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Pregnancy outcome following in utero exposure to hydroxychloroquine: A prospective comparative observational study
Reproductive Toxicology 39 (2013) 58–62
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Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Pregnancy outcome following in utero exposure to hydroxychloroquine: A prospective comparative observational study夽 Orna Diav-Citrin a,b,∗ , Shani Blyakhman c,1 , Svetlana Shechtman a , Asher Ornoy a,b a b c
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel The Hebrew University Hadassah Medical School, Jerusalem, Israel The Division of Clinical Pharmacy, The Hebrew University of Jerusalem, Israel
a r t i c l e
i n f o
Article history: Received 9 December 2012 Received in revised form 2 April 2013 Accepted 4 April 2013 Available online 17 April 2013 Keywords: Hydroxychloroquine Rheumatologic diseases Pregnancy Congenital anomalies
a b s t r a c t Objective: To evaluate pregnancy safety of hydroxychloroquine (HCQ) for rheumatologic diseases. Design: Prospective comparative observational study done at the Israeli teratology information service between 1998 and 2006. Results: 114 HCQ-exposed pregnancies (98.2% in the first trimester, T1) were followed-up and compared with 455 pregnancies of women counseled for non-teratogenic exposure. The difference in the rate of congenital anomalies was not statistically significant [7/97 (7.2%) vs. 15/440 (3.4%), p = 0.094]. The analysis was repeated among those exposed in T1 excluding genetic or cytogenetic anomalies or congenital infections [5/95 (5.3%) vs. 14/440 (3.2%), p = 0.355]. There were no cases of neonatal lupus erythematosus. The gestational age at delivery was earlier, rate of preterm delivery higher, and birth weight lower, in the HCQ group. Conclusion: The present study suggests that HCQ treatment in pregnancy is not a major human teratogen. The earlier gestational age and lower birth weight might be associated with maternal disease. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Hydroxychloroquine (HCQ) sulfate is a 4-aminoquinoline antimalarial medication and an anti-inflammatory agent. It is used in the treatment of rheumatological diseases including systemic lupus erythematosus (SLE), discoid lupus (DL) and rheumatoid arthritis (RA), at higher than anti-malarial doses [1]. These illnesses are more common in women and can occur at childbearing age. HCQ crosses the human placenta [2]. Animal reproductive studies are available only for the closely related agent, chloroquine. Chloroquine produced anophthalmia and microphthalmia at high doses (1000 mg/kg) in rats [3]. In animal models retinal toxicity of chloroquine has been documented [4]. Retinal degeneration has been reported in two infants after prenatal exposure to chloroquine for malaria prophylaxis [5]. Congenital anomalies were reported in three siblings whose mother was treated during pregnancy with 250–500 mg/d of chloroquine for discoid lupus. Two of the
夽 Previous presentation at the 22nd conference of the Organization of Teratology Information Specialists (OTIS), Rio Grande, Puerto Rico, 2009. ∗ Corresponding author at: The Israeli Teratology Information Service, Israel Ministry of Health, P.O. Box 1176, Jerusalem 9446724, Israel. Tel.: +972 2 5080441; fax: +972 2 6474822. E-mail address: [email protected] (O. Diav-Citrin). 1 Acknowledgment: This work is part of the MSc thesis in Clinical Pharmacy of the Hebrew University of Mrs. Shani Blyakhman. 0890-6238/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.reprotox.2013.04.005
siblings were born with cochlear-vestibular paresis and one with left hemihypertrophy and Wilms’ tumor [6]. Ocular and auditory side effects are known toxicities of chloroquine. Chloroquine has been safely used during pregnancy in chemosuppression of malaria [7–9]. Several case series have been published on the safe use of HCQ in pregnancy at antirheumatic doses [10–15]. Two case series focused on ocular assessment of children exposed to HCQ in pregnancy and found no ophthalmic abnormalities [16,17]. Contrary to the above negative studies, neurophysiological visual disturbances were detected on electroretinograms and visual evoked potentials testing in a subset of infants exposed in utero to HCQ [18]. Concerns were later raised in regard to the methodology used [19] and answered by the authors [20]. There is a case control study reporting safe use of HCQ in pregnant patients with rheumatic disease [21]. Three additional controlled studies have been published on the safety of HCQ in pregnancy in rheumatic diseases [22–24]. The largest one included evaluations of hearing, vision, growth and development with no apparent adverse effects [23]. In a recent meta-analysis the odds ratio of congenital defects in live-births of women taking HCQ during pregnancy for auto-immune diseases was 0.66 (95% CI 0.25, 1.75) [25]. SLE has been associated with an increased risk of pregnancy loss (miscarriage and stillbirth), intrauterine growth restriction, preeclampsia, and preterm delivery [26,27]. Neonatal lupus erythematosus, consisting of congenital heart block, transient cutaneous lupus lesions, cytopenia, hepatic or/and other systemic
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manifestations has been described in infants born to mothers with SLE, Sjögren’s syndrome, or other rheumatic diseases with positive anti-Ro or anti-La antibodies [26]. The primary objective of the present study was to prospectively evaluate the rate of major congenital anomalies after in utero exposure to HCQ compared to a group counseled for non-teratogenic exposures. Secondary endpoints of interest were pregnancy outcome, birth weight, and gestational age at delivery. In addition, the aim was to prospectively evaluate the rate of neonatal lupus erythematosus or congenital cardiac block among the infants born to mothers with rheumatic diseases. 