Zoloftbirthdefectslawyers.com

First-Trimester Use of Selective Serotonin-Reuptake Inhibitors Carol Louik, Sc.D., Angela E. Lin, M.D., Martha M. Werler, Sc.D., Sonia Hernández-Díaz, M.D., Sc.D., Background
The risk of birth defects after antenatal exposure to selective serotonin-reuptake From the Slone Epidemiology Center at
Boston University (C.L., M.M.W., S.H.-D., inhibitors (SSRIs) remains controversial.
A.A.M.), the Genetics Unit, Massachu-setts General Hospital for Children (A.E.L.), and the Department of Epidemi-ology, Harvard School of Public Health We assessed associations between first-trimester maternal use of SSRIs and the risk (S.H.-D.) — all in Boston. Address reprint of birth defects among 9849 infants with and 5860 infants without birth defects requests to Dr. Louik at the Slone Epide- participating in the Slone Epidemiology Center Birth Defects Study.
miology Center, 1010 Commonwealth Ave., Boston, MA 02215, or at [email protected].
Results
In analyses of defects previously associated with SSRI use (involving 42 comparisons), N Engl J Med 2007;356:2675-83.
Copyright 2007 Massachusetts Medical Society. overall use of SSRIs was not associated with significantly increased risks of cranio- synostosis (115 subjects, 2 exposed to SSRIs; odds ratio, 0.8; 95% confidence interval [CI], 0.2 to 3.5), omphalocele (127 subjects, 3 exposed; odds ratio, 1.4; 95% CI, 0.4 to 4.5), or heart defects overall (3724 subjects, 100 exposed; odds ratio, 1.2; 95% CI, 0.9 to 1.6). Analyses of the associations between individual SSRIs and specific de- fects showed significant associations between the use of sertraline and omphalocele (odds ratio, 5.7; 95% CI, 1.6 to 20.7; 3 exposed subjects) and septal defects (odds ratio, 2.0; 95% CI, 1.2 to 4.0; 13 exposed subjects) and between the use of paroxetine and right ventricular outflow tract obstruction defects (odds ratio, 3.3; 95% CI, 1.3 to 8.8; 6 exposed subjects). The risks were not appreciably or significantly increased for other defects or other SSRIs or non-SSRI antidepressants. Exploratory analyses involving 66 comparisons showed possible associations of paroxetine and sertraline Conclusions
Our findings do not show that there are significantly increased risks of craniosyn-
ostosis, omphalocele, or heart defects associated with SSRI use overall. They suggest that individual SSRIs may confer increased risks for some specific defects, but it should be recognized that the specific defects implicated are rare and the absolute n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Symptoms of clinical depression af- identified from statewide birth-defect registries. fect 8 to 20% of women1,2; during pregnan- Infants with isolated minor defects (e.g., accessory cy, about 10% of women are affected,3 and nipples, dislocatable hips, and low-set ears) are many of these women are treated with antidepres- excluded. Nonmalformed infants were identified sants. In the late 1980s, a new class of antide- at study hospitals until 1998; subsequently, enroll- pressants, selective serotonin-reuptake inhibitors ment was expanded to include a population-based (SSRIs), appeared and rapidly gained widespread random sample of newborns in Massachusetts. acceptance because they have fewer side effects This study has been approved by the institutional than the older tricyclic antidepressants and pose review boards at Boston University and other par- less risk when taken in overdose.4 However, con- ticipating institutions.
cern has been raised about their potential effects Mothers of identified infants are invited to on the fetus. Neonatal effects, known as “SSRI participate by completing a 45-to-60-minute inter- neonatal withdrawal syndrome” or “SSRI absti- view (in person until 1998 and by telephone there- nence syndrome,”5-9 are now well established, but after) within 6 months after delivery, conducted the relation of antenatal SSRI exposure to birth by trained study nurses who are unaware of the study hypotheses. Oral informed consent is ob- Early studies9-15 demonstrated that SSRIs were tained from the mothers. The interview elicits not “major teratogens” similar to thalidomide or information on demographic, reproductive, and isotretinoin.16 More recently, however, elevated medical factors, cigarette smoking, and the con- risks of birth defects overall,17,18 as well as elevat- sumption of alcohol and caffeine. Detailed data ed risks of omphalocele,19 craniosynostosis,19 and are collected on all medications (prescription, congenital heart defects,18,20-22 have been report- over-the-counter, vitamins and minerals, and ed in association with the use of SSRIs. One study herbal products) used at any time from 2 months specifically identified paroxetine as increasing before conception through the end of the preg- the risk of omphalocele,19 and three have associ- nancy.
