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Take home messages on management of Wilson Disease in the Indian scenario Chairpersons: Aabha Nagral, Prashanth LK,SK Yachha Wilson disease and pregnancy Chairpersons: Aabha Nagral, Prashanth LK,SK Yachha Talk: RK Dhiman Wilson’s Disease and Pregnancy Radha K Dhiman, MD, DM, FAMS, FACG, FRCP Edin, FRCP London, FAASLD Department of Hepatology PGIMER, Chandigarh Email: [email protected] Concerns in WD’s Female Patients Menstruation, Marriage, conception, pregnancies, Recurrent abortions, Teratogenicity secondary to drugs, Breast-feeding, Genetic counseling Pregnancies in Symptomatic and Asymptomatic Wilson’s Disease N=341, Retrospective M:F = 239:102 (74 in reproductive age group (15–45 years) 16 women conceived at least once on 59 occasions 7 (31.8%) failed to conceive Spontaneous abortions - 24 occasions (40.7%) 3 (5.1%) stillbirths 30 (50.8%) successful pregnancies and deliveries in 12 mothers Sinha S, Neurological Sciences 2004 Pregnancies in Symptomatic and Asymptomatic Wilson’s Disease None of the neurological signs or symptoms worsened during pregnancy 6 patients on treatment for several years Penicillamine (250 mg/day) and zinc sulphate (1320 mg/day) during pregnancy No teratogenicity Sinha S, Neurological Sciences 2004 Fertility Amenorrhea, oligomenorrhea, irregular menses, and multiple miscarriages Nonspecific consequences of hepatic dysfunction Diffusion of non–ceruloplasmin-bound copper from plasma into tissues, a process that may affect the ovarian follicular aromatase activity Kaushanksy A, et al, Fertil Steril 1987 Spontaneous Abortions Recurrent spontaneous abortions Chronic liver disease, endocrinal disorders and anemia Increased copper deposition in uterus prevents implantation of fetus Rate of spontaneous abortion in India is 5% versus WD - 40.7% More in untreated group Scheinberg IH, NEJM 1975; Sinha S, Neurological Sciences 2004 Teratogenicity - Penicillamine Documented in laboratory animals and patients treated for other conditions like RA and cystinuria Cutis laxa like syndrome, micrognathia, low-set ears, hyperflexibility of joints, fragile veins, varicosity and impaired wound healing Major factor – copper deficiency in the fetus High proportion of unbound copper, which is chelated by penicillamine and excreted, thus effectively reducing the penicillamine levels. Rosa et al, Teratology 1986; Cohen et al, Drug-Nutr Interact 1983; Keen et al, Teratology 1983; Mjolnerod et al, Lancet 1971; Solomon et al, MEJM 1977 Breast Feeding Women taking D-penicillamine should not breast-feed Drug is excreted into breast milk and might harm the infant. Little is known about the safety of trientine and zinc in breast milk. Pregnancies in Women Taking Penicillamine Women Pregnancies Normal Defects (n) (n) Neonates Wilson’s Disease Center 43 71 69 2 therapeutic abortions Case Reports 32 41 38 1 mannosidosis, 1 cleft lip and palate, 2 transient Cutis laxa Walshe 35 40 36 1 premature, 2 Therapeutic abortions, 1 miscarriage Westermark 1 1 1 111 153 144 Total Sternlieb, Hepatology 2000 Pregnancies in Women Taking Trientine Women (n) Pregnancies Normal Defects (n) Neonates Wilson’s Disease Center 4 6 6 Case Reports 2 2 2 Walshe 2 14 11 Total 11 22 19 1 miscarriage, 1 therapeutic abortion, 1 isochromosome x Sternlieb, Hepatology 2000 Drugs Used in WD Drug Advantage Disadvantage In pregnancy Penicillamine [Reductive Fast acting 20-50% risk of neurologic worsening High incidence of toxicity 100% efficacy, Teratogenic in animals Trientine [Reductive chelation and cupruria] Rapid action High incidence of adverse 100% efficacy, toxicity Teratogenic in Moderate incidence of toxicity animals Zinc [Induction of Low toxicity Slow acting Disease progression chelation and cupruria] intestinal cell metallothionein] No teratogenicity EASL/AASLD Recommendation Treatment for Wilson’s disease should be continued during pregnancy, but dosage reduction is advisable for D-penicillamine and trientine EASL - GRADE II-3, B, 1 AASLD - Class I, Level C Therapy Mothers and infants tolerate pregnancy safely, providing that compliance with the prescribed regimen is maintained. Dose First 2 trimesters - 0.75 to 1 g of either penicillamine or trientine Last trimester - 0.5 g/d Interruption of therapy carries a high risk of hemolytic episodes with hepatic insufficiency and fatality for the mother Teratogenic effects of either penicillamine or trientine are not supported by data Shimono N, et al. Gastroenterol Jpn 1991 Save Dates Many sessions for Pediatric Gastroenterology and Hepatology Complementary “Registration, Accommodation and Travel” for Students/Trainees (MD, DM, DNB and PhDs) Thank You Therapy Interruption of therapy carries a high risk of hemolytic episodes with hepatic insufficiency and fatality for the mother. Five successful pregnancies in same women with WD