2. Materials and methods Women who contacted the Israeli Teratology Information Service (TIS), Jerusalem, Israel, in regard to gestational exposure to HCQ between the years 1998 and 2006, were enrolled in the present prospective comparative observational study. The Israeli TIS offers counseling services in regard to environmental exposures during pregnancy. The HCQ-exposed group was compared to a randomly selected group of women among those who contacted the Israeli TIS during pregnancy being exposed to agents known not to be teratogenic in a similar time frame (comparison group), at a 1:4 ratio. Details of exposure were collected during pregnancy, at the initial contact to the TIS and before pregnancy outcome was known, using a structured questionnaire. Verbal consent to participate in the study was given by each woman at initial contact. Since the study was observational with no intervention, no Institutional Review Board approval was required, consistent with the internal policy of Israel Ministry of Health at the time the study was performed. In addition, the following information was recorded: maternal demographics, medical and obstetrical histories, and exposure details (dose, duration, and timing in pregnancy). Retrospective cases were not included in the study. Pregnant women who contacted the TIS after an anomaly had been identified on prenatal testing were also excluded. After the expected date of delivery, pregnancy outcome was actively sought after in the HCQ-exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies and neonatal complications. In addition, HCQ and other exposures were ascertained. In Israel, each neonate undergoes at least two physical examinations before being discharged from the hospital. The interview was conducted after these physical examinations. Data collection methods were similar in the HCQ-exposed and comparison groups. Major anomalies were defined as structural anomalies in the offspring that have serious medical, surgical or cosmetic consequences [28]. Children with minor anomalies or functional problems without any morphological changes (e.g. systolic heart murmur with normal echocardiography, slight developmental delay) or complications of preterm delivery were not considered as having major anomalies. Septal defects were considered major anomalies in the present study. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) were included in our study, since antenatal screening for major anomalies is routinely performed in Israel. The analysis of major congenital anomalies was performed among all liveborn infants and fetuses with diagnosed anomalies. In the case of multiple births, each live-born offspring was included in the analysis.
3. Statistical analysis Categorical data were compared by 2 or Fisher exact tests and are expressed as ratios or percentages. Continuous data are presented using mean ± SD or median with interquartile range and compared using the Student-t or Mann–Whitney tests, depending on whether they followed normal distribution, or did not. Statistical calculations were done using SPSS Version 16 or Epi InfoTM software (Center for Disease Control and Prevention, Atlanta Epidemiology Program Office, Atlanta, GA, USA).
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6.2%. Additional medications for the rheumatic disease were taken in 79.8% of the HCQ group. Two or more additional medications were taken by 47.4% of the cohort. Concurrent medications included: steroids (60.5%), low dose aspirin (31.6%), low molecular weight heparins (23.7%), azathioprine (15.8%), non-steroidal anti-inflammatory drugs (14.0%), and sulfasalazine or mesalamine (9.6%). The comparison group consisted of 455 pregnancies of women counseled for non-teratogenic exposure by the Israeli TIS. A comparison of maternal characteristics and obstetrical history between the two groups is presented in Table 1. The gestational age at initial contact was earlier in the HCQ group compared to the comparison group. There were no significant differences between the groups either in the pregnancy order, parity, or history of miscarriages, elective terminations of pregnancy (ETOP), and stillbirths, except for a higher proportion of women in the HCQ group who had no liveborn children yet and who had one previous ETOP. There were no significant differences between the groups in maternal age or distribution of cigarette smokers. A comparison of pregnancy outcome between the groups is presented in Table 2. There was a 2.1-fold increase in the rate of miscarriages in the HCQ group. In order to analyze the increase in the miscarriage rate in the HCQ group, logistic regression was performed. Various predictors were entered into the model (smoking status, maternal age, history of miscarriage, gestational age at initial contact and type of exposure). The higher rate of miscarriages was significantly associated with an earlier age at initial contact (p < 0.001) and a higher maternal age (p = 0.003). The adjusted odds ratio for miscarriages for the HCQ vs. the comparison group was 1.35 [95% confidence interval (CI) 0.61–2.97]. There were no significant differences in the rate of elective terminations of pregnancy or stillbirths between the groups. The rate of congenital anomalies was higher in the HCQ group [7/97 (7.2%) vs. 15/440 (3.4%), p = 0.094], however, the difference was not statistically significant. The rate of major anomalies, after first trimester exposure without chromosomal or genetic anomalies or congenital infections, was also not significantly different between the two groups [5/95 (5.3%) (HCQ) vs. 14/440 (3.2%) (comparison), p = 0.355). The median gestational age at delivery was two weeks earlier, the rate of preterm delivery was 3.6-fold higher and the median birth weight was 500 g lower in the HCQ group compared to the comparison group. The difference in the mean birth weight was significant but less pronounced (275 g lower in the HCQ group) when the comparison was conducted among singleton full-term infants only. The difference in mean birth weight was similar and approximately 300 g lower in both subgroups of neonates exposed to HCQ in the first trimester only or in the third trimester. There was a higher rate of Cesarean sections in the HCQ group. The list of major congenital anomalies in the HCQ group is presented in Table 3. The anomalies varied with no observed pattern. All the anomalies in the HCQ group were diagnosed during pregnancy or in the first year of life, most perinatally. There were no cases of neonatal lupus erythematosus or of congenital cardiac block among the neonates born to mothers treated with HCQ in pregnancy for rheumatic diseases.