ated this SSRI with congenital heart defects.20-22 Using a multilevel approach,25 we first ask However, none of these studies considered risks women whether they had any of a list of spe- of cardiac defects in relation to other specific cific illnesses during pregnancy and what drugs SSRIs. Using data from the Slone Epidemiology they used to treat those conditions. We then ask Center Birth Defects Study, an ongoing program about use of medications for specific indications, of case–control surveillance of medications in re- including “anxiety,” “depression,” and “other psy- lation to birth defects, we evaluated these hypoth- chological conditions.” Finally, independent of eses and also considered other specific birth de- their responses to the previous questions, each fects in relation to first-trimester use of specific woman is asked about her use of named medica- tions, identified by brand name, including Prozac (fluoxetine), Zoloft (sertraline), Paxil (paroxetine), Effexor (venlafaxine), Elavil (amitriptyline), Celexa (citalopram), Luvox (fluvoxamine), Lexapro (esci- Study Design
talopram), and Wellbutrin (bupropion).
The Birth Defects Study began in 1976, focusing The current analysis was restricted to women both on testing existing hypotheses and on iden- whose last menstrual period occurred between tifying previously unsuspected associations; the January 1, 1993, and December 31, 2004. We ex- methods have been described.23,24 Infants with cluded subjects whose infants had chromosomal any of a wide range of malformations are identi- defects, known mendelian inherited disorders, fied in five study centers that include the areas syndromes, defects with a known cause (e.g., surrounding Boston, Philadelphia, Toronto, and fetal alcohol syndrome), and metabolic disorders San Diego, as well as a portion of New York State. (e.g., phenylketonuria and glucose-6-phosphate Research staff identify subjects by reviewing clini- dehydrogenase deficiency). Among subjects, 22.7% cal and surgical logs, reviewing admission and of mothers and 25.4% of controls declined to discharge lists, and contacting newborn nurseries participate. Another 15.6% of mothers and 14.7% and labor and delivery rooms. Subjects in New of controls either did not respond to repeated York State and, since 1998, in Massachusetts are contacts or were unavailable for interview.
n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. first-trimester SSRIs and risk of Birth Defects Assessment of Previously Reported
which an apparent association between an out- Associations
come and medication is actually due to the con- Previous reports have associated craniosynostosis, dition for which the medication is used, we also omphalocele, and congenital heart defects with investigated exposure to non-SSRI antidepressants the use of SSRIs. Because heart defects represent (e.g., tricyclic antidepressants, bupropion, and ven- developmentally diverse outcomes, we created lafaxine; the latter has both serotonin and nor- seven developmentally based subgroups.26 In order epinephrine activity and represented 20% of this of embryologic development, these are looping, group). The reference group for all analyses was laterality, and single-ventricle defects (e.g., situs women not exposed to any antidepressant at any inversus totalis and double-inlet left ventricle); time from 56 days before the last menstrual peri- conotruncal defects (e.g., tetralogy of Fallot and od through the end of pregnancy. To avoid mis- double-outlet right ventricle); atrioventricular ca- classification, we excluded women whose only nal defects (e.g., endocardial cushion defect and exposure to antidepressants was between 28 and common atrioventricular canal defect); right ven- 56 days before the last menstrual period or after tricular outflow tract obstruction (e.g., pulmonary lunar month 4.
