key: cord-0899338-1gn1zhvt
authors: HUYBRECHTS, Krista F.; BATEMAN, Brian T.; ZHU, Yanmin; STRAUB, Loreen; MOGUN, Helen; KIM, Seoyoung C.; DESAI, Rishi J.; HERNANDEZ-DIAZ, Sonia
title: Hydroxychloroquine early in Pregnancy and Risk of Birth Defects
date: 2020-09-19
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.09.007
sha: 17865564af77f7d6df83b73495a8aefd8ca6cf4c
doc_id: 899338
cord_uid: 1gn1zhvt

Background Hydroxychloroquine (HCQ) is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to HCQ is important both in the context of its ongoing use for rheumatological disorders as well as its potential future use for COVID-19 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for COVID-19 treatment having been negative. Objective The study objective was to evaluate the risk of major congenital malformations associated with exposure to HCQ during the first trimester, the period of organogenesis. Study Design We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2,045 HCQ exposed and 3,198,589 unexposed pregnancies continuously enrolled in their respective insurance program from 3 months before the last menstrual period through at least one month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women with HCQ use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (N= 1,867 HCQ exposed; 19,080 unexposed pregnancies). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery, and specific malformation types for which there were at least 5 exposed events: oral clefts, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects. Results Overall, 54.8 per 1,000 infants exposed to HCQ were born with a major congenital malformation versus 35.3 per 1,000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% CI, 1.27–1.81). Patient characteristics were balanced in the restricted, propensity score matched cohort. The adjusted relative risk was 1.26 (1.04–1.54); it was 1.33 (1.08-1.65) for a daily dose ≥400mg and 0.95 (0.60-1.50) for <400mg. Among the different malformation groups considered, more substantial increases in the risk for oral clefts, respiratory anomalies and urinary defects were observed, although estimates were imprecise. No pattern of malformations was identified. Conclusions Our findings suggest a small increase in the risk of malformations associated with first trimester HCQ use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If HCQ were shown to be effective for COVID-19 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.

Hydroxychloroquine (HCQ) is an antimalarial drug widely used in the treatment of systemic 116 lupus erythematosus (SLE) and other rheumatic disorders. It is generally considered to be safe 117 for treatment of autoimmune rheumatic conditions during pregnancy and continuation of HCQ 118 during pregnancy is commonly recommended to improve disease management and pregnancy 119 outcomes. 1-3 Studies have been too small, however, to evaluate teratogenicity. Over the last 120 several months, there has been heightened interest in HCQ due to it being a candidate drug for 121 the treatment and/or prophylaxis of Coronavirus Disease 2019 . Health Organization has discontinued the HCQ arm of the Solidarity Trial evaluating its efficacy 128 for the treatment of hospitalized patients, 7 numerous randomized controlled studies are still 129 ongoing in particular to evaluate its effects for pre-exposure prophylaxis 8 and including a trial in 130 pregnant women. 9 131

