pregnancy outcomes after first trimester exposure to phentermine/fenfluramine.

BACKGROUND: Fenfluramine was withdrawn from the U.S. market in 1997 because of its association with cardiac-valve abnormalities in adults. The combination of fenfluramine and phentermine had been widely used to promote weight loss, and many women were inadvertently exposed during the first trimester of pregnancy. The possible effect on the developing fetus has not been studied. METHODS: Controlled prospective cohort study comparing 98 women who had taken phentermine/fenfluramine to 233 women who had not, all of whom contacted the California Teratogen Information Service during pregnancy. RESULTS: The proportion of liveborn infants with major structural anomalies was similar in the two groups (3.6% vs. 1.0%, relative risk (RR) 3.59; 95% confidence interval (CI) 0.61, 21.10), as was the proportion of infants with >or=3 minor anomalies (11.7% vs. 7.6%, RR 1.53; 95% CI 0.61, 3.82). Furthermore, no pattern of malformation was identified. There were no significant differences between the groups in spontaneous pregnancy loss (6.1% vs. 8.2%, P = 0.65) or premature delivery (8.6% vs. 7.7%, P = 0.95). Birth weight and head circumference were significantly increased in the exposed group; however, these differences were not associated with anorexiant use itself. The rate of gestational diabetes was significantly increased in pregnant women who took phentermine/fenfluramine during the first trimester of pregnancy. CONCLUSIONS: Although it is not possible from this study to rule out weak to moderate associations, the lack of an increased risk of spontaneous pregnancy loss, and major or minor anomalies in the offspring of women who took phentermine/fenfluramine at the recommended daily dose during the first trimester of pregnancy is reassuring.