valve atresia or stenosis and Ebstein’s anomaly); left ventricular outflow tract obstruction (e.g., statistical Analysis
aortic valve atresia or stenosis and hypoplastic left Odds ratios and 95% confidence intervals were heart); septal defects (e.g., ventricular septal de- calculated separately for each exposure and out- fect and atrial septal defect); and total or partial come by multiple logistic regression. To assess anomalous pulmonary venous return. A complete confounding, we explored factors that were asso- list is provided in the Supplementary Appendix, ciated with exposure to any SSRI and to the risk available with the full text of this article at www. of birth defects overall, including maternal age, maternal race or ethnic group (self-reported), ma- A clinical geneticist trained in pediatric cardi- ternal education, year of last menstrual period, ology reviewed the International Classification of Dis- parity, study center, first-trimester smoking, first- eases, Ninth Revision, Clinical Modification (ICD-9-CM), trimester alcohol consumption, history of a birth codes of each case and, where possible, assigned defect in a first-degree relative, prepregnant body- the case to one or more of the seven groups. mass index, seizures, diabetes mellitus, hyperten- Cases were assigned to as many of these catego- sion, infertility, and first-trimester use of folic ries as their ICD codes would indicate, but in acid. Because some birth defects have been asso- some situations, considerations of developmental ciated with obesity,27-30 we also explored effect processes took precedence. For example, a case modification by body-mass index for each outcome with anomalous pulmonary venous return and a with an increased risk. No statistical adjustment septal defect, along with the additional diagnosis was made for multiple testing.
of asplenia, was assigned to the developmentally appropriate category of “laterality defect.” exploratory analyses
A total of 9849 infants with malformations and In addition to the defects previously associated 5860 control infants were included in the analysis. with SSRIs, we examined other specific defects Among outcomes previously reported to be asso- that were present in at least 100 subjects overall ciated with SSRI use, there were 127 cases of omphalocele, 115 cases of craniosynostosis, and 3724 cases of congenital heart defects; the latter Exposure
included 186 looping or laterality defects, 620 We considered first-trimester exposure to include conotruncal defects, 164 atrioventricular defects, use of any SSRI from 28 days before the last men- 363 right ventricular outflow tract obstruction strual period through the fourth lunar month defects, 482 left ventricular outflow tract obstruc- (112 days after the last menstrual period). The tion defects, 1161 septal defects, and 17 cases of analysis of specific SSRIs excluded 79 women who anomalous pulmonary venous return.
took more than one SSRI during this period. To For exploratory analyses, we identified 17 diag- consider possible “confounding by indication,” in nosis groups that had 100 or more subjects. Six n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e groups were excluded from further analysis be- Assessment of Previous Hypotheses
cause they had fewer than 5 subjects who had Table 2 shows the results for the 42 comparisons been exposed to an SSRI: esophageal atresia (189 related to craniosynostosis, omphalocele, congen- subjects, 4 exposed), absent kidney (178 subjects, ital heart defects, and the four specific cardiac- 4 exposed), horseshoe or accessory kidney (127 defect groups, adjusted for potential confounders.
subjects, 4 exposed), abnormal intestinal rotation There was no significant increase in the risk of (149 subjects, 3 exposed), cystic kidney (179 sub- craniosynostosis associated with the use of SSRIs jects, 2 exposed), and small intestinal atresia (129 overall or with individual SSRIs; only 2 of 115 subjects with craniosynostosis had been exposed Table 1 shows the rates of exposure to any to an SSRI (1 to sertraline and 1 to paroxetine). SSRI, specific SSRIs, and non-SSRI antidepres- For omphalocele, 3 of 127 subjects had been ex- sants for each outcome and for the control sub- posed to an SSRI, all to sertraline (odds ratio, 5.7; jects, who had no malformations. Because few 95% confidence interval [CI], 1.6 to 20.7).
subjects had been exposed to fluvoxamine (five We found no appreciable or significantly in- subjects) and escitalopram (eight subjects), these creased risk of congenital heart defects overall medications were not considered further. Similar- in relation to the use of SSRIs overall (odds ratio, ly, we did not analyze looping and laterality de- 1.2; 95% CI, 0.9 to 1.6). However, when we as- fects (two SSRI-exposed subjects), atrioventricular sessed associations between specific heart-defect canal defects (no SSRI-exposed subjects), and subgroups and individual SSRIs, the odds ratios anomalous pulmonary venous return (no SSRI- ranged from 0.5 to 3.3, and two risk estimates had lower bounds that exceeded 1.0: sertraline Table 1. Rates of Exposure to Antidepressants within Outcome Groups.
Total No.
