Table 1.

Cohort studies investigating association between antihistamines and birth defects included in systematic review (n=31)

Author, Year	Setting	Antihistamines studied	Comparison group	Exposure ascertainment	Birth defects outcomes	Total # pregnancies; # exposed; # unexposed	# Birth defects among exposed and unexposed	Measures of association
Aselton et al. 198525*	United States (Washington, Group Health Cooperative of Puget Sound), 1980-1982	Diphenhydramine, triprolidine + pseudoephedrine, chlorpheniramine, brompheniramine, promethazine; use during first trimester	Baseline risk in total cohort	Pharmacy claims data from Group Health Cooperative	Any major birth defect ascertained through hospital discharge data with medical record reviews for suspected cases; clinical geneticist review of selected records	Total pregnancies: 6,509; diphenhydramine: 270; triprolidine + pseudoephedrine: 244; chlorpheniramine: 175; brompheniramine + phenylephrine + phenylpropanolamine: 172; promethazine: 63; phenylpropanolamine + chlorpheniramine: 82	Diphenhydramine: 4/270 (1.5%); triprolidine + pseudoephedrine: 3/244 (1.3%); chlorpheniramine: 2/175 (1.1%); brompheniramine + phenylephrine + phenylpropanolamine: 5/172 (2.9%); promethazine: 0/63 (0%); phenylpropanolamine + chlorpheniramine: 2/82 (2.4%); baseline risk of birth defects: 16 per 1,000 (1.6%)	Not calculated
Ashkenazi-Hoffnung et al. 201320	Israel Teratogen Information Service, 2008-2010	Doxylamine + pyridoxine; use typically began during first trimester	Women taking metoclopramide	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure	Any major birth defect ascertained through follow-up interview with mothers up to two years after initial inquiry	Total pregnancies: 58 (59 infants); doxylamine + pyridoxine: 29; metoclopramide: 29	Doxylamine + pyridoxine: 0/29; metoclopramide: 1/29 (3.4%)	Not calculated
Asker et al. 200513	Sweden, 1995-2002	Meclizine; cyclizine; promethazine; diphenhydramine; use during first, second, and/or third trimester	Baseline risk in total cohort	Interview at first prenatal care visit (~10-12 weeks gestation) captured first trimester exposures; drugs prescribed during prenatal care were documented prospectively in medical record; analysis focused on first trimester use	Any major birth defect ascertained through record linkage with other national databases	Total pregnant women: 665,572 (676,198 infants); first trimester exposure: meclizine: 18,008; cyclizine: 1,221; promethazine:1,961; diphenhydramine: 147;	Any antiemetic: 3.1%; meclizine: 3.1%; cyclizine: 3.6%; promethazine: 3.2% diphenhydramine: 1.1% Baseline risk of birth defects: 3.5%;	Adjusted OR (95% CI) for exposure anytime during pregnancy and any birth defect: meclizine: 0.89 (0.82-0.96); cyclizine: 1.08 (0.86-1.35); promethazine: 0.91 (0.75-1.11); diphenhydramine: not calculated
Boskovic et al. 200421	Canada Teratogen Information Service (Motherisk), 2001-2003	Doxylamine + pyridoxine: standard dose and “supradose”; use typically began late in the first trimester (mean: 9 ± 2 weeks gestation) Note: Primary exposure of interest was lack of morning sickness	Pregnancies without NVP	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about first trimester exposure	Any major birth defect ascertained through postnatal follow-up interview with mother; maternal reporting of birth defects verified by written report requested from pediatrician	NVP + standard dose of doxylamine + pyridoxine: 122; NVP + “supradose” of doxylamine + pyridoxine: 124 No NVP: 130	NVP + standard dose of doxylamine + pyridoxine: 2/122 (1.6%); NVP + “supradose” of doxylamine + pyridoxine: 0/124; No NVP in pregnancy: 0/130	Not calculated
Bsat et al. 200328	United States (Clinical outpatient setting), 1994-1996	Promethazine; use typically began late in the first trimester (mean: 8.6 ± 2 weeks gestation)	Women taking B6-metoclopramide or prochlorperazine	Administered through randomized clinical trial	Any major birth defect; method of ascertainment not stated	Singleton pregnanices: 156; promethazine: 52 B6-metoclopramide: 54 prochlorperazine: 50	Promethazine: 0/52 B6-metoclopramide: 0/54;prochlorperazine: 1/50	Not calculated
