The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark.
The Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø, Denmark.
Hum Reprod. 2022 May 30;37(6):1324-1333. doi: 10.1093/humrep/deac041.
Is female infertility among women seeking medically assisted reproduction (MAR) associated with prevalent as well as incident multiple sclerosis (MS)?
Women with a record of female infertility did not have an increased risk of developing MS compared with apparent fertile women; however, the prevalence of MS was slightly higher among women undergoing MAR compared with women who had a child without MAR, but this was not related to origin of infertility (i.e. male versus female factor infertility).
Women with MS have fewer children compared with women without MS. Persons with MS more often have other coexisting autoimmune disorders including hypothyroidism compared with the general population. Thyroid dysfunction is associated with ovarian cause of infertility, miscarriage and ovarian failure. Conversely, women with endometriosis, that is highly associated with infertility, also more often have other coexisting autoimmune diseases including MS and hypothyroidism compared with the general population. However, whether the low fertility rate among women with MS is due to a genetically predisposition to other autoimmune and endocrine disorders that leads to reduced fertility, or an active choice of the woman, disease-related pathology or treatment-specific effect on endocrine and/or ovarian function, is not completely understood.
STUDY DESIGN, SIZE, DURATION: A register-based cohort study of a total of 310 357 women from 1996 to 2018. A cross-sectional design was used for analysing prevalence of MS, whereas a cohort design with up to 24 years of follow-up was used for analysing incidence of MS.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Three cohorts were included in the study (i) 55 404 women with a female infertility diagnosis registered in the Danish IVF register; (ii) 25 096 women with only male factor infertility recorded in the IVF register and thus no female infertility diagnosis and (iii) 229 857 age- and calendar-matched women with a record of first child birth in the Danish Medical Birth Register (DMBR) and no record ever in the IVF register. The prevalence and incidence of MS in the female infertility cohort were compared with the two control cohorts of apparent fertile women using log-binomial regression and Cox proportional hazard regression, respectively.
The crude prevalence of having MS per 1000 persons was 3.2 for women who had undergone MAR treatment regardless of origin of infertility (i.e. male versus female factor infertility) and 2.3 for fertile DMBR controls. The age, calendar and educational level adjusted prevalence ratio of having a diagnosis of MS at the first MAR treatment was 1.27 (95% CI 1.07-1.52) for infertile women compared with fertile DMBR controls, and 1.00 (95% CI 0.77-1.31) for comparison to women with a male partner with infertility who had also undergone MAR treatment. We found no association between incident MS and female infertility compared with either of the control groups of fertile women.
LIMITATIONS, REASON FOR CAUTION: The cohort of infertile women is highly selected on the basis of their choice of having fertility treatment and thus does not include women with unestablished infertility or women who, for some reason, have chosen not to have MAR treatment. Additionally, due to the nature of the observational study design, we cannot exclude the possibility of unmeasured and/or residual confounding.
Our results suggest that women with MS may undergo MAR treatment more often than women without MS due to more awareness about the possibility of MAR treatments, sexual dysfunction related to MS disease, but also need for timing of the pregnancy to avoid an unnecessary long time period without disease modifying therapy-especially of high efficacy-and hence a wish to conceive quickly. These findings are important for clinicians dealing with women with MS of childbearing age.
STUDY FUNDING/COMPETING INTEREST(S): The authors received no financial support for the study. T.I.K. has served on a scientific advisory board for Novartis and has received support for congress participation from Biogen. M.M. has served on scientific advisory boards for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie and Alexion. She has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck and Novartis. The remaining authors declare no conflict of interest.
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在接受医学辅助生殖（MAR）治疗的女性中，女性不孕与多发性硬化症（MS）的现患率和发病率是否相关？
与明显生育能力的女性相比，有记录的女性不孕的女性发生 MS 的风险没有增加；然而，与没有 MAR 生育的女性相比，正在接受 MAR 的女性的 MS 患病率略高，但这与不孕的起源（即男性因素与女性因素不孕）无关。
与没有 MS 的女性相比，患有 MS 的女性生育的孩子较少。患有 MS 的人更常患有其他共存的自身免疫性疾病，包括甲状腺功能减退症，比一般人群更常见。甲状腺功能障碍与卵巢性不孕、流产和卵巢衰竭有关。相反，患有子宫内膜异位症的女性，其与不孕高度相关，也比一般人群更常患有其他共存的自身免疫性疾病，包括 MS 和甲状腺功能减退症。然而，患有 MS 的女性生育率低是由于遗传易感性导致其他自身免疫和内分泌疾病，从而降低了生育能力，还是女性的主动选择、疾病相关的病理或治疗对内分泌和/或卵巢功能的特定影响，目前尚不完全清楚。
研究设计、规模、持续时间：一项基于注册的队列研究，共纳入了 1996 年至 2018 年的 310357 名女性。采用横断面设计分析 MS 的现患率，采用队列设计并随访长达 24 年分析 MS 的发病率。
参与者/材料、设置、方法：研究纳入了三个队列：（i）55404 名在丹麦 IVF 登记处登记的女性不孕症诊断患者；（ii）25096 名仅在 IVF 登记处记录有男性因素不孕的女性，因此没有女性不孕症诊断；（iii）229857 名在丹麦医疗出生登记处（DMBR）记录有首次分娩且从未在 IVF 登记处记录的年龄和日历匹配的女性。使用对数二项式回归和 Cox 比例风险回归分别比较女性不孕症队列与两个对照组（有生育能力的 DMBR 对照组）中 MS 的现患率和发病率。
MAR 治疗的女性中，每 1000 人中有 3.2 人患有 MS，无论不孕的原因（即男性因素与女性因素不孕）如何，而 DMBR 有生育能力的对照组为 2.3。与 DMBR 有生育能力的对照组相比，首次 MAR 治疗时诊断为 MS 的年龄、日历和教育水平调整后患病率比为 1.27（95%CI 1.07-1.52），与接受过 MAR 治疗的男性伴侣有不育症的女性相比为 1.00（95%CI 0.77-1.31）。与两个有生育能力的女性对照组相比，我们没有发现女性不孕与新发 MS 之间存在关联。
局限性、谨慎的原因：不孕女性队列是基于她们选择接受生育治疗的高度选择性，因此不包括未确诊不孕的女性或出于某种原因选择不接受 MAR 治疗的女性。此外，由于观察性研究设计的性质，我们不能排除未测量和/或残留混杂的可能性。
我们的研究结果表明，患有 MS 的女性可能比没有 MS 的女性更经常接受 MAR 治疗，原因可能是她们对 MAR 治疗的可能性有更多的认识、与 MS 疾病相关的性功能障碍，以及为了避免不必要的长时间没有疾病修正治疗（尤其是高疗效的治疗）而希望尽快怀孕的愿望。这些发现对治疗生育年龄的 MS 女性的临床医生很重要。
研究资金/利益冲突：作者没有从这项研究中获得任何经济支持。TIK 曾担任过诺华和百健的科学顾问委员会成员，并因参加大会获得了罗氏、诺华、默克、艾伯维和亚力兄的支持。她曾因在 Biogen、Merck、Novartis、Sanofi 和 Genzyme 发表演讲而获得酬金，并从 Biogen、Merck、Novartis、Sanofi 和 Genzyme 获得研究支持和参加大会的支持。其余作者均声明不存在利益冲突。
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