Non-SSRI
of Subjects
Fluoxetine
Sertraline
Paroxetine
Citalopram
Antidepressant
n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. first-trimester SSRIs and risk of Birth Defects Table 2. Adjusted Odds Ratios and 95% Confidence Intervals for Specific SSRIs in Relation to Outcomes Previously Reported to Be
Associated with SSRI Use.*
Non-SSRI
Fluoxetine
Sertraline
Paroxetine
Citalopram
Antidepressant
odds ratio (95% confidence interval) * Odds ratios are adjusted for maternal age; maternal race or ethnic group (self-reported); maternal education; year of last menstrual period; study center; first-trimester smoking status; first-trimester alcohol consumption; history of a birth defect in a first-degree relative; prepreg- nancy body-mass index; parity; presence or absence of seizures, diabetes mellitus, hypertension, or infertility; and first-trimester use of folic acid. The reference group was all women not exposed to any antidepressant. Dashes indicate no exposed subjects.
in relation to septal defects (odds ratio, 2.0; 95% We also investigated effect modification by CI, 1.2 to 4.0, based on 13 exposed subjects) and body-mass index for associations with elevated paroxetine in relation to right ventricular outflow risks. Although there was a tendency for risks to tract obstruction defects (odds ratio, 3.3; 95% CI, be higher in overweight and obese women than 1.3 to 8.8, based on 6 exposed subjects). No ap- in women of normal weight, there were too few preciable or significantly increased risks were exposed women in each category to generate associated with fluoxetine (range of odds ratios, stable results (data not shown).
1.0 to 1.6), nor were there appreciable or signif- icant associations between non-SSRI antidepres- sants and any of the specific birth defects ex- Our analysis did not confirm previously reported associations between overall use of SSRIs and Exploratory Analyses
craniosynostosis, omphalocele, or heart defects Table 3 presents risk estimates for other birth de- as a group. Alwan et al.19 previously reported in- fects, adjusted for potential confounders. Among creased risks of craniosynostosis and omphalo- 66 comparisons, 4 had lower confidence bounds cele associated with maternal SSRI use and found that exceeded 1.0: sertraline in relation to anal paroxetine to be most strongly associated with atresia and limb-reduction defects (3 exposed sub- omphalocele. We did not replicate these findings: jects for each defect) and paroxetine in relation no infant with omphalocele and only one with to neural-tube defects and clubfoot (4 and 10 ex- craniosynostosis was exposed to paroxetine among posed subjects, respectively). One association, that our study population. The only significant asso- between paroxetine use and undescended testis, ciation we found between either of these two de- had a lower confidence bound of 1.0. For non- fects and the use of SSRIs was an association be- SSRI antidepressants, risk estimates ranged from tween sertraline use and omphalocele (odds ratio, 0.6 to 1.2, with one exception: an odds ratio of 2.2 5.7; 95% CI, 1.6 to 20.7), which was based on only for anal atresia, based on three exposed subjects three exposed subjects.
(lower 95% confidence bound, 0.6). For positive We did not find significantly increased risks associations, no mothers of exposed subjects of congenital heart defects overall associated with reported exposure to any suspected teratogenic overall use of SSRIs or of non-SSRI antidepres- sants. However, using an embryologically based n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 3. Adjusted Odds Ratios and 95% Confidence Intervals for Specific SSRIs in Relation to Outcomes Not Previously Reported to Be
Associated wtih SSRI Use.*
Non-SSRI
Fluoxetine
Sertraline
Paroxetine
Citalopram
Antidepressant
odds ratio (95% confidence interval) * Odds ratios are adjusted for maternal age; maternal race or ethnic group (self-reported); maternal education; year of last menstrual period; study center; first-trimester smoking status; first-trimester alcohol consumption; history of a birth defect in a first-degree relative; prepreg- nancy body-mass index; parity; presence or absence of seizures, diabetes mellitus, hypertension, or infertility; and first-trimester use of folic acid. The reference group was all women not exposed to any antidepressant. Dashes indicate no exposed subjects.
classification of heart defects, we found a dou- tified warrant particularly cautious interpretation. bling of the risk of septal defects associated with In the absence of preexisting hypotheses and the sertraline use (odds ratio, 2.0), based on 13 ex- presence of multiple comparisons, distinguishing posed subjects, and a tripling of the risk of right random variation from true elevations in risk is ventricular outflow tract obstruction defects asso- difficult. Despite the large size of our study over- ciated with paroxetine use (odds ratio, 3.3), based all, we had limited numbers to evaluate associa- on 6 exposed subjects. The latter finding is sup- tions between rare outcomes and rare exposures. ported by an odds ratio of 2.5, based on seven We included results based on small numbers of exposed subjects (95% CI, 1.0 to 9.6), identified exposed subjects in order to allow other research- by Alwan et al. in an article in this issue of the ers to compare their observations with ours, but Journal.31 These more detailed findings were de- we caution that these estimates should not be rived from two case–control surveillance studies interpreted as strong evidence of increased risks. with data sets large enough to consider both spe- On the basis of the magnitude of the risk estimate cific malformations and specific SSRIs.
and the number of exposed subjects, certain asso- Our observations of significant increases in ciations warrant further exploration: sertraline in the risk of selected cardiac defects with the use relation to anal atresia and limb-reduction de- of certain SSRIs may reflect different teratologic fects, and paroxetine in relation to neural-tube effects among specific drugs within a given phar- defects and clubfoot.
macologic class.32 For SSRIs, this possibility is Among all defects evaluated, we found that, supported by the fact that various class members for fluoxetine, no risk estimate exceeded 2.0 and have parent compounds and metabolites with dif- none had a lower confidence bound exceeding ferent pharmacologic characteristics.33-35 How- 1.0. For non-SSRI antidepressants, no risk esti- ever, we cannot rule out the possibility of chance mate exceeded 1.2, except for anal atresia, and associations, given the multiple comparisons per- the confidence interval for that estimate, based on three exposed subjects, did not exclude 1.0. The previously unreported associations we iden- On the other hand, sertraline and paroxetine were n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. first-trimester SSRIs and risk of Birth Defects associated with significant increases in specific as cardiac anomalies. The current study suggests birth defects, none of which were common to that specific SSRIs may increase the risk of spe- cific birth defects, and further studies will need Recall bias may be a concern, since mothers sufficient power to pursue these important clini- of infants with malformations may recall and re- cal questions. In the meantime, it is important to port exposures more completely than mothers of keep in perspective that the absolute risks of these the control subjects who had no malformations. rare defects are small. For example, the baseline However, we consider this unlikely, since antide- prevalences of anal atresia37 and right ventricular pressants are typically used on a regular basis for outflow tract obstruction defects26 are each esti- nontrivial indications, and recall of their use may mated to be about 5.5 cases per 10,000 live births; be less subject to such bias than medications used thus, even if a specific SSRI increased rates by a infrequently and more casually. Further, the use factor of four, the risk of having an affected child of a multilevel structured questionnaire to iden- would still be only 0.2%.
tify medication use should minimize recall bias25 The Slone Epidemiology Center Birth Defects Study was sup- and has been shown to elicit rates of use similar ported in part by grants from the National Institute of Child to estimates from marketing data.36 Moreover, Health and Human Development (HD27697) and the National the null effects we observed among the non- Heart, Lung, and Blood Institute (HL50763). Additional support was provided by Aventis and Sanofi Pasteur. This data analysis SSRI antidepressants argue against recall bias, was supported in part by a contract from GlaxoSmithKline, the and recall bias would not explain risks associated manufacturer of Paxil (paroxetine). Responsibility for this analy- with some individual SSRIs but not with others. sis and the manuscript rests solely with the authors.