Colin Jones et al. 198559	Scotland, 1978-1979	Cimetidine; use anytime during pregnancy	Unexposed to cimetidine	Prescriptions reported by general practitioners	Any “abnormal children” reported by general practitioners	Total pregnancies:42; cimetidine: 20; unexposed: 22	Cimetidine: 1/20 (5%); unexposed: 0/22	Not calculated
Diav-Citrin et al. 200329	Israel, Teratogen Information Service, 1995-2001 (loratadine exposure); 1990-2001 (comparison populations)	Loratadine; other antihistamines (astemizole, chlorpheniramine, terfenadine, hydroxyzine, promethazine);use during first trimester and anytime during pregnancy	Exposed to NTS	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure	Any major birth defect ascertained through postnatal follow-up interview with mother, typically within one year after delivery	Total pregnancies:1,406; loratadine: 210; OAH: 267; NTS: 929 [Note: these numbers differ from the number of exposed with pregnancy outcome information due to loss to follow-up]	Anytime during pregnancy: Loratadineloratadine: 4/175 (2.3%), OAH: 10/247 (4.0%), NTS: 25/844 (3.0%); During first trimester: loratadine: 1/126 (0.8%), OAH: 7/146 (4.8%), NTS:25/844 (3.0%)	Unadjusted RR (95% CI) for exposure anytime during pregnancy: loratadine vs. OAH: 0.56 (0.18-1.77); loratadine vs. NTS: 0.77 (0.27-2.19); for first trimester exposure: loratadine vs. OAH: 0.17 (0.02-1.33); loratadine vs. NTS: 0.27 (0.04-1.94)
Einarson et al. 199722	Canada Teratogen Information Service (Motherisk), 1989-1994;	Hydroxyzine, cetirizine; use during first trimester and entire pregnancy	Unexposed to antihistamines; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure	Any major birth defect ascertained through maternal self-report during postnatal follow-up telephone interview; outcomes of interest confirmed whenever possible by the child's pediatrician.	Hydroxyzine: 81 (43 with first trimester exposure and live births); cetirizine: 39 (33 with first trimester exposure and live births); unexposed: 120	Hydroxyzine: 2/43 (4.6%); cetirizine: 0/33; unexposed: 0/120	Not calculated
Erez et al. 197123	Turkey, 1967-1969	Hydroxyzine; administered twice daily for 3 weeks during first two months of pregnancy	Placebo	Administered through double-blind placebo controlled trial	Any major birth defect ascertained by study pediatrician and obstetrician examining each delivered infant within 40 hours after birth (115 out of 150 were followed up until delivery)	Total pregnancies: 150; hydroxyzine: 100; placebo: 50	Hydroxyzine: 1/100 (1%); placebo: 0/50	Not calculated
Garbis et al. 200560	European Network of Teratology Information Services (ENTIS), 1990-1997 for exposed cohort; 1990-1999 for unexposed cohort	H2-receptor antagonists: ranitidine (n=335), cimetidine (n=113); famotidine (n=75); nizatidine (n=15); roxatidine (n=15); use anytime during pregnancy though most were exposed during first trimester	Exposed to NTS	Self-reported through structured questionnaire; women (or their healthcare providers) called one of the 18 participating TIS because of question about exposure	Any major birth defect ascertained by each center through follow-up interview with the mother within a year of estimated date of delivery.	H2-receptor antagonists: 635; (lost to follow-up: 82; followed for pregnancy outcome: 553); NTS: 1,390	H2-receptor antagonists: 13/553 (2.7%); NTS: 44/1,390 (3.5%)	Unadjusted RR (95% CI) for H2-receptor antagonist use at any time during pregnancy and any major birth defect: 0.78 (0.42 - 1.44)
Jick et al. 198126*	United States (Washington, Group Health Cooperative of Puget Sound), 1977-1979	Triprolidine hydrochloride + pseudoephedrine hydrochloride; diphenhydramine; use during first trimester	Baseline risk in total cohort	Pharmacy records	Any major birth defect identified from hospital discharge codes; all potential cases had medical records review to confirm diagnosis	Total pregnancies: 6,837; triprolidine + pseudoephedrine: 384; diphenhydramine: 361	Triprolidine + pseudoephedrine: 6/384 (16 per 1,000); diphenhydramine: 1/361 (3 per 1,000); baseline risk of birth defects: 11.7 per 1,000 (1.2%)	Not calculated
