|TERIS Agent Number:||2765||Bibliographic Search Date:||05/2020|
|Hydroxychloroquine is a 4-aminoquinoline compound that is administered orally to treat malaria, systemic lupus erythematosus, antiphospholipid syndrome, or other autoimmune disorders. Hydroxychloroquine is eliminated from the body very slowly following cessation of treatment. The half-life in blood is about 50 days.|
Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
Quality and Quantity of Data on Which Risk Estimate is Based:
1) THERAPEUTIC DOSES OF HYDROXYCHLOROQUINE DURING PREGNANCY ARE UNLIKELY TO POSE A SUBSTANTIAL TERATOGENIC RISK, BUT THE DATA ARE INSUFFICIENT TO STATE THAT THERE IS NO RISK.
2) MATERNAL HYDROXYCHOLOROQUINE TREATMENT APPEARS TO REDUCE THE OCCURRENCE OF NEONATAL LUPUS-ASSOCIATED HEART BLOCK IN HIGH-RISK PREGNANCIES (SEE BELOW).
3) MATERNAL HYDROXYCHOLOROQUINE TREATMENT DURING PREGNANCY MAY LOWER THE RISK OF PREECLAMPSIA AND IMPROVE PREGNANCY OUTCOMES IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS OR ANTIPHOSPHOLIPID ANTIBODY SYNDROME (SEE BELOW).
Summary of Teratology Studies:
MAJOR CONGENITAL ANOMALIES
A meta-analysis of seven observational cohort studies and one randomized controlled trial published between 1996 and 2014 showed no significant increase in major malformations in the infants of a total of 698 women with autoimmune diseases who had been treated with hydroxychloroquine during the first trimester of pregnancy in comparison to infants of women who were not treated during pregnancy (Kaplan et al., 2016). No increase in the frequency of craniofacial, cardiovascular, genitourinary, or nervous system malformations among infants whose mothers had been treated with hydroxychloroquine was found in these studies, either, but the statistical power of these comparisons is limited (Kaplan et al., 2016). The findings were similar in a partially-overlapping systematic review of earlier studies (Sperber et al., 2009).
No abnormalities of growth, development, vision, or hearing related to the mothers’ hydroxychloroquine treatment during pregnancy were found among more than 250 children who were assessed at one to three years of age (Klinger et al., 2001; Levy et al., 2001; Costedoat-Chalumeau et al., 2003, 2004; Cimaz et al., 2004; Motta et al., 2005; Clowse et al., 2006; Osadchy et al., 2011; Tarfaoui et al., 2013). Abnormalities were observed on the electroretinograms of six of 21 three- to seven-month-old infants whose mothers had been treated with hydroxychloroquine during pregnancy in another study (Renault et al., 2009), but the reliability of the techniques used for neurophysiological assessment of vision in this study have been questioned (Ingster-Moati & Albuisson, 2010). Ocular abnormalities did not appear to be unusually frequent among 309 children whose mothers had taken hydroxychloroquine during pregnancy in a recent systematic review (Gaffar et al., 2019).
Four epidemiological studies have reported that maternal hydroxychloroquine use during pregnancy is associated with a lower risk of neonatal lupus-associated cardiac block in high risk pregnancies (Izmirly et al., 2010; 2012; Tunks et al., 2013; Barsalou et al., 2018).
No abnormality of immunological function was found at one, six, or 12 months of life among 19 infants whose mothers had been treated during pregnancy with immunosuppressive agents for autoimmune disease (Motta et al., 2007). The maternal therapy included hydroxychloroquine in 15 of these cases.
OTHER ADVERSE PERINATAL OUTCOMES
Hydroxychloroquine is used to treat systemic lupus erythematosus, antiphospholipid syndrome, and other autoimmune diseases that, when present during pregnancy, are associated with increased risks of spontaneous abortion, pre-eclampsia and other adverse pregnancy outcomes (Schreiber & Hunt, 2019; Petri, 2020). Finding such outcomes in women who are treated with hydroxychloroquine during pregnancy may reflect confounding by indication, and reduced rates of these conditions among treated women may reflect improvements in the mother's health rather than any direct effect on the embryo or fetus.
An increased risk of spontaneous abortions (odds ratio=1.85, 95% confidence interval 1.10-3.13) was found in a meta-analysis that included 373 pregnancies in women who were treated hydroxychloroquine, but this association may reflect confounding by underlying disease activity (Kaplan et al., 2016). Stillbirths were not increased in 571 hydroxychloroquine-treated pregnancies in this meta-analysis. No significant association with spontaneous abortion or fetal death was seen among pregnancies in women with autoimmune diseases who had been treated with hydroxychloroquine in a systematic review of studies published between 1980 and 2007 (Sperber et al., 2009).
In two partially overlapping meta-analyses of recent epidemiological studies, Kaplan et al. (2016) and Guillotin et al. (2018) found no association of maternal hydroxychloroquine treatment during pregnancy with low birth weight. Similarly, the risk of low birth weight for gestational age was no greater than expected among the infants of 114 mothers treated with hydroxychloroquine during pregnancy in a Canadian population-based record linkage study (Howren et al., 2020).
A significantly lower rate of preterm delivery was observed among women treated with hydroxychloroquine during pregnancy compared to untreated pregnant women with lupus or antiphospholipid antibody syndrome in three retrospective cohort studies (Leroux et al., 2015; Sciascia et al., 2016; Do et al., 2020). Another recent cohort study found that preterm delivery occurred at later gestational ages in women with lupus who were treated with hydroxychloroquine (Kroese et al. 2017).
Premature delivery was no more frequent than expected for women who were treated with hydroxychloroquine during pregnancy in two partially overlapping reviews of other recent studies (Kaplan et al., 2016, Guillotin et al., 2018).
ANIMAL TERATOLOGY STUDIES
Animal teratology studies of hydroxychloroquine conducted by the manufacturer have not been published in the peer-reviewed literature.
Barsalou J, Costedoat-Chalumeau N, Berhanu A, Fors-Nieves C, Shah U, Brown P, Laskin CA, Morel N, Levesque K, Buyon JP, Silverman ED, Izmirly PM: Effect of in utero hydroxychloroquine exposure on the development of cutaneous neonatal lupus erythematosus. Ann Rheum Dis 77(12):1742-1749, 2018. [E]
Cimaz R, Brucato A, Meregalli E, Muscara M, Sergi P: Electroretinograms of children born to mothers treated with hydroxychloroquine during pregnancy and breast-feeding: comment on the article by Costedoat-Chalumeau et al. Arthritis Rheum 50(9):3056-3057, 2004. [S]
Clowse ME, Magder L, Witter F, Petri M: Hydroxychloroquine in lupus pregnancy. Arthritis Rheum 54(11):3640-3647, 2006. [E]
Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DLT, Sebbough D, Wechsler B, Vauthier D, Denjoy I, Lupoglazoff J-M, Piette J-C: Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 48(11):3207-3211, 2003. [E]
Costedoat-Chalumeau N, Amoura Z, Sebbough D, Piette J-C: Electroretinograms of children born to mothers treated with hydroxychloroquine during pregnancy and breast-feeding: comment on the article by Costedoat-Chalumeau et al. Arthritis Rheum 50(9):3057-3058, 2004. [S]
Do SC, Rizk NM, Druzin ML, Simard JF: Does hydroxychloroquine protect against preeclampsia and preterm delivery in systemic lupus erythematosus pregnancies? Am J Perinatol 37(9):873-880, 2020. [E]
Gaffar R, Pineau CA, Bernatsky S, Scott S, Vinet E: Risk of ocular anomalies in children exposed in utero to antimalarials: a systematic literature review. Arthritis Care Res 71(12):1606-1610, 2019. [R]
Guillotin V, Bouhet A, Barnetche T, Richez C, Truchetet M-E, Seneschal J, Duffau P, Lazaro E; Federation Hospitalo-Universitaire ACRONIM: Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: a systematic review and meta-analysis. Joint Bone Spine 85(6):663-668, 2018. [R]
Howren A, Rebic N, Sayre EC, Tsao NW, Amiri N, Baldwin C, De Vera MA: Perinatal exposure to conventional synthetic disease-modifying anti-rheumatic drugs in women with rheumatic disease and neonatal outcomes: a population-based study. Clin Exp Rheumatol 2020 Mar 5 (published online ahead of print). [E]