Drs. Louik, Mitchell, and Werler report receiving support from Selection bias is unlikely, since mothers are invit- Sanofi Pasteur to identify rates of use of various vaccines in preg- ed to participate without knowledge of exposure. nancy. Dr. Mitchell reports participating (unpaid) in an advisory Detection bias is also unlikely, given the differ- committee for GlaxoSmithKline’s Lamotrigine Pregnancy Reg- istry and serving as principal investigator of the Isotretinoin ential effects of non-SSRIs as compared with spe- Survey (2002–2006), sponsored by Barr Pharmaceuticals, Ranbaxy cific SSRIs and variability in the effects among Laboratories, and Genpharm; all these companies manufacture generic forms of antidepressants included in this study. Dr. Werler reports participating in scientific advisory boards for Confounding by uncontrolled factors is always pregnancy registries of rheumatoid arthritis medications mar- possible in observational studies. We considered keted by Sanofi-Aventis, Abbott Laboratories, and Amgen. No a large number of relevant demographic, medical, other potential conflict of interest relevant to this article was and reproductive factors. A major potential con- We thank Dawn Jacobs, Fiona Rice, Rita Krolak, Kathleen founder is the effect of depression itself, unrelat- Sheehan, Karen Bennett Mark, Clare Coughlin, Nastia Dynkin, ed to drug treatment. However, the absence of Nancy Rodriquez-Sheridan, and Meghan Malone-Moses for their assistance in data collection and computer programming; the significantly increased risks of various birth de- staff of the Massachusetts Department of Public Health Center fects associated with the use of non-SSRI antide- for Birth Defects Research and Prevention, Charlotte Druschel pressants suggests that depression itself is un- and the New York State Health Department, and Christina Cham- bers and Kenneth Jones of the University of California, San Diego likely to be the cause of the defects studied. The (UCSD), as well as the medical and nursing staff at the following possibility that chance accounts for some or all participating hospitals for assistance with case ascertainment: of these results cannot be ruled out, especially in Baystate Medical Center, Beth Israel Deaconess Medical Center, Boston Medical Center, Brigham and Women’s Hospital, Brockton view of the many comparisons that were made in Hospital, Cambridge Hospital, Caritas Good Samaritan Medical these analyses (42 in assessing previously report- Center, Charlton Memorial Hospital, Boston Children’s Hospi- ed associations and 66 in exploratory analyses). tal, Emerson Hospital, Falmouth Hospital, Haverhill–Hale Hos- pital, Jordan Hospital, Kent Hospital, Lawrence General Hospital, For that reason, we place greater reliance on find- Lowell General Hospital, Melrose–Wakefield Hospital, Metro ings that are consistent with previous studies, West Medical Center–Framingham, Mt. Auburn Hospital, New and we await further research on newly reported England Medical Center, Newton–Wellesley Hospital, North Shore Medical Center, Rhode Island Hospital, Saints Memorial Medical Center, South Shore Hospital, Southern New Hampshire Our understanding of the risks to the fetus of Medical Center, St. Elizabeth’s Medical Center, St. Luke’s Hospi- SSRI use has evolved from initial small cohort tal, St. Vincent Hospital, University of Massachusetts Memorial Health Care, Women & Infants’ Hospital, Abington Memorial studies that ruled out major teratogenic risks to Hospital, Albert Einstein Medical Center, Alfred I. duPont Hos- more recent efforts that have raised questions pital for Children, Bryn Mawr Hospital, Chester County Hospi- about moderate overall increases in risk as well tal, Children’s Hospital of Philadelphia, Christiana Care Health Services, Community Hospital, Crozer–Chester Medical Center, as increases in broad categories of defects, such Doylestown Hospital, Frankford Hospital, Hahnemann University n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Hospital, the Hospital of the University of Pennsylvania, Lanke- London, St. Joseph’s Health Centre–Toronto, St. Joseph’s Health- nau Hospital, Lancaster General Hospital, Lehigh Valley Hospi- care–Hamilton, St. Michael’s Hospital, Sunnybrook & Women’s tal, Nanticoke Memorial Hospital, Pennsylvania Hospital, Sacred College Health Sciences Center, Toronto East General Hospital, Heart Hospital, St. Christopher’s Hospital for Children, St. Mary Toronto General Hospital, Trillium Health Center, William Osler Medical Center, Temple University Health Sciences Center, Read- Heath Centre, York Central Hospital, York County Hospital, Al- ing Hospital & Medical Center, Thomas Jefferson University Hos- varado Hospital, Balboa Naval Medical Center, Camp Pendleton pital, Grand River Hospital, Guelph General Hospital, Hamilton Naval Hospital, Children’s Hospital and Health Center, Kaiser Health Sciences Corporation, the Hospital for Sick Children, Zion Medical Center, Palomar Medical Center, Pomerado Hospi- Humber River Regional Hospital–Church Site, Humber River tal, Scripps Mercy Hospital, Scripps Memorial Hospital–Chula Regional Hospital–Finch Site, Joseph Brant Memorial Hospital, Vista, Scripps Memorial Hospital–Encinitas, Scripps Memorial Lakeridge Health Corporation, London Health Sciences Center, Hospital–La Jolla, Sharp Chula Vista Hospital, Sharp Coronado Mt. Sinai Hospital, North York General Hospital, Oakville Trafal- Hospital, Sharp Grossmont Hospital, Sharp Mary Birch Hospital, gar Memorial Hospital, Scarborough Hospital–General Division, Tri-City Medical Center, and UCSD Medical Center. We also thank Scarborough Hospital–Grace Division, St. Joseph’s Health Centre– all the mothers who participated in the study.
References
1. Kessler RC, McGonagle KA, Swartz M, 12. Chambers CD, Johnson KA, Dick LM, congenital heart defect. Reprod Toxicol
Blazer DG, Nelson CB. Sex and depres- Felix RJ, Jones KL. Birth outcomes in preg- 2006;21:221-2.
sion in the National Comorbidity Survey. nant women taking fluoxetine. N Engl J 23. Mitchell AA, Rosenberg L, Shapiro S,
I. Lifetime prevalence, chronicity and re- Med 1996;335:1010-5.
Slone D. Birth defects related to Bendec- currence. J Affect Disord 1993;29:85-96.
13. Ericson A, Kallen B, Wiholm B. Deliv-
tin use in pregnancy. I. Oral clefts and 2. Llewellyn AM, Stowe ZN, Nemeroff ery outcome after the use of antidepres-
cardiac defects. JAMA 1981;245:2311-4.
CB. Depression during pregnancy and the sants in early pregnancy. Eur J Clin Phar- 24. Werler MM, Hayes C, Louik C, Shapiro
puerperium. J Clin Psychiatry 1997;58: macol 1999;55:503-8.
14. Nulman I, Rovet J, Stewart DE, et al. tation and risk of birth defects. Am J Epi-
3. Bennett HA, Einarson A, Taddio A, Neurodevelopment of children exposed in demiol 1999;150:675-82.
Koren G, Einarson TR. Prevalence of de- utero to antidepressant drugs. N Engl J 25. Mitchell AA, Cottler LB, Shapiro S.
pression during pregnancy: systematic Med 1997;336:258-62.
Effect of questionnaire design on recall of review. Obstet Gynecol 2004;103:698-709. 15. Sivojelezova A, Shuhaiber S, Sarkissian drug exposure in pregnancy. Am J Epide-
L, Einarson A, Koren G. Citalopram use in miol 1986;123:670-6.
4. Committee on Drugs, American Acad-
pregnancy: prospective comparative evalu- 26. Ferencz CL, Correa-Villasenor A, Lof-
emy of Pediatrics. Use of psychoactive ation of pregnancy and fetal outcome. Am fredo CA, Wilson PD, eds. Perspectives in medication during pregnancy and possi- J Obstet Gynecol 2005;193:2004-9.
pediatric cardiology: genetic and environ- ble effects on the fetus and newborn. Pedi- 16. Mitchell AA. Systematic identifica- mental risk factors of major cardiovascu-
tion of drugs that cause birth defects — lar malformations. Armonk, NY: Futura 5. Cohen LS, Heller VL, Bailey JW, Grush a new opportunity. N Engl J Med 2003; Publishing, 1997.
L, Ablon JS, Bouffard SM. Birth outcomes 349:2556-9.
27. Anderson JL, Waller DK, Canfield MA,
following prenatal exposure to fluoxetine. 17. Epidemiology study: updated prelimi- Shaw GM, Watkins ML, Werler MM. Ma-
nary report on bupropion in pregnancy ternal obesity, gestational diabetes, and 6. Levinson-Castiel R, Merlob P, Linder and the occurrence of cardiovascular and central nervous system birth defects. Epi-
N, Sirota L, Klinger G. Neonatal absti- major congenital malformation. Glaxo- demiology 2005;16:87-92.
nence syndrome after in utero exposure SmithKline, 2005. (Accessed June 1, 2007, 28. Mikhail LN, Walker CK, Mittendorf R.
to selective serotonin reuptake inhibitors at http://www.gsk.com/media/paroxetine/ Association between maternal obesity and in term infants. Arch Pediatr Adolesc Med ingenix_study.pdf.) 18. Wogelius P, Norgaard M, Gislum M, Americans. J Natl Med Assoc 2002;94:695-
7. Malm H, Klaukka T, Neuvonen PJ. et al. Maternal use of selective serotonin 700.
Risks associated with selective serotonin reuptake inhibitors and risk of congeni- 29. Moore LL, Singer MR, Bradlee ML,
reuptake inhibitors in pregnancy. Obstet tal malformations. Epidemiology 2006;17: Rothman KJ, Milunsky A. A prospective 8. Sanz EJ, De-las-Cuevas C, Kiuru A, 19. Alwan S, Reefhuis J, Rasmussen S, associated with maternal obesity and dia-
Bate A, Edwards R. Selective serotonin re- Olney R, Friedman JM. Maternal use of betes mellitus. Epidemiology 2000;11:689- uptake inhibitors in pregnant women and selective serotonin re-uptake inhibitors 94.
neonatal withdrawal syndrome: a database and risk for birth defects. Birth Defects Res 30. Watkins ML, Rasmussen SA, Honein
A Clin Mol Teratol 2005;73:291. abstract.
9. Simon GE, Cunningham ML, Davis RL. 20. Cole JA, Ng EW, Ephross SA, Cosma-
sity and risk for birth defects. Pediatrics Outcomes of prenatal antidepressant expo- tos IS, Walker AM. Paroxetine in the first 2003;111:1152-8.
sure. Am J Psychiatry 2002;159:2055-61.
trimester of pregnancy and the prevalence 31. Alwan S, Reefhuis J, Rasmussen SA,
10. Pastuszak A, Schick-Boschetto B, Zu-
of congenital malformations. Pharmaco- Olney RS, Friedman JM. Use of selective ber C, et al. Pregnancy outcome follow- epidemiol Drug Saf 2006;15:S6. abstract.
serotonin-reuptake inhibitors in pregnan- ing first-trimester exposure to fluoxetine 21. Diav-Citrin O, Shechtman S, Wein- cy and the risk of birth defects. N Engl J
baum D, et al. Paroxetine and fluoxetine Med 2007;356:2684-92.
11. Kulin NA, Pastuszak A, Sage SR, et al. in pregnancy: a multicenter prospective, 32. Mitchell AA. Studies of drug-induced
Pregnancy outcome following maternal controlled study. Reprod Toxicol 2005;20: birth defect. In: Strom BL, ed. Pharmaco- use of the new selective serotonin reuptake 459. abstract.
inhibitors: a prospective controlled multi- 22. Kallen BAJ, Olausson PO. Antidepres- 2005:501-14.
sant drugs during pregnancy and infant 33. Hemeryck A, Belpaire FM. Selective
n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved. first-trimester SSRIs and risk of Birth Defects serotonin reuptake inhibitors and cyto- 35. Preskorn SH. Clinically relevant phar- lation to Bendectin use in pregnancy. II.
chrome P-450 mediated drug-drug inter- macology of selective serotonin reuptake Pyloric stenosis. Am J Obstet Gynecol actions: an update. Curr Drug Metab 2002; inhibitors: an overview with emphasis on 1983;147:737-42.
pharmacokinetics and effects on oxidative 37. Heinonen OP, Slone D, Shapiro S, et
34. Nemeroff CB, DeVane CL, Pollock BG. drug metabolism. Clin Pharmacokinet al. Birth defects and drugs in pregnancy.
Newer antidepressants and the cytochrome 1997;32:Suppl 1:1-21.
Littleton, MA: Publishing Sciences Group, P450 system. Am J Psychiatry 1996;153: 36. Mitchell AA, Schwingl PJ, Rosenberg 1977.
L, Louik C, Shapiro S. Birth defects in re- Copyright 2007 Massachusetts Medical Society. n engl j med 356;26 www.nejm.org june 28, 2007 Downloaded from www.nejm.org by ROBYN J. BARST MD on June 28, 2007 . Copyright 2007 Massachusetts Medical Society. All rights reserved.

Source: http://www.zoloftbirthdefectslawyers.com/wp-content/uploads/2011/06/First-Trimester-Use-of-Selective-Serotonin-Reuptake-Inhibitors.pdf