Källén and Mottet, 200319	Sweden, 1995-2001	Meclizine; use during early pregnancy (~before 10-12 weeks gestation)	Unexposed to meclizine	Exposure during “early pregnancy” ascertained prospectively during prenatal care by midwives, typically by 10-12 weeks gestation	Spectrum of major birth defects ascertained through linkage with other national databases	Total pregnancies: 540,660 (549,569 infants); meclizine: 16,536	Meclizine: 524/16,536 (3.16%); prevalence among unexposed not stated	Unadjusted OR (95% CI) for any birth defect identified in the Medical Birth Registry: 0.91 (0.83-0.99); table 6 shows observed/expected analyses (RRs and 95% CIs) for several selected defects; none are significantly elevated or decreased; potential signals for anal atresia (2.29; 0.99-4.50) and body wall defect (2.33; 0.94-4.81)
Källén and Olausson, 200130‡	Sweden, 1995-2001	Loratadine; use during early pregnancy (~before 10-12 weeks gestation)	Baseline risk in total cohort	Exposure during “early pregnancy” ascertained prospectively during prenatal care by midwives; for cases, medical records were gathered to validate exposure though timing of loratadine use was not well-reported and unreliable.	Hypospadias as documented by ICD codes in the Swedish ; Registry of Congenital Malformations	Total pregnancies: 540,660 (549,569 infants); loratadine: 2,780	Loratadine: 15/2,780 (0.5%) baseline hypospadias prevalence: 1/500;	Adjusted OR (95% CI) for association between loratadine exposure and hypospadias: 2.39 (1.43-3.38) if the twins were counted separately and 2.27 (1.33-3.87) if the twins were counted as a single occurrence.
Källén and Olausson, 200631‡	Sweden, 1995-2004	Loratadine; use during early pregnancy (~before 10-12 weeks gestation)	Expected number of hypospadias cases in birth population exposed to loratadine	Exposure during “early pregnancy” ascertained prospectively during prenatal care typically by 10-12 weeks gestation by midwives	Hypospadias as documented by ICD codes in the Swedish Registry of Congenital Malformations and Hospital Discharge Register	Updating of 2001 analysis: loratadine (1995-2001): 2,780; loratadine (2002-2004): 1,911	Prevalence of hypospadias among women exposed to loratadine: 1995-2001: 25/2,780 (0.9 %), 2002-2004: 2/1,911(0.1%), 1995-2004 combined: 27/4,691 (0.6%); expected number of hypospadias cases in birth population exposed to loratadine: 1995-2001:12.5, 2002-2004:4.3; 1995-2004 combined: 16.8.	Calculated ratio of observed to expected (95% CI) using an exact Poisson distribution; for re-analysis of 1995-2001 data: 2.0 (1.29-2.95); for 2002-2004: 0.47 (0.06-1.68); for 1995-2004: 1.61 (1.04-2.34)
Källén, 199861	Sweden, 1995-1996	H2-receptor antagonists (included cimetidine, ranitidine, famotidine, nizatidine, cimetidine + famotidine, ranitidine + famotidine); use during early pregnancy (~before 10-12 weeks gestation)	Baseline risk in total cohort	Maternal self-report of medication used before first prenatal visit at 10-12 weeks gestation	Any major birth defect ascertained through linkages with several national registries	Acid-suppressing drugs: 547 pregnancies (553 infants); H2-antagonists only or H2-antagonists + proton pump inhibitors: 275 cimetidine (n=35), ranitidine (n=156), famotidine (n=58), nizatidine (n=3), cimetidine + famotidine (n=1), ranitidine + famotidine (n=2)	H2-receptor antagonists only: 6/255 (2.4%) Baseline birth defects prevalence: 3.9%;	Adjusted OR (95% CI) for H2-receptor antagonists use in first trimester and any major birth defect: 0.46 (0.17-1.20)
Källén, 200212	Sweden, 1995-1999	Wide array of first and second generation H1 receptor antagonists (see paper table 1 for complete list); use during early pregnancy (~ before 10-12 weeks gestation) Note: all analyses conducted by indication (NVP or allergy), not by medication	Baseline risk in total cohort	Exposure during “early pregnancy” ascertained prospectively during prenatal care by midwives (typically at 10-12 weeks gestation)	Spectrum of specific defects ascertained through linkage with other national databases	Total exposed pregnancies: 17,776 (18,197 infants)	Total birth defects among exposed: 579; NVP indication: 402; Allergy indication: 177 Baseline birth defects prevalence: 3.16%;	Unadjusted OR (95% CI); among those with NVP indication: association with all birth defects: 0.98 (0.89-1.09); “selected” major birth defects: 0.94 (0.83-1.07); congenital heart defects: 0.89 (0.71-1.11); specific congenital heart defects: 0.78 (0.60-1.01); among those with allergy indication: all birth defect: 1.03 (0.89-1.20); “selected” major birth defects: 1.06 (0.88-1.28); congenital heart defects: 0.89 (0.63-1.24); specific congenital heart defects: 0.81 (0.55-1.20) [Reported in paper table 5]; only association reported for a specific defect was for congenital hip subluxation (previously associated with promethazine [Kullander and Källén14]): 1.05 (0.83-1.32) for any antihistamine used for NVP and 0.77 (0.51-1.18) for any antihistamine used for allergy
Kullander and Källén, 197614	Sweden, 1963-1965	Promethazine, diphenhydramine, and meclizine; any “anti-emetic”; use during first trimester	No antiemetic use	Self-report	Any major birth defect as ascertained by pediatrician and documented in medical records up to one year after birth	Total pregnancies: 6,376; pregnancies with infant follow-up: 5,753: antiemetics: 778; promethazine: 617; prochlorperazine: 91; diphenhydramine: 46; meclizine: 19; no antiemetics: 4,975	Any antiemetic: 34/778 (4.4%); promethazine: 27/617 (4.4%); diphenhydramine: 3/46 (6.5%); meclizine: 0/19; no antiemetics: 166/4,975 (3.3%) (See table V for more detailed results)	Not calculated; authors noted increased risk of congenital diaphragmatic hernia associated with promethazine exposure
Lalkin et al. 199865	Canada, Italy (2) and France, Teratogen Information Services	“Histamine blockers”; any use during pregnancy [89% used in first trimester] Note: exposure of interest was omeprazole; exposure to “histamine blockers” was comparison exposure	Exposed to NTS; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) TIS because of question about exposure	Any major birth defect ascertained through maternal self-report during postnatal follow-up telephone interview	Exposure anytime during pregnancy: “Histamine blockers”: 113; NTS: 113 Exposure during first trimester and had live birth: “Histamine blockers”: 98; NTS: 66	“Histamine blockers”: 3/98 (3.1%); NTS: 2/66 (3.0%)	Not calculated; there was no significant difference in prevalence of birth defects among those exposed and unexposed to medications during pregnancy
Loebstein et al. 199932	Canada (Motherisk) and Italy, Teratogen Information Services	Terfenadine; use during first trimester and entire pregnancy	Exposed to NTS; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) called Canada or Italy TIS because of question about exposure	Any major birth defect ascertained through maternal self-report during postnatal follow-up telephone interview; outcomes of interest confirmed in writing by the child's pediatrician.	Terfenadine: 118 from both Canada (102) and Italy (16); first trimester exposure: 65; unexposed: 118	Terfenadine: 0/65; unexposed: 2/111 (1.8%)	Matched RR (95% CI); association between first trimester terfenadine exposure and any major birth defect: 0.57 (0.06-5.39)
Magee et al. 199662	Canada Teratogen Information Service (Motherisk), 1985-1993	H2-receptor antagonists (ranitidine, cimetidine, famotidine, nizatidine); use during first trimester	Exposed to NTS; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure.	Any major birth defect ascertained in interview with mother within one year after delivery	H2-receptor antagonists: 142 live births; NTS: 143	H2-receptor antagonists: 3/142 (2.1%); NTS: 5/143 (3.5%)	Risk difference (95% CI) comparing frequency of birth defects among users of H2-receptor antagonists during the first trimester and NTS: −1.4% (−5.2%, 2.4%)
Matok et al. 201063	Israel (Southern District), 1998-2007	H2-receptor antagonists (famotidine, ranitidine, cimetidine), alone and in combination; use during first trimester	Unexposed to H2-receptor antagonists (or to famotidine, ranitidine, or cimetidine)	Prescription records	Any major birth defect, excluding those with chromosomal malformations	Total pregnancies: 84,823; H2-receptor antagonists: 1,148; famotidine: 878; ranitidine: 276	H2-receptor antagonist: 65/1,148 (5.7%) vs.unexposed to H2-receptor antagonist: 4,400/83,675 (5.3%); famotidine: 58/878 (6.6%) vs.unexposed to famotidine: 4,407/83,945 (5.2%); ranitidine: 6/276 (2.2%) vs. unexposed to ranitidine: 4,459/84,547 (5.3%)	Adjusted OR (95% CI) for association between H2-receptor antagonist use in the first trimester and major birth defects: any use: 1.03 (0.80-1.32); famotidine: 1.21 (0.92-1.58); ranitidine: not calculated (fewer than 7 birth defects noted)
