Service de Médecine Interne et RECIF, Centre Hospitalo-Universitaire Amiens-Picardie, Amiens, France.
Laboratoire d'Hématologie, Centre de Biologie Humaine, Centre Hospitalo-Universitaire Amiens-Picardie, Amiens, France.
Hum Reprod. 2024 Sep 1;39(9):1934-1941. doi: 10.1093/humrep/deae146.
What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester?
In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages.
Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL.
STUDY DESIGN, SIZE, DURATION: The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth.
One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P = 0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31-7.83], P = 0.01).
LIMITATIONS, REASONS FOR CAUTION: Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered.
Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system.
STUDY FUNDING/COMPETING INTEREST(S): The research received no specific funding, and the authors declare no competing interests.
clinicaltrial.gov NCT05557201.
在有复发性妊娠丢失（RPL）病史的女性中，暴露于羟氯喹（HCQ）的妊娠结局如何？哪些因素可以预测这些妊娠在孕 12 周后继续妊娠的情况？
在我们的 RPL 病史女性妊娠队列中，我们发现，唯一决定这些妊娠结局的因素是既往流产的次数。
母体免疫系统失调在 RPL 中起作用。HCQ 具有双重免疫调节和血管保护作用，是治疗不明原因 RPL 的潜在药物。
研究设计、规模、持续时间：FALCO（早发性复发性流产的因素）注册是一个正在进行的法国多中心不孕不育注册中心，成立于 2017 年，包括来自几家大学医院的有自发性 RPL（至少三次早期流产（≤12 周妊娠（WG））病史的 18 至 49 岁的女性。
参与者/材料、设置、方法：FALCO 注册中心招募了有 HCQ 暴露史（受孕前或妊娠早期）的自发性妊娠。排除同时暴露于肿瘤坏死因子抑制剂、白细胞介素-1 和 -2 抑制剂、静脉免疫球蛋白和/或静脉内脂质乳剂输注的妊娠。允许同时使用小剂量阿司匹林（LDA）、低分子量肝素（LMWH）、孕酮和/或泼尼松治疗。所有患者均接受了 RPL 调查的推荐评估。那些怀孕的患者按照法国的建议接受了产科护理，并进行了前瞻性随访。主要终点是妊娠持续超过 12 WG，次要终点是活产。
评估了 74 名女性中 100 例有 HCQ 暴露的妊娠。女性的平均年龄为 34.2 岁，既往流产的中位数为 5 次。78%（78 例）的妊娠同时暴露于泼尼松，56%（56 例）的妊娠同时暴露于 LDA，41%（41 例）的妊娠同时暴露于 LMWH。62%（62 例）的妊娠在 12 WG 内结束，38%（38 例）的妊娠在 12 WG 后继续。经历额外早期自发性流产的风险随着既往流产次数的增加而增加，但与年龄无关。在≤12 WG 的妊娠和在 12 WG 后继续妊娠的妊娠中，RPL 调查中发现的异常分布和其他药物的暴露分布相似。具有至少一种阳性自身抗体（Ab）（即抗核 Ab 滴度≥1:160、≥1 种阳性传统和/或非传统抗磷脂 Ab 和/或≥1 种抗甲状腺 Ab 阳性）且无卵巢储备功能减退的妊娠中，妊娠进展超过 12 WG 的发生率并不高于无此类自身抗体的妊娠（18/51，35.3%）与无此类自身抗体的妊娠（18/45，40.0%）（P=0.63）。多变量分析显示，在调整年龄和受孕前 HCQ 使用时间后，既往流产≤4 次是预测妊娠>12 WG 的唯一显著因素（调整后优势比（OR）=3.13 [1.31-7.83]，P=0.01）。
局限性、谨慎的原因：我们的研究有一些局限性，包括缺乏对照组、一些患者的 RPL 诊断程序数据不完整、以及无法进行子宫内膜活检结果，以及关于父亲年龄和行为因素的信息。因此，并非所有潜在的混杂因素都能被考虑到。
在有 RPL 病史的女性妊娠早期暴露于 HCQ 似乎并不能阻止进一步的流产，这表明它对与母体免疫系统相关的机制影响有限。
研究资金/利益冲突：该研究没有获得特定的资金支持，作者没有利益冲突。
clinicaltrial.gov NCT05557201。
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