4. Results A total of 114 HCQ-exposed pregnancies were prospectively followed-up in the present study. The exposure was at least in the first trimester of pregnancy in 98.2% of the HCQ group. The medication was taken throughout pregnancy in 59.6% of the HCQexposed pregnancies. The median daily dose [interquartile range (IQR) between the 25 and 75th percentiles] of HCQ was 300 mg (200–400). The indications for the treatment with HCQ in the exposed group were as follows: SLE in 69.0%, RA in 22.1%, DL in 2.7%, and other (Behc¸et’s disease and Sjögren’s syndrome) in
5. Discussion In the present prospective observational comparative cohort study, 114 HCQ-exposed pregnancies were followed-up. There was a higher rate of congenital anomalies in the HCQ group, however, not statistically significant. A sample size of 95 live-births or elective terminations of pregnancy due to prenatally diagnosed anomalies in the HCQ group exposed in the first trimester of pregnancy enables detection of a 3.5-fold increase in the overall rate of
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Table 1 Maternal characteristics and obstetrical history. HCQ group n = 114
Comparison group n = 455
30 (27–34)
30 (27–34)
0.356
36/109 (33.0) 61/109 (56.0) 12/109 (11.0)
117/422 (27.7) 247/422 (58.5) 58/422 (13.7)
0.276 0.628 0.452
Paritya (%) 0 1–4 ≥5
12/73 (16.4) 59/73 (80.8) 2/73 (2.7)
22/304 (7.2) 266/304 (87.5) 16/304 (5.3)
0.014 0.137 0.364
Previous miscarriagea (%) 0 1–3 ≥4
48/72 (66.7) 22/72 (30.6) 2/72 (2.8)
221/305 (72.5) 80/305 (26.2) 4/305 (1.3)
0.328 0.457 0.322
Previous ETOPa (%) 0 1 ≥2 Previous stillbirtha (%) Gestational age at initial contact median (IQR)
57/72 (79.2) 13/72 (18.1) 2/72 (2.8) 3/72 (4.2) 7 (5–12)
265/305 (86.9) 30/305 (9.8) 10/305 (3.3) 3/305 (1.0) 10 (6–17)
0.095 0.048 1.000 0.052 <0.001
Cigarette smoking (%) 0 <10cig./d ≥10cig./d
100/106 (94.3) 3/106 (2.8) 3/106 (2.8)
371/400 (92.8) 12/400 (3.0) 17/400 (4.3)
0.795 1.000 0.799
Maternal age (years) median (IQR) Pregnancy order (%) 1 2–4 ≥5
p value
IQR: interquartile range; ETOP: elective termination of pregnancy. a Calculations were made excluding women who called regarding their first pregnancy. Table 2 Pregnancy outcome.
Multiple gestations Live-born infants Delivery (%) Miscarriage (%) ETOP (%) Stillbirth (%) Major anomalies (%)b Major anomalies without chromosomal or genetic anomalies or congenital infections, T1 (%)b Gestational age at delivery weeks median (IQR) Preterm delivery, ≤36 (%) Birth weight g median (IQR) Birth weight, singleton full-term, g mean ± SD Birth weight, singleton full-term, T1 , g mean ± SD Birth weight, singleton full-term, T3 , g mean ± SD Delivery method (%) Vaginal spontaneous uncomplicated C/S Vacuum Other (Vaginal induced, forceps)
HCQ group n = 114
Comparison group n = 455
2 twin setsa 96 95/115 (82.6) 13/115 (11.3) 6/115 (5.2) 1/115 (0.9) 7/97 (7.2) 5/95 (5.3)
14 twin sets, 1 triplets 434 418/455 (91.9) 24/455 (5.3) 9/455 (2.0) 4/455 (0.9) 15/440 (3.4) 14/440c (3.2)
p value
38 (36–39) 27/95 (28.4) 2750 (2275–3300) 3050 ± 527 3016 ± 433 3025 ± 603
40 (38–41) 33/413 (8.0) 3250 (2880–3543) 3325 ± 448 3308 ± 457c 3308 ± 457c
<0.001 <0.001 <0.001 <0.001 0.002 0.004
44/95 (46.3) 29/95 (30.5) 7/95 (7.4) 15/95 (15.8)
299/417 (71.7) 81//417 (19.4) 21/417 (5.0) 16/417 (3.8)
<0.001 0.017 0.367 <0.001
0.003 0.019 0.093 1.000 0.094 0.355
IQR: interquartile range; ETOP: elective termination of pregnancy; SD: standard deviation; T1 : first trimester; T3 : third trimester; C/S: Cesarean section. a One twin pregnancy counted as two outcomes (ETOP and delivery). b Including ETOPs (elective termination of pregnancy) due to prenatally diagnosed anomalies. c Irrespective of trimester of exposure. Table 3 List of major congenital anomalies in the HCQ group. Anomaly
HCQ details, disease
Outcome, w
Gender, BW g
Additional medications
Comments
Spina bifida DDH DDH VSD Congenital hypothyroidism (permanent) Inguinal herniaa Congenital toxoplasmosis, blindness (right)a
400 mg/d T1 , RA 200 mg/d T1 , SLE 400 mg/d T1 , RA 200 mg/d T1 , SLE 200 mg/d T1–3 , SLE, CD
ETOP, 13 Delivery, 39 Delivery, 38 Delivery, 38 Delivery, 36
F F, 3300 M, 2750 M, 3225 F, 1888
One of twins Braces Braces Closed at 1.5 y Thyroxine treatment
200 mg/d T3 , SLE 400 mg/d T1–3 , SLE
Delivery, 37 Delivery, 34
M, 2800 M, 1900
Prednisone 10 mg/d, sulfasalazine 2 g/d Prednisone 2.5 mg/d None Aspirin 100 mg/d Budesonide 6 mg/d, azathioprine 100 mg/d, mesalamine 3g/d Aspirin 100 mg/d, enoxaparin Prednisone 7.5 mg/d, azathioprine 100 mg/d
Operated Diagnosed after birth
DDH: developmental dysplasia of hip; VSD: ventricular septal defect. a Excluded from the repeated analysis because the exposure was not in the first trimester or if the anomaly was a result of a congenital infection, HCQ: hydroxychloroquine; T1 : first trimester; T3 : third trimester; RA: rheumatoid arthritis; SLE: systemic lupus; CD: Crohn’s disease; w: gestational week; ETOP: elective termination of pregnancy; BW g: birth weight in grams; F: female; M: male; y: year.
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major anomalies. This calculation is based on a baseline risk of 3.2% for major anomalies with a ratio of 1:4.6 (95:440) to the comparison group, 80% power and 95% CI. The rate of major anomalies in both the HCQ and the comparison groups was within the expected baseline risk for the general population. The results of the present study are consistent with most previous reports, not associating HCQ exposure during pregnancy with a teratogenic risk in humans. This study confirms that HCQ does not represent a major teratogenic risk when used in clinically recommended doses in humans [10–17,21–25]. The lack of cases of neonatal lupus erythematosus among the neonates born to mothers treated for rheumatic diseases is not surprising, due to the relatively small sample size for specific rare outcomes. In the present study, the higher rate of miscarriages was associated with an earlier gestational age at initial contact (with higher miscarriage rate in women calling earlier in pregnancy) and a higher maternal age, but not with the exposure group (HCQ vs. nonteratogenic exposure in the comparison group), as verified by the regression analysis. Some investigators have shown a correlation between disease activity, miscarriages and fetal loss in pregnant SLE patients [29]. Pregnancy loss rates were reported in 11–24% in lupus patients [30–33]. Based on a recently published metaanalysis [25], the OR of miscarriage was 0.92 (95% CI 0.49–1.72), and of stillbirth 0.97 (95% CI 0.14–6.54), favoring patients taking HCQ. The earlier gestational age at delivery, the higher rate of preterm deliveries and the lower birth weight in the HCQ group may be associated with the underlying maternal disease, HCQ effect, or a combination of the two. A higher incidence of preterm deliveries was reported in SLE patients, especially those with active disease [30,34]. Based on the published meta-analysis [25], there was no significant increase in the risk of preterm delivery associated with HCQ treatment [OR 1.10 (95% CI 0.75–1.61)]. The subgroup analysis showing similar decrease in birth weight in women exposed to HCQ only in the first trimester of pregnancy and women exposed in the third trimester of pregnancy suggests the disease as the underlying factor rather than a drug effect. The present study has certain limitations and advantages. It is based on TIS population, which may not represent the general population, but has an appropriate comparison group. Other limitations of the study are: reliance on maternal interview as a source for outcome data and lack of medical records in most cases, lack of direct physical examination including visual and hearing evaluation as part of the study protocol, lack of a comparison group with similar disease unexposed to HCQ, a nonrandomized design, limited number of participants, and therefore, insufficient statistical power, especially for specific rare outcomes. However, applying the same procedure to both arms of the study and the prospective nature minimize the potential biases. In pregnancy, randomized controlled trials are often not feasible, due to ethical considerations. All data are from a single center. Data were available on elective terminations of pregnancies and were included in the analysis. Finally, the relatively large number of HCQ-exposed cases gives reasonable power. In conclusion, the present prospective observational comparative cohort study supports the safety of HCQ use in pregnant women. The lack of cases of neonatal lupus erythematosus or of congenital cardiac block among the neonates born to mothers treated with HCQ in pregnancy for rheumatic diseases suggests that the absolute risk for these complications is low.
Conflict of interest The authors declare that there is no conflict of interest.
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Contents lists available at SciVerse ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Pregnancy outcome following in utero exposure to hydroxychloroquine: A prospective comparative observational study夽 Orna Diav-Citrin a,b,∗ , Shani Blyakhman c,1 , Svetlana Shechtman a , Asher Ornoy a,b a b c
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel The Hebrew University Hadassah Medical School, Jerusalem, Israel The Division of Clinical Pharmacy, The Hebrew University of Jerusalem, Israel
a r t i c l e
i n f o
Article history: Received 9 December 2012 Received in revised form 2 April 2013 Accepted 4 April 2013 Available online 17 April 2013 Keywords: Hydroxychloroquine Rheumatologic diseases Pregnancy Congenital anomalies
a b s t r a c t Objective: To evaluate pregnancy safety of hydroxychloroquine (HCQ) for rheumatologic diseases. Design: Prospective comparative observational study done at the Israeli teratology information service between 1998 and 2006. Results: 114 HCQ-exposed pregnancies (98.2% in the first trimester, T1) were followed-up and compared with 455 pregnancies of women counseled for non-teratogenic exposure. The difference in the rate of congenital anomalies was not statistically significant [7/97 (7.2%) vs. 15/440 (3.4%), p = 0.094]. The analysis was repeated among those exposed in T1 excluding genetic or cytogenetic anomalies or congenital infections [5/95 (5.3%) vs. 14/440 (3.2%), p = 0.355]. There were no cases of neonatal lupus erythematosus. The gestational age at delivery was earlier, rate of preterm delivery higher, and birth weight lower, in the HCQ group. Conclusion: The present study suggests that HCQ treatment in pregnancy is not a major human teratogen. The earlier gestational age and lower birth weight might be associated with maternal disease. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Hydroxychloroquine (HCQ) sulfate is a 4-aminoquinoline antimalarial medication and an anti-inflammatory agent. It is used in the treatment of rheumatological diseases including systemic lupus erythematosus (SLE), discoid lupus (DL) and rheumatoid arthritis (RA), at higher than anti-malarial doses [1]. These illnesses are more common in women and can occur at childbearing age. HCQ crosses the human placenta [2]. Animal reproductive studies are available only for the closely related agent, chloroquine. Chloroquine produced anophthalmia and microphthalmia at high doses (1000 mg/kg) in rats [3]. In animal models retinal toxicity of chloroquine has been documented [4]. Retinal degeneration has been reported in two infants after prenatal exposure to chloroquine for malaria prophylaxis [5]. Congenital anomalies were reported in three siblings whose mother was treated during pregnancy with 250–500 mg/d of chloroquine for discoid lupus. Two of the
夽 Previous presentation at the 22nd conference of the Organization of Teratology Information Specialists (OTIS), Rio Grande, Puerto Rico, 2009. ∗ Corresponding author at: The Israeli Teratology Information Service, Israel Ministry of Health, P.O. Box 1176, Jerusalem 9446724, Israel. Tel.: +972 2 5080441; fax: +972 2 6474822. E-mail address: [email protected] (O. Diav-Citrin). 1 Acknowledgment: This work is part of the MSc thesis in Clinical Pharmacy of the Hebrew University of Mrs. Shani Blyakhman. 0890-6238/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.reprotox.2013.04.005
siblings were born with cochlear-vestibular paresis and one with left hemihypertrophy and Wilms’ tumor [6]. Ocular and auditory side effects are known toxicities of chloroquine. Chloroquine has been safely used during pregnancy in chemosuppression of malaria [7–9]. Several case series have been published on the safe use of HCQ in pregnancy at antirheumatic doses [10–15]. Two case series focused on ocular assessment of children exposed to HCQ in pregnancy and found no ophthalmic abnormalities [16,17]. Contrary to the above negative studies, neurophysiological visual disturbances were detected on electroretinograms and visual evoked potentials testing in a subset of infants exposed in utero to HCQ [18]. Concerns were later raised in regard to the methodology used [19] and answered by the authors [20]. There is a case control study reporting safe use of HCQ in pregnant patients with rheumatic disease [21]. Three additional controlled studies have been published on the safety of HCQ in pregnancy in rheumatic diseases [22–24]. The largest one included evaluations of hearing, vision, growth and development with no apparent adverse effects [23]. In a recent meta-analysis the odds ratio of congenital defects in live-births of women taking HCQ during pregnancy for auto-immune diseases was 0.66 (95% CI 0.25, 1.75) [25]. SLE has been associated with an increased risk of pregnancy loss (miscarriage and stillbirth), intrauterine growth restriction, preeclampsia, and preterm delivery [26,27]. Neonatal lupus erythematosus, consisting of congenital heart block, transient cutaneous lupus lesions, cytopenia, hepatic or/and other systemic
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manifestations has been described in infants born to mothers with SLE, Sjögren’s syndrome, or other rheumatic diseases with positive anti-Ro or anti-La antibodies [26]. The primary objective of the present study was to prospectively evaluate the rate of major congenital anomalies after in utero exposure to HCQ compared to a group counseled for non-teratogenic exposures. Secondary endpoints of interest were pregnancy outcome, birth weight, and gestational age at delivery. In addition, the aim was to prospectively evaluate the rate of neonatal lupus erythematosus or congenital cardiac block among the infants born to mothers with rheumatic diseases. 2. Materials and methods Women who contacted the Israeli Teratology Information Service (TIS), Jerusalem, Israel, in regard to gestational exposure to HCQ between the years 1998 and 2006, were enrolled in the present prospective comparative observational study. The Israeli TIS offers counseling services in regard to environmental exposures during pregnancy. The HCQ-exposed group was compared to a randomly selected group of women among those who contacted the Israeli TIS during pregnancy being exposed to agents known not to be teratogenic in a similar time frame (comparison group), at a 1:4 ratio. Details of exposure were collected during pregnancy, at the initial contact to the TIS and before pregnancy outcome was known, using a structured questionnaire. Verbal consent to participate in the study was given by each woman at initial contact. Since the study was observational with no intervention, no Institutional Review Board approval was required, consistent with the internal policy of Israel Ministry of Health at the time the study was performed. In addition, the following information was recorded: maternal demographics, medical and obstetrical histories, and exposure details (dose, duration, and timing in pregnancy). Retrospective cases were not included in the study. Pregnant women who contacted the TIS after an anomaly had been identified on prenatal testing were also excluded. After the expected date of delivery, pregnancy outcome was actively sought after in the HCQ-exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies and neonatal complications. In addition, HCQ and other exposures were ascertained. In Israel, each neonate undergoes at least two physical examinations before being discharged from the hospital. The interview was conducted after these physical examinations. Data collection methods were similar in the HCQ-exposed and comparison groups. Major anomalies were defined as structural anomalies in the offspring that have serious medical, surgical or cosmetic consequences [28]. Children with minor anomalies or functional problems without any morphological changes (e.g. systolic heart murmur with normal echocardiography, slight developmental delay) or complications of preterm delivery were not considered as having major anomalies. Septal defects were considered major anomalies in the present study. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) were included in our study, since antenatal screening for major anomalies is routinely performed in Israel. The analysis of major congenital anomalies was performed among all liveborn infants and fetuses with diagnosed anomalies. In the case of multiple births, each live-born offspring was included in the analysis.
3. Statistical analysis Categorical data were compared by 2 or Fisher exact tests and are expressed as ratios or percentages. Continuous data are presented using mean ± SD or median with interquartile range and compared using the Student-t or Mann–Whitney tests, depending on whether they followed normal distribution, or did not. Statistical calculations were done using SPSS Version 16 or Epi InfoTM software (Center for Disease Control and Prevention, Atlanta Epidemiology Program Office, Atlanta, GA, USA).
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6.2%. Additional medications for the rheumatic disease were taken in 79.8% of the HCQ group. Two or more additional medications were taken by 47.4% of the cohort. Concurrent medications included: steroids (60.5%), low dose aspirin (31.6%), low molecular weight heparins (23.7%), azathioprine (15.8%), non-steroidal anti-inflammatory drugs (14.0%), and sulfasalazine or mesalamine (9.6%). The comparison group consisted of 455 pregnancies of women counseled for non-teratogenic exposure by the Israeli TIS. A comparison of maternal characteristics and obstetrical history between the two groups is presented in Table 1. The gestational age at initial contact was earlier in the HCQ group compared to the comparison group. There were no significant differences between the groups either in the pregnancy order, parity, or history of miscarriages, elective terminations of pregnancy (ETOP), and stillbirths, except for a higher proportion of women in the HCQ group who had no liveborn children yet and who had one previous ETOP. There were no significant differences between the groups in maternal age or distribution of cigarette smokers. A comparison of pregnancy outcome between the groups is presented in Table 2. There was a 2.1-fold increase in the rate of miscarriages in the HCQ group. In order to analyze the increase in the miscarriage rate in the HCQ group, logistic regression was performed. Various predictors were entered into the model (smoking status, maternal age, history of miscarriage, gestational age at initial contact and type of exposure). The higher rate of miscarriages was significantly associated with an earlier age at initial contact (p < 0.001) and a higher maternal age (p = 0.003). The adjusted odds ratio for miscarriages for the HCQ vs. the comparison group was 1.35 [95% confidence interval (CI) 0.61–2.97]. There were no significant differences in the rate of elective terminations of pregnancy or stillbirths between the groups. The rate of congenital anomalies was higher in the HCQ group [7/97 (7.2%) vs. 15/440 (3.4%), p = 0.094], however, the difference was not statistically significant. The rate of major anomalies, after first trimester exposure without chromosomal or genetic anomalies or congenital infections, was also not significantly different between the two groups [5/95 (5.3%) (HCQ) vs. 14/440 (3.2%) (comparison), p = 0.355). The median gestational age at delivery was two weeks earlier, the rate of preterm delivery was 3.6-fold higher and the median birth weight was 500 g lower in the HCQ group compared to the comparison group. The difference in the mean birth weight was significant but less pronounced (275 g lower in the HCQ group) when the comparison was conducted among singleton full-term infants only. The difference in mean birth weight was similar and approximately 300 g lower in both subgroups of neonates exposed to HCQ in the first trimester only or in the third trimester. There was a higher rate of Cesarean sections in the HCQ group. The list of major congenital anomalies in the HCQ group is presented in Table 3. The anomalies varied with no observed pattern. All the anomalies in the HCQ group were diagnosed during pregnancy or in the first year of life, most perinatally. There were no cases of neonatal lupus erythematosus or of congenital cardiac block among the neonates born to mothers treated with HCQ in pregnancy for rheumatic diseases.
4. Results A total of 114 HCQ-exposed pregnancies were prospectively followed-up in the present study. The exposure was at least in the first trimester of pregnancy in 98.2% of the HCQ group. The medication was taken throughout pregnancy in 59.6% of the HCQexposed pregnancies. The median daily dose [interquartile range (IQR) between the 25 and 75th percentiles] of HCQ was 300 mg (200–400). The indications for the treatment with HCQ in the exposed group were as follows: SLE in 69.0%, RA in 22.1%, DL in 2.7%, and other (Behc¸et’s disease and Sjögren’s syndrome) in
5. Discussion In the present prospective observational comparative cohort study, 114 HCQ-exposed pregnancies were followed-up. There was a higher rate of congenital anomalies in the HCQ group, however, not statistically significant. A sample size of 95 live-births or elective terminations of pregnancy due to prenatally diagnosed anomalies in the HCQ group exposed in the first trimester of pregnancy enables detection of a 3.5-fold increase in the overall rate of
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Table 1 Maternal characteristics and obstetrical history. HCQ group n = 114
Comparison group n = 455
30 (27–34)
30 (27–34)
0.356
36/109 (33.0) 61/109 (56.0) 12/109 (11.0)
117/422 (27.7) 247/422 (58.5) 58/422 (13.7)
0.276 0.628 0.452
Paritya (%) 0 1–4 ≥5
12/73 (16.4) 59/73 (80.8) 2/73 (2.7)
22/304 (7.2) 266/304 (87.5) 16/304 (5.3)
0.014 0.137 0.364
Previous miscarriagea (%) 0 1–3 ≥4
48/72 (66.7) 22/72 (30.6) 2/72 (2.8)
221/305 (72.5) 80/305 (26.2) 4/305 (1.3)
0.328 0.457 0.322
Previous ETOPa (%) 0 1 ≥2 Previous stillbirtha (%) Gestational age at initial contact median (IQR)
57/72 (79.2) 13/72 (18.1) 2/72 (2.8) 3/72 (4.2) 7 (5–12)
265/305 (86.9) 30/305 (9.8) 10/305 (3.3) 3/305 (1.0) 10 (6–17)
0.095 0.048 1.000 0.052 <0.001
Cigarette smoking (%) 0 <10cig./d ≥10cig./d
100/106 (94.3) 3/106 (2.8) 3/106 (2.8)
371/400 (92.8) 12/400 (3.0) 17/400 (4.3)
0.795 1.000 0.799
Maternal age (years) median (IQR) Pregnancy order (%) 1 2–4 ≥5
p value
IQR: interquartile range; ETOP: elective termination of pregnancy. a Calculations were made excluding women who called regarding their first pregnancy. Table 2 Pregnancy outcome.
Multiple gestations Live-born infants Delivery (%) Miscarriage (%) ETOP (%) Stillbirth (%) Major anomalies (%)b Major anomalies without chromosomal or genetic anomalies or congenital infections, T1 (%)b Gestational age at delivery weeks median (IQR) Preterm delivery, ≤36 (%) Birth weight g median (IQR) Birth weight, singleton full-term, g mean ± SD Birth weight, singleton full-term, T1 , g mean ± SD Birth weight, singleton full-term, T3 , g mean ± SD Delivery method (%) Vaginal spontaneous uncomplicated C/S Vacuum Other (Vaginal induced, forceps)
HCQ group n = 114
Comparison group n = 455
2 twin setsa 96 95/115 (82.6) 13/115 (11.3) 6/115 (5.2) 1/115 (0.9) 7/97 (7.2) 5/95 (5.3)
14 twin sets, 1 triplets 434 418/455 (91.9) 24/455 (5.3) 9/455 (2.0) 4/455 (0.9) 15/440 (3.4) 14/440c (3.2)
p value
38 (36–39) 27/95 (28.4) 2750 (2275–3300) 3050 ± 527 3016 ± 433 3025 ± 603
40 (38–41) 33/413 (8.0) 3250 (2880–3543) 3325 ± 448 3308 ± 457c 3308 ± 457c
<0.001 <0.001 <0.001 <0.001 0.002 0.004
44/95 (46.3) 29/95 (30.5) 7/95 (7.4) 15/95 (15.8)
299/417 (71.7) 81//417 (19.4) 21/417 (5.0) 16/417 (3.8)
<0.001 0.017 0.367 <0.001
0.003 0.019 0.093 1.000 0.094 0.355
IQR: interquartile range; ETOP: elective termination of pregnancy; SD: standard deviation; T1 : first trimester; T3 : third trimester; C/S: Cesarean section. a One twin pregnancy counted as two outcomes (ETOP and delivery). b Including ETOPs (elective termination of pregnancy) due to prenatally diagnosed anomalies. c Irrespective of trimester of exposure. Table 3 List of major congenital anomalies in the HCQ group. Anomaly
HCQ details, disease
Outcome, w
Gender, BW g
Additional medications
Comments
Spina bifida DDH DDH VSD Congenital hypothyroidism (permanent) Inguinal herniaa Congenital toxoplasmosis, blindness (right)a
400 mg/d T1 , RA 200 mg/d T1 , SLE 400 mg/d T1 , RA 200 mg/d T1 , SLE 200 mg/d T1–3 , SLE, CD
ETOP, 13 Delivery, 39 Delivery, 38 Delivery, 38 Delivery, 36
F F, 3300 M, 2750 M, 3225 F, 1888
One of twins Braces Braces Closed at 1.5 y Thyroxine treatment
200 mg/d T3 , SLE 400 mg/d T1–3 , SLE
Delivery, 37 Delivery, 34
M, 2800 M, 1900
Prednisone 10 mg/d, sulfasalazine 2 g/d Prednisone 2.5 mg/d None Aspirin 100 mg/d Budesonide 6 mg/d, azathioprine 100 mg/d, mesalamine 3g/d Aspirin 100 mg/d, enoxaparin Prednisone 7.5 mg/d, azathioprine 100 mg/d
Operated Diagnosed after birth
DDH: developmental dysplasia of hip; VSD: ventricular septal defect. a Excluded from the repeated analysis because the exposure was not in the first trimester or if the anomaly was a result of a congenital infection, HCQ: hydroxychloroquine; T1 : first trimester; T3 : third trimester; RA: rheumatoid arthritis; SLE: systemic lupus; CD: Crohn’s disease; w: gestational week; ETOP: elective termination of pregnancy; BW g: birth weight in grams; F: female; M: male; y: year.
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major anomalies. This calculation is based on a baseline risk of 3.2% for major anomalies with a ratio of 1:4.6 (95:440) to the comparison group, 80% power and 95% CI. The rate of major anomalies in both the HCQ and the comparison groups was within the expected baseline risk for the general population. The results of the present study are consistent with most previous reports, not associating HCQ exposure during pregnancy with a teratogenic risk in humans. This study confirms that HCQ does not represent a major teratogenic risk when used in clinically recommended doses in humans [10–17,21–25]. The lack of cases of neonatal lupus erythematosus among the neonates born to mothers treated for rheumatic diseases is not surprising, due to the relatively small sample size for specific rare outcomes. In the present study, the higher rate of miscarriages was associated with an earlier gestational age at initial contact (with higher miscarriage rate in women calling earlier in pregnancy) and a higher maternal age, but not with the exposure group (HCQ vs. nonteratogenic exposure in the comparison group), as verified by the regression analysis. Some investigators have shown a correlation between disease activity, miscarriages and fetal loss in pregnant SLE patients [29]. Pregnancy loss rates were reported in 11–24% in lupus patients [30–33]. Based on a recently published metaanalysis [25], the OR of miscarriage was 0.92 (95% CI 0.49–1.72), and of stillbirth 0.97 (95% CI 0.14–6.54), favoring patients taking HCQ. The earlier gestational age at delivery, the higher rate of preterm deliveries and the lower birth weight in the HCQ group may be associated with the underlying maternal disease, HCQ effect, or a combination of the two. A higher incidence of preterm deliveries was reported in SLE patients, especially those with active disease [30,34]. Based on the published meta-analysis [25], there was no significant increase in the risk of preterm delivery associated with HCQ treatment [OR 1.10 (95% CI 0.75–1.61)]. The subgroup analysis showing similar decrease in birth weight in women exposed to HCQ only in the first trimester of pregnancy and women exposed in the third trimester of pregnancy suggests the disease as the underlying factor rather than a drug effect. The present study has certain limitations and advantages. It is based on TIS population, which may not represent the general population, but has an appropriate comparison group. Other limitations of the study are: reliance on maternal interview as a source for outcome data and lack of medical records in most cases, lack of direct physical examination including visual and hearing evaluation as part of the study protocol, lack of a comparison group with similar disease unexposed to HCQ, a nonrandomized design, limited number of participants, and therefore, insufficient statistical power, especially for specific rare outcomes. However, applying the same procedure to both arms of the study and the prospective nature minimize the potential biases. In pregnancy, randomized controlled trials are often not feasible, due to ethical considerations. All data are from a single center. Data were available on elective terminations of pregnancies and were included in the analysis. Finally, the relatively large number of HCQ-exposed cases gives reasonable power. In conclusion, the present prospective observational comparative cohort study supports the safety of HCQ use in pregnant women. The lack of cases of neonatal lupus erythematosus or of congenital cardiac block among the neonates born to mothers treated with HCQ in pregnancy for rheumatic diseases suggests that the absolute risk for these complications is low.
Conflict of interest The authors declare that there is no conflict of interest.
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