McBride, 196915	Austraila (Sydney), 1956-1961	Cyclizine; use during first trimester	Unexposed to cyclizine	Not stated	CPO	Total pregnancies: 25,333; first trimester use of cyclizine: 1,125; unexposed: 24,208; women with NVP and unexposed: 1,100	CPO among first trimester users of cyclizine: 5/1125 (4.4/1,000); CPO among unexposed: 19/24,208 (0.78/1,000); CPO among women with NVP (and unexposed): 4/1,100 (3.64/1,000)	Not calculated; among individuals with NVP, there was no significant difference in prevalence of CPO among those exposed and unexposed to cyclizine in the first trimester
Michaelis et al. 198324*	Germany, 1964-1972	Miscellaneous antiemetics (meclizine, triflupromazine, dimenhydrinate, chlorpheniramine); use during first trimester	Unexposed to antiemetics; unexposed matched to exposed on several potential confounders	Self-report and report by physician	Major, minor, other abnormalities ascertained from pediatric records; suspected cases underwent clinical review by panel of physicians	Total pregnancies: 13,643; miscellaneous antiemetics: 628; unexposed: 628	Miscellaneous antiemetics: 11/628; Unexposed: 12/628	Matched OR (90% CI) for miscellaneous antiemetic use in the first trimester and any birth defect: 0.92 (90% CI: 0.42, 2.00)
Milkovich and van den Berg, 197616†	United States (Northern California, Kaiser Permanente), 1959-1966	Meclizine, cyclizine; use during first trimester use and throughout pregnancy	Women with NVP but no prescription for treatment of condition	Medical record reviewed to identify first trimester prescriptions	Any major birth defect	Total pregnancies: 11,481; use of meclizine in the first trimester: 613; use of cyclizine in the first trimester: 111; NVP but no prescription for NVP medications: 4,353	Prevalence of birth defects identified by 1 month, 1 year and 5 years of age: Meclizine use in first trimester: 2.0%, 2.9%, 4.1%; cyclizine use in first trimester: 1.8%, 1.8%, 3.7%; among those with NVP but no medication use:1.5%, 2.2%, 3.2%	Not calculated; there were no significant differences in prevalence of birth defects comparing those with meclizine or cyclizine use in the first trimester with the unmedicated group
Moretti et al. 200333	Canada, Italy, Israel, Brazil Teratogen Information Services (dates not stated)	Loratadine; use during first trimester	NTS; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure	Any major birth defect ascertained through maternal self-report during postnatal follow-up telephone interview; outcomes of interest confirmed in writing by the child's pediatrician.	Total pregnancies: 322; loratadine: 161; NTS: 161	Loratadine: 5/143 (3.5%); NTS: 6/150 (4.0%)	Not calculated by authors, p-value of 0.95 provided; RR (95% CI) for comparison of proportion of exposed and unexposed with major birth defect: 0.87 (0.26-2.91) (calculated via EpiSheet)
Pastuszak et al. 199634	Canada and United States (Philadelphia) Teratogen Information Services, 1989-1994	Astemizole; use during first trimester	NTS; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure	Any major birth defect ascertained through maternal self-report during postnatal follow-up telephone interview	Astemizole: 114; NTS: 114	Astemizole: 2/114 (1.8%) (one case of hypospadias and one case of spina bifida occulta); unexposed: 2/114 (1.8%) (one case of ventricular septal defect and one case of ocular myopathy)	Not calculated; there was no significant differences in prevalence of birth defects among those exposed and unexposed in the first trimester
Ruigómez et al. 199964	United Kingdom and Italy, 1991-1996	Cimetidine, ranitidine; use from 30 days before LMP date to 100 days after the LMP date	Unexposed to cimetidine, ranitidine, or omeprazole	Ascertained from medical records (United Kingdom) or prescriptions (Italy); women receiving more than one acid-suppressing drug during the first trimester were excluded from analysis	Any major or minor birth defect identified through general practitioners' records (United Kingdom) or hospital discharge data (Italy)	In both cohorts combined: liveborn infants: 2,261; stillbirths: 20; cimetidine: 237; ranitidine: 330; unexposed: 1,575	United Kingdom cohort: cimetidine: 9/227 (4%); ranitidine: 17/229 (7.4%), unexposed: 37/651 (5.7%); Italy cohort: cimetidine: 2/10 (20%); ranitidine: 3/101 (3%); unexposed: 27/924 (2.9%)	Adjusted RR (95% CI) for medication use in the first trimester and any birth defect (in both cohorts combined): cimetidine: 1.3 (0.7-2.6), ranitidine: 1.5 (0.9-2.6)
Schatz et al. 199727	United States (California, Kaiser-Permanente Prospective Study of Asthma During Pregnancy), 1978-1989	Chlorpheniramine, tripelenamine or other antihistamine (not otherwise specified); use during first trimester and throughout pregnancy	Unexposed to chlorpheniramine tripelennamine, or other antihistamines; unexposed matched to exposed on several potential confounders	Maternal self-report at initial visit (< 28 weeks gestation) then daily diary for all medications through delivery	Any major birth defect ascertained from medical records	824 women with and 678 women without asthma (total n = 1,502) who delivered a singleton birth later than 20 weeks' gestation and for whom complete information regarding medications taken during pregnancy was available; chlorpheniramine, tripelennamine, or other antihistamines used in first trimester: 321; unexposed: 1,175	Chlorpheniramine, tripelennamine, or other antihistamines used in first trimester: 3.7%; unexposed: 5.5%;	Not calculated
Shapiro et al. 197817	United States (Collaborative Perinatal Project), 1959-1966	Meclizine; use during first four lunar months	Not exposed to meclizine in the first four lunar months	Self-report	Any major birth defect	“Mother-child pairs”: 50,282; meclizine: 1,014; unexposed: 49,268	Meclizine: 36/1,014 (3.6%); unexposed: 1,357/49,268 (2.8%)	Standardized RR (95% CI) for meclizine use in the first four lunar months of pregnancy and major malformations: 1.20 (0.90-1.61) [See paper table for specific organ systems -- significant association with eye and ear defects (2.79 (1.12-5.73)]
Weber-Schoendorfer and Schaefer 200835	Germany (Berlin Teratogen Information Service), 1992-2006	Cetirizine; use during the first trimester	Exposed to NTS; unexposed matched to exposed on several potential confounders	Self-reported through structured questionnaire; women (or their healthcare providers) called TIS because of question about exposure	Any major birth defect, excluding genetic syndromes ascertained during postnatal questionnaire to the mother and/or physician 8 weeks after delivery	Cetirizine: 196; NTS: 1,686	Cetirizine: 3/177 (1.7%); NTS: 24/1,521 (1.6%)	Unadjusted OR (95% CI) of the association of cetirizine use in the first trimester and any major birth defect: 1.07 (0.21-3.59)
Yerushalmy and Milkovich, 196518†	United States (Northern California, Kaiser Permanente), 1960-1964	Meclizines, cyclizines, OAN; medications prescribed during the first 12 weeks of pregnancy	No antinauseant drugs prescribed	Maternal self-report at time of first prenatal visit (2/3 report in the first trimester); record of prescribed medications in medical record	Any “severe” birth defect, and by organ systems -- see Table 3 in paper	Total pregnancies: 4,277; meclizines/ cyclizines: 315; OAN: 449; unexposed: 3,902	Meclizines/cyclizines: 9/315 (3.2%); OAN: 11/449 (3.3%); unexposed: 101/3,902 (3.8%)	Not calculated; there were no significant differences in prevalence of birth defects among those exposed and unexposed to medications

CI, confidence interval; CL/P, cleft lip with or without cleft palate; CPO, cleft palate only; LMP, last menstrual period; NTD, neural tube defects; NTS, nonteratogenic substances; NVP, nausea and vomiting of pregnancy; OAN, other antinauseant; OAH, other antihistamines; OR, odds ratio; RR, risk ratio; TIS, Teratogen Information Service

^*Manuscript reported results for doxylamine+pyridoxine which are not included in this systematic review

^†Overlapping data from Kaiser Permanente

^‡Overlapping data from Swedish surveillance systems