Most studies regarding the safety of HCQ when used for malaria and for rheumatic disorders 132 like SLE suggest no increase in the risk of common adverse obstetrical outcomes such as 133 spontaneous abortion, prematurity, and intrauterine growth restriction. [10] [11] [12] [13] However, data 134 regarding the risk of major congenital malformations associated with early pregnancy exposure 135 is very limited, with the largest published cohort study including fewer than 200 exposed 136 pregnancies (Supplementary Table 1 ). 13 Quantification of the risk of congenital malformations 137 associated with early pregnancy exposure to HCQ is therefore important both in the context of 138 its ongoing use for rheumatological disorders as well as its potential future use for 139 J o u r n a l P r e -p r o o f although based on the results of initial trials, its usefulness in this clinical context remains highly 140 uncertain. Given the limited data currently available, we evaluated the risk for major congenital 141 malformations associated with HCQ using two large healthcare utilization databases. include demographic and insurance enrollment information, medical visits and hospitalizations, 149 diagnoses and procedures received as an in-or outpatient, and prescriptions filled on an 150 outpatient basis. The development of the linked mother-infant pregnancy cohorts has been 151 described previously. 14,15 Briefly, we identified all completed pregnancies in women 12 to 55 152 years of age and linked these pregnancies to liveborn infants by state, family identification 153 number and delivery/birth dates. Using a validated algorithm, 16 we estimated the date of the last 154 menstrual period on the basis of the delivery date and diagnostic codes indicative of preterm 155 delivery. Mothers were required to be continuously insured from 3 months before the start of 156 pregnancy until 1 month after delivery. Infants were required to be insured from birth until 3 157 months thereafter, unless they died sooner. These restrictions did not affect the age or race 158 distribution in MAX, but resulted in a decrease in the proportion of who become Medicaid 159 eligible due to the occurrence of pregnancy and a corresponding increase in the proportion who 160 become eligible based on other criteria. 17 Pregnancies with exposure to a known teratogenic 161 medication (i.e., warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) 162 during the first trimester and pregnancies with a chromosomal abnormality were excluded. 163 J o u r n a l P r e -p r o o f Exposure. Women were considered exposed if they filled a prescription for HCQ during the first 164 trimester of pregnancy (defined as date of the last menstrual period through day 90 of 165 pregnancy), the etiologically relevant exposure window for congenital malformations. The 166 reference group consisted of women without a prescription for HCQ from 3 months before the 167 start of pregnancy through the end of the first trimester given HCQ's long half-life and to reduce 168 the probability of exposure during early pregnancy from use of HCQ dispensed at an earlier time 169 point. 170

Outcomes. The outcome of interest was major congenital malformations overall. In secondary 171 analyses we also evaluated specific malformation types for which we observed at least 5 172 exposed events across the two cohorts: oral clefts, cardiac, respiratory, gastrointestinal, genital, 173 urinary, musculoskeletal, and limb defects. The presence of malformations was defined using 174 validated algorithms based on inpatient or outpatient diagnoses and procedures, which have 175 been shown to identify the outcomes with high specificity (i.e., more than one date with the 176 respective diagnostic codes recorded, or one diagnostic code and a code for a 177 procedure/surgery or infant death). 18 Isolated congenital heart block was not included in the 178 definition for cardiac malformations because its risk is increased in babies born to women with 179 SLE. 19 (Supplementary Table 2 

Covariates. Potential confounders and proxies for confounders considered included 181 sociodemographic information (e.g., state of residence, age, race/ethnicity (MAX only)), 182 autoimmune rheumatic disorders (e.g., rheumatoid arthritis, SLE, ankylosing spondylitis, 183 psoriatic arthritis), other maternal conditions (e.g., diabetes, hypertension, psychiatric 184 conditions, renal disease, neurological conditions, chronic respiratory conditions, anemia, 185 infections), concomitant medication use (e.g., systemic steroids, non-biologic and biologic 186 disease modifying antirheumatic drugs (DMARDs), psychiatric medications, NSAIDs, suspected 187 teratogens), and general markers of the burden of illness (e.g., maternal comorbidity index, 188 healthcare utilization measures) (Table 1, Supplementary Table 3 and 4) . 189

Analyses. Baseline characteristics were compared between women exposed to HCQ and the 190 reference group of unexposed women. Relative risks (RR) with their 95% confidence intervals 191 (CI) were estimated using generalized linear models. As a first level of adjustment, the 192 reference group was restricted to women with a recorded diagnosis of autoimmune rheumatic 193 disorders commonly treated with HCQ ('restricted cohort'). In fully adjusted analyses, exposed 194 and unexposed women in the restricted cohort were matched on their propensity score (PS), 195 using a 1:200 variable ratio matching and a 0.01 caliper ('restricted matched cohort'). The PS, 196 which reflects the probability of being treated with HCQ, was estimated using a logistic 197 regression model including all (>80) pre-specified covariates. When evaluating the balance in 198 baseline characteristics in the restricted matched cohort, the counts for the unexposed group 199 were weighted to account for the variable ratio matching. We conducted analyses stratified by 200 dose, using the highest daily dose dispensed during the first trimester (< 400mg and ≥ 400mg 201 daily) as well as duration of exposure (≤60 days and >60 days). In a sensitivity analysis, both 202 the exposed and the reference group were restricted to women with a recorded diagnosis of 203 autoimmune rheumatic disorders. Estimates from both cohorts were combined using a meta-204 analytic approach with random effects. 205

For all analyses presented, results were described as similar or different from the reference 206 group based on the magnitude of the point estimates, taking into account the precision of each 207 estimate as reflected in the width of its 95% CI. We focused on estimating magnitude of effects 208 in preference to dichotomizing the results as statistically significant or not. 20 The research was 209 approved by the institutional review board of Brigham and Women's Hospital, which waived the 210 need for informed consent. The combined cohort included 2,045 pregnancies exposed to HCQ during the first trimester 214 (686 in MAX and 1,359 in MS), and 3,198,589 unexposed pregnancies (1,881,069 in MAX and 215 1,317,520 in MS). The mean daily dose of HCQ was 371mg (standard deviation, 379mg) and 216 61% of women used a daily dose of 400mg. Among exposed women, 25.9% were exposed for 217 ≤30 days, 33.6% for 31 to 60 days, and 40.5% for >60 days during the first trimester. 218

Women exposed to HCQ tended to be older, had more comorbid conditions, took more 219 concomitant medications (especially pain medications, steroids, NSAIDs, and DMARDs) and 220 had greater health care utilization. After cohort restriction and adjustment through PS matching, 221 all covariates -including treatment indications -were well balanced ( Table 3 

The pooled risk of any congenital malformation was 54.8 per 1,000 HCQ exposed infants 224 (n=112 events) and 35.3 per 1,000 unexposed infants in the general population (n=112,908 225 events), corresponding to a pooled unadjusted RR of 1.51 (95% CI, 1.27 -1.81). Restricting the 226 reference group to women with rheumatic disorders resulted in an absolute risk of 44.1 per 227 1,000 unexposed infants (n=506 events out of 11,468) and a RR of 1.26 (95% CI, 1.04-1.53). 228

Adjusting for all potential cofounding variables through PS matching did not result in further 229 attenuation of the association (RR=1.26; 95% CI, 1.04-1.54). Estimates were consistent 230 between the two cohorts. The risk of malformations among the HCQ exposed was the same 231 regardless of whether women had concomitant exposure to steroids. The adjusted RR was 1.33 232 (95% CI, 1.08-1.65) for a daily dose of ≥ 400mg and 0.95 (95% CI, 0.60-1.50) for <400mg. The 233 risk was not affected by the duration of exposure (Figure 1) , and results were similar when 234 restricting both the exposed and the reference group to women with a recorded diagnosis of 235 autoimmune rheumatic disorders (Supplementary Table 5) . 236 J o u r n a l P r e -p r o o f

In the context of few events, risk estimates for the specific malformation types considered were 237 relatively imprecise ( Figure 2 ). The point estimates indicated an approximately 2 to 4-fold 238 increase in the risks for oral clefts (RR=3.70; 95% CI, 1.55-8.82), respiratory defects (RR=1.85; 239 95% CI, 0.94-3.64), and urinary defects (RR=2.21; 95% CI, 1.26-3.86), which were consistent 240 between the two cohorts. None of the HCQ exposed cases of oral clefts had concomitant 241 exposure to steroids. The upper limit of the 95% CI for the pooled estimates suggested no more 242 than a 2-fold increase in risk for other specific malformation types with the exception of genital 243 defects (upper limit 95% CI=4.76). Among the 112 exposed infants with malformations, 12 244 

Utilizing data from health plans that provide coverage for large populations of both commercially 250 and publicly insured individuals in the US, we identified a cohort of pregnant women with 251 chronic autoimmune rheumatic diseases and assessed the relative prevalence of major 252 congenital malformations in their newborns following exposure to HCQ during early pregnancy. 253

Women who filled prescriptions for HCQ during the first trimester had a higher risk of 254 malformations in their newborn than the general population. Upon restriction to women with the 255 indication (mainly SLE and rheumatoid arthritis), the relative risk attenuated but was still 256 elevated. In utero exposed newborns had an adjusted risk of major congenital malformations 257 26% higher than unexposed overall, and 33% higher for daily doses of 400mg or greater (while 258 no increased risk was observed for lower doses based on the point estimate, reflecting the 259 estimate most consistent with the data). A more substantial increase in the risk for oral clefts, 260 respiratory anomalies and urinary defects was observed, although confidence intervals for 261 specific malformations were wide. No pattern of malformations was identified. 262

Prior studies evaluating the safety of HCQ in pregnancy included between 36 and 194 women 264 and overall suggested no increased risk of pregnancy losses, prematurity, intrauterine growth 265 retardation, pre-eclampsia, fetal distress or induction of delivery compared to reference 266 groups. 10, 12, [21] [22] [23] [24] Since flares are associated with these and other complications and HCQ is 267 effective at controlling them, drug use in pregnancy may improve pregnancy outcomes for 268 women with rheumatic disorders, 23 as well as reduce the risk for congenital heart block in the 269 neonate. 25 Moreover, HCQ use reduces the dose of prednisone needed during pregnancy. 12 270

However, most of these studies were too small to assess the risk of major malformations, and 271 many based their conclusion on the statistical significance of underpowered comparisons. 26 272

Given that HCQ crosses the placenta 21 and inhibits cell division and DNA synthesis, 27 and that 273 initial reports suggested an increased risk of chromosomal damage attributable to chloroquine, 28 274 concerns regarding effects on the rapidly dividing embryonic cells remain. Specific 275 malformations reported among exposed newborns included cleft lip and palate (1 out of 79) 12 276 and pulmonary hypoplasia in a preterm infant (1 out of 133). 21 Moreover, two of the largest 277 studies found a meaningful, though not statistically significant, increased risk of malformations 278 overall. In one study, malformations were more common in the 194 HCQ exposed (6.7%) than 279 in the reference (2.3%) group (adjusted RR 3.11; 95% CI, 0.99-9.77), with no clear pattern. 13 In 280 another study, the 114 HCQ exposed had a prevalence of malformations of 7.2% (7/97) and the 281 reference group of 3.4% (15/440) with a p-value of 0.094, 22 again with no clear pattern. 282

For pregnant women with malaria or rheumatic disorders the benefits of HCQ may still outweigh 284 the potential risk, 2 especially given that discontinuation of HCQ after conception would not 285 necessarily prevent birth defects because the half-life is more than a month, and would increase 286 the risk for flares and their complications. Therefore, our findings of a potential small increase in 287 the risk of malformations -while important for prescribers to be aware of -should not 288 necessarily alter the treatment recommendation for a given woman with malaria or rheumatic 289 disorders. For COVID-19, it will depend on whether the currently ongoing clinical trials 290 demonstrate meaningful benefits of HCQ in reducing COVID-19 infection or its severity. While 291 initial trials using HCQ to treat COVID-19 have failed to demonstrate efficacy, trials regarding its 292 use for preexposure prophylaxis have not yet been reported. 293

In addition to several strengths (including a large and nationally representative population, as 295 well as robust control for confounding through restriction and matching), our study is also 296 subject to certain limitations, most of which would bias the results towards the null. First, we 297 included only women with a live-born delivery because abortions and stillbirths are incompletely 298 recorded in healthcare utilization data. This approach may have resulted in the exclusion of 299 pregnancies with the outcome, as fetuses with malformations are more likely to experience fetal 300 death or termination. Therefore, the incidence of major malformations reported in this study 301 could underestimate the risk in pregnant women. If a higher proportion of women on HCQ had 302 lethal malformations, more prenatal screening or a higher propensity to terminate an affected 303 pregnancy, this study would also underestimate the relative risk. However, differential 304

terminations have been shown to be an unlikely source of selection bias. 29 Second, 305 identification of major congenital malformations was based on diagnosis and/or procedure 306 codes recorded in claims. Misclassification would tend to bias relative risks towards the null 307 unless a higher proportion of malformation diagnoses were identified in women exposed to 308 HCQ. While others and we have shown a high positive predictive value for malformations 13,18,30 , 309 the potential for some misclassification remains. Third, information on HCQ exposure is 310 obtained from claims of filled prescriptions. Since some women may fill prescriptions for 311 medications but not use them, our study may misclassify unexposed pregnancies into the HCQ 312 group, thus underestimating any potential effect; however, a large fraction of our cohort filled 313 prescriptions for HCQ throughout the first trimester. Fourth, it is possible that some women in 314 the reference group were taking immunomodulatory agents in lieu of HCQ. If these agents were 315 teratogenic, we would be underestimating the effect of HCQ. However, their use is negligible 316 during pregnancy and upon restriction and propensity score matching our exposed and 317 reference groups were balanced in the use of these medications. Fifth, disease flares in women 318

with rheumatic disorders such as SLE have been associated with poor pregnancy outcomes 319 and HCQ use during pregnancy improves disease activity and reduces the antiphospholipid 320 syndrome. 12, 23 Therefore, the reference group of women with the disease and without HCQ 321 could have a higher risk, thus potentially underestimating the relative risk for flare-related 322 adverse pregnancy outcomes including fetal loss, fetal growth retardation and prematurity. 323

Alternatively, it is possible that there is misclassification of the unexposed with respect to the 324 presence of underlying rheumatic disease or that women being treated with HCQ have more 325 severe underlying disease than women without HCQ. Although neither rheumatic disorders nor 326 flares have been associated with congenital malformations, it is conceivable that women with 327 more severe disease receive higher doses of steroids and this may not be fully captured in our 328 data. However, recent studies 31,32 have refuted initial reports of strong associations between 329 steroids and oral clefts. 33 More directly, in the current study, the absolute risk of malformations 330 was the same among HCQ exposed pregnancies with and without concomitant exposure to 331 systemic steroids, and none of the cases of oral clefts in the HCQ exposed were exposed to 332 steroids. Together, this suggests that steroid exposure is not a major threat to the validity of our 333 analyses. Sixth, the MAX cohort included data through 2014 -the most recent data available at 334 the time of study conduct -and MarketScan included data through 2015, to avoid the use of 335 ICD-10 based algorithms for cohort creation and outcome identification that have not yet been 336 validated. However, the biological association between HCQ exposure and malformations 337

should not change over time. Finally, despite being the largest exposed cohort to date, the 338 numbers were small for specific malformation groups and confidence intervals were wide; 339 specific individual defects could not be examined. However, there is enough information to 340 suggest that the magnitude of a potential risk of malformations would not be on the order of that 341 associated with major teratogens. 342

In this study, there was no evidence of a large increase in prevalence of major congenital 344 malformations in the newborn from first-trimester maternal exposure to HCQ. However, it is the 345 third study to suggest a moderate increased risk. For most patients with autoimmune rheumatic 346 disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If proven 347 effective for COVID-19 prophylaxis in ongoing randomized trials, the benefits of HCQ would 348 need to be weighed against the potential risk in pregnancy. rheumatic disorders, the number of outcome events and the total number of deliveries in both 457 the hydroxychloroquine exposed and the unexposed group are not meaningful for absolute risk 458 estimation; therefore, counts after restriction to deliveries with rheumatic disorders but before 459 the propensity score matching are reported in Figure 2 . Table 1 Selected patient characteristics for hydroxychloroquine exposed and unexposed pregnancies Miscarriage risk was 13% in exposed and 4% in unexposed; and stillbirth 8% and 6%, respectively. Among the 47 liveborn exposed, 1 had cleft lip and palate. In the 145 unexposed 3 fetuses had fatal congenital anomalies and 1 had an abdominal hernia.

Limited sample to estimate the relative risk of malformations. Controlled study. In-and outpatient claims in the infant record between date of birth (DoB) and DoB+90 days and/or in the maternal record between delivery and delivery+30 days are considered.

• ≥ 2 dates with a code for a malformation within the group o Exception: Codes 747.3x, 746.02, 745.5x, 747.0x require ≥ 2 dates with a code for a malformation of which at least one code is documented at ≥ 6 weeks after DoB • ≥ 1 date with a code for a malformation within the subgroup and cardiac procedure o Exception: Code 746.02 • ≥ 1 date with a code for a malformation within the subgroup and infant died • If codes identified in the maternal record between LMP and LMP+105 days AND there are no codes in the infant record between DoB and DoB+90 days (i.e., only maternal codes between delivery and delivery+30), the defect is considered a pre-existing maternal defect.

• Any of the subgroups of cardiovascular anomalies is present • ≥ 2 dates with a code for any of the cardiac malformations (regardless of the subgroup [1])

• ≥ 1 date with a code for any of the cardiac malformations [1] and cardiac procedure • ≥ 1 date with a code for any of the cardiac malformations [1] and infant died • If codes identified in the maternal record between LMP and LMP+105 days AND there are no codes in the infant record between DoB and DoB+90 days (i.e., only maternal codes between delivery and delivery+30), the defect is considered a pre-existing maternal defect.

• ≥ 2 dates with a code for the malformation group/subgroup o Exception: for gastroschisis: if code 756.79 was used (before 10/2009), require ≥ 1 date with a code AND ICD-9 procedure 54.71 • ≥ 1 date with a code for the malformation group/subgroup and malformation-specific procedure • ≥ 1 date with a code for the malformation group/subgroup and infant died • If codes identified in the maternal record between LMP and LMP+105 days AND there are no codes in the infant record between DoB and DoB+90 days (i.e., only maternal codes between delivery and delivery+30), the defect is considered a pre-existing maternal defect.

• Any of the malformation groups/subgroups mentioned above is present.

[ (1) Given the variable ratio matching, the counts for the unexposed group are weighted counts to demonstrate the balance in baseline covariates.

(2) Autoimmune rheumatic disorders were measured from 3 months before the start through the end of pregnancy (3) Maternal conditions and concomitant medication use were measured from 3 months before the start of pregnancy through the end of the first trimester (4) Women exposed to known teratogens have been excluded (i.e., warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide). Suspected teratogens considered include danazol, methimazole, propylthiouracil, aminoglycosides, trimethoprim, triamterene, sulfasalazine, spasmophen, cholestyramine, potassium iodide, tetracycline, fluconazole (5) General markers of the burden of illness were measured during the 3 months before but not during pregnancy, as these measures may be affected by early detection of pregnancy complications Cell size <11 for MAX cohort are suppressed in accord with the CMS cell size suppression policy. Abbreviations: HCQ, hydroxychloroquine; N, number; NSAIDs, nonsteroidal anti-inflammatory drugs; DMARDs, disease modifying antirheumatic drugs; SD, standard deviation; Stand Diff, standardized difference

American College of 352 Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and 353 Musculoskeletal Diseases

BSR and BHPR guideline on prescribing drugs in 355 pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-356 rheumatic drugs and corticosteroids

Trends in use of hydroxychloroquine during 358 pregnancy in systemic lupus erythematosus patients from

Observational Study of Hydroxychloroquine in 361 Hospitalized Patients with Covid-19

Association of Treatment With 364 Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-365 19 in New York State

A Randomized Trial of 367 Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Drug Evaluation during the Covid-19 Pandemic. The New England 373 journal of medicine 2020

Hydroxychloroquine Efficacy and Safety in Preventing SARS-CoV-2 Infection and 375 COVID-19 Disease Severity During Pregnancy (COVID-Preg). NCT04410562 Available 376 at ClinicalTrials.gov

Safety of hydroxychloroquine in 381 pregnant patients with connective tissue diseases: a study of one hundred thirty-three 382 cases compared with a control group

Brief report: Risk of adverse fetal outcomes 386 associated with immunosuppressive medications for chronic immune-mediated diseases 387 in pregnancy

Harnessing the Medicaid Analytic eXtract 389 (MAX) to Evaluate Medications in Pregnancy: Design Considerations

Identifying pregnancies in insurance claims data: Methods and application to retinoid 393 teratogenic surveillance

Algorithms to estimate the beginning of pregnancy in administrative databases

Pregnancy outcome following first trimester exposure to chloroquine

Hydroxychloroquine and lupus pregnancy: review of a series of 36 cases

Hydroxychloroquine in pregnant patients with systemic lupus erythematosus

Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study

Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group

Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation

Hydroxychloroquine in lupus pregnancy

Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers

Pregnancy outcome following in utero exposure to hydroxychloroquine: a prospective comparative observational study

Brief report: Risk of adverse fetal outcomes associated with immunosuppressive medications for chronic immune-mediated diseases in pregnancy

Longterm outcomes of children born to mothers with SLE exposed to hydroxychloroquine in pregnancy

Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus