Abstract INTRODUCTION The acute hepatic porphyrias (AHPs) are disorders of heme biosynthesis characterized by neurovisceral symptoms and significant morbidity. Acute attacks are triggered by induction of the hepatically-synthesized enzyme, aminolevulinic acid synthase-1 (ALAS-1). Common precipitating factors include medications and fluctuations in hormones, particularly progesterone, during the menstrual cycle. Notably, over 90% of patients with symptomatic AHP are female; however, existing data on the impact of the menstrual cycle, contraceptive use, pregnancy, and menopause on AHP symptoms are scarce. To address this critical knowledge gap, we sought to comprehensively characterize the influence of these reproductive health factors in AHP with the goal of informing and improving clinical decision making. METHODS We conducted a nationwide survey of adult female patients in the US with documented AHP. Patients were recruited by their porphyria specialists or by targeted advertisement through a patient advocacy organization. We collected detailed data on overall AHP severity and the relationship between AHP symptoms and menstrual cycles, contraceptive use, pregnancy, and menopause. Responses about symptom changes (much worse to much better) were scored on a 5-point ordinal scale. Only patients with at least one lifetime porphyria attack were included in the analysis. We used Wilcoxon signed-rank test and Generalized Estimating Equations to compare observed response distributions to those expected under the null hypothesis of no change. RESULTS Of 120 patients contacted, 103 (85.8%) completed the survey. Three patients reported no lifetime attacks and were excluded from subsequent analysis, resulting in 100 who were eligible for inclusion. The distribution of AHPs included acute intermittent porphyria (79.0%), variegate porphyria (10.0%), hereditary coproporphyria (9.0%), and unknown subtype (2.0%). Fifty-seven percent reported ≥10 lifetime porphyria attacks. During the 5 years prior to survey completion, 51 patients received hemin and 44 received givosiran (an RNAi that suppresses hepatic ALAS-1). AHP symptoms were reported to be worse immediately before menstruation in 61 participants, during menstruation in 33, and after menstruation in 14, with respondents able to select multiple choices. Lifetime contraceptive use included combined estrogen-progestin oral contraceptive pills (cOCPs; 60 participants), levonorgestrel intrauterine device (LNG-IUD; 23 participants) progesterone-only pills (POPs; 9 participants), depot medroxyprogesterone (11 participants), and estrogen-progestin vaginal rings (7 participants). Use of cOCPs (p0.001), POPs (p=0.048), and depot medroxyprogesterone (p=0.003) were significantly associated with symptom worsening, whereas LNG-IUD (p=0.69) and copper IUD (p=0.66) were not associated with perceived worsening or improvement in symptoms. Sixty-eight patients experienced 156 pregnancies, with a median of 2 (IQR, 1-3) per patient. During pregnancy, thirty-six patients (52.9%) reported no change in their AHP symptoms, 13 (19.1%) reported improvement, and 19 (27.9%) reported worsening. Eighteen (11.5%) of pregnancies were complicated by gestational hypertension, 12 (7.7%) by pre-eclampsia, and 6 (3.8%) by fetal growth restriction. Five patients received hemin during pregnancy, and no patient was treated with givosiran during pregnancy. Of 45 women who breastfed, 44 (97.8%) reported no worsening of their symptoms with lactation. Postmenopausal participants (n=37) reported no significant change in AHP symptoms with menopause (p=0.19), although perimenopause (n=43) was associated with symptom worsening (p0.001). CONCLUSION In this US nationwide study of 100 female patients with AHP, we characterized the relationships between reproductive health factors and disease burden. Use of cOCPs, POPs, and depot medroxyprogesterone was associated with worsening of AHP symptoms, while LNG and copper IUDs appeared to be better tolerated. Pregnancy and lactation generally did not exacerbate symptoms of AHP, whereas perimenopause was associated with symptom worsening. We found no significant change in symptoms during menopause. These results highlight the complex relationship between reproductive health and AHP and underscore the need for additional dedicated research in this area.
Leaf et al. (Mon,) studied this question.