Ingster-Moati I, Albuisson E: Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero. Acta Paediatr 99(1):4, 2010. [O]
Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, Friedman D, Llanos C, Piette J-C, Buyon JP: Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 126(1):76-82, 2012. [E]
Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, Salmon JE, Buyon JP: Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis 69(10):1827-1830, 2010. [E]
Kaplan YC, Ozsarfati J, Nickel C, Koren G: Reproductive outcomes following hydroxychloroquine use for autoimmune diseases: a systematic review and meta-analysis. Br J Clin Pharmacol 81(5):835-848, 2016. [R]
Klinger G, Morad Y, Westall CA, Laskin C, Spitzer KA, Koren G, Ito S, Buncic RJ: Ocular toxicity and antenatal exposure to chloroquine or hydroxychloroquine for rheumatic diseases. Lancet 358(9284):813-814, 2001. [S]
Kroese SJ, de Hair MJH, Limper M, Lely AT, van Laar JM, Derksen RHWM, Fritsch-Stork RDE: Hydroxychloroquine use in lupus patients during pregnancy is associated with longer pregnancy duration in preterm births. J Immunol Res 2017:2810202. 2017. [E]
Leroux M, Desveaux C, Parcevaux M, Julliac B, Gouyon J-B, Dallay D, Pellegrin JL, Boukerrou M, Blanco P, Lazaro E: Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study. Lupus 24(13):1384-1391, 2015. [E]
Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JLMB, Tura BR, Albuquerque EMN, Jesus NR: Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 10(6):401-404, 2001. [E]
Motta M, Ciardelli L, Marconi M, Tincani A, Gasparoni A, Lojacono A, Chirico G: Immune system development in infants born to mothers with autoimmune disease, exposed in utero to immunosuppressive agents. Am J Perinatol 24(8):441-447, 2007. [E]
Motta M, Tincani A, Faden D, Zinzini E, Lojacono A, Marchesi A, Frassi M, Biasini C, Zatti S, Chirico G: Follow-up of infants exposed to hydroxychloroquine given to mothers during pregnancy and lactation. J Perinatol 25(2):86-89, 2005. [S]
Osadchy A, Ratnapalan T, Koren G: Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol 38(12):2504-2508, 2011. [R]
Petri M: Pregnancy and systemic lupus erythematosus. Best Pract Res Clin Obstet Gynaecol 64:24-30, 2020. [R]
Renault F, Flores-Guevara R, Renaud C, Richard P, Vermersch AI, Gold F: Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero. Acta Paediatr 98(9):1500-1503, 2009. [S]
Schreiber K, Hunt BJ: Managing antiphospholipid syndrome in pregnancy. Thromb Res 181(Suppl 1):S41-S46, 2019. [R]
Sciascia S, Hunt BJ, Talavera-Garcia E, Lliso G, Khamashta MA, Cuadrado MJ: The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol 214(2):273.e1-273.e8, 2016. [E]
Sperber K, Hom C, Chao CP, Shapiro D, Ash J: Systematic review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr Rheumatol Online J 7:9, 2009. [R]
Tarfaoui N, Autret-Leca E, Mazjoub S, Cissoko H, Jonville-Bera AP: [Hydroxychloroquine during pregnancy: a review of retinal toxicity in the newborns.] Therapie 68(1):43-47, 2013. [R]
Tunks RD, Clowse MEB, Miller SG, Brancazio LR, Barker PCA: Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol 208(1):64.e1-64.e7, 2013. [E]
The Organization of Teratology Information Services (OTIS) is conducting a nationwide, prospective study in an effort to gain additional information regarding autoimmune diseases, their treatment during pregnancy, and the potential effects of the treatment on the developing embryo or fetus.
Women within their first 19 weeks of pregnancy, living in the United States or Canada, who have an autoimmune disease, and who may or may not be using medication are eligible to enroll. All information collected will remain strictly confidential. Identity of the women and their children will not be used in any report or publication and all files are kept in a locked cabinet.
The coordinating center for the study is located at the University of California, San Diego Medical Center in the Department of Pediatrics. The medical director is Dr. Kenneth Lyons Jones, a pediatrician and specialist in birth defects. More information about the study can be found at the MotherToBaby (OTIS) website: https://mothertobaby.org/ongoing-studies/
Contact Information for Referrals: