immunosuppressive drugs & treatment of HTN in pregnancy Nephrology dept. R2 우용식

immunosuppressive drugs in pregnancy

GLUCOCORTICOIDS cleft palate, mental retardation, and fatal adrenal hypoplasia reported in humans after in utero steroid exposure during preg. PROM and intrauterine growth restriction. pregnancy-induced HTN, gestational DM, osteoporosis suppression of the hypothalamic pituitary adrenal axis in newborn : infrequent and transient Recommendations : lowest effective glucocorticoid dose possible, avoidance of therapy during 1st trimester > 20 mg PDL, interval of breast feeding – 4hrs FDA use in pregnancy rating - B

CYCLOPHOSPHAMIDE 1 st trimester : cyclophosphamide embryopathy – growth restriction, ear & facial abnormalities, absence of digits, hypoplastic limbs 2 nd,3 rd trimester : 2 women treated for SLE fetal demise. (Clowse et al. 2005) 36 women treated for breast cancer without reported adverse pregnancy or neonatal events (Berry et al. 1999) Recommendations : avoid during preg. except life-threatening, no alternative. breast feeding is prohibited preg. test before theraphy if, child bearing age FDA use in pregnancy rating - D

AZATHIOPRINE 64 ~ 93% administered to mothers appears in fetal blood as inactive metabolites. - fetal liver lack of inosinate pyrophosphorylase lower birth wt., prematurity, jaundice, RDS, aspiration, dose-related myelossupresion Recommendations : can be used,necessary during pregnancy. feeding no recommended d/t excreted in to breast FDA use in pregnancy rating - D

CYCLOSPORINE conflicting reports on transfer of cyclosporine across the human placenta during preg. PROM and intrauterine growth restriction. pregnancy-induced HTN, gestational DM complication rate in newborns was slightly lower in cyclosporine group and no malformations were seen. (Armeti et al. Transplantation 1994, 27 : 502)

CYCLOSPORINE cyclosporine metabolism increased during preg. - higher dose requirement to therapeutic level pre-eclampsia complicated by cyclosporin - limited to 2~4mg/kg/day Recommendations : alternative to other immunosuppressant during preg. long-term effects, exposed in utero is unknown. breast feeding not recommended FDA use in pregnancy rating - C

TACROLIMUS paucity of data about effect of tacrolimus 60% premature among 100 pregnancies in 84 women (Kaniz et al. Transplantation 2000) 4 babies with malformations - no consistent pattern of anatomic abnormality FDA use in pregnancy rating - C

MYCOPHENOLATE MOFETIL animals, cause problems with development of ova humans, case report of in utero exposure causing hypoplastic nails,short 5th fingers ; no other abnormalities were noted Recommendations : avoid using medication during preg.,nursing d/t paucity of available information, FDA use in pregnancy rating - C

OKT3 Immunoglobulin G - cross placenta 4 surviving infants among 5 woman with OKT3 - NTPR reported, 1997 FDA use in pregnancy rating - C

CONCLUSION immunosuppressive regimen of transplant recipients - glucocorticoids, azathioprine, cyclosporine. for pregnant,autoimmune disease mild – immunosuppressant avoided. low dose glucocorticoids (PDL 5~15mg/day) moderate to severe - glucocorticoids, azathioprine, cyclosporine, IVIG tolerated by fetus. life-threatening - high-dose steroid, cyclosporine azathioprine cyclophosphamide reserved for cases of no alternative available.

CONCLUSION Nephrol Dial Transplant : 703

Treatment of hypertension in pregnancy

Blood pressure goal preg. without end-organ damage systolic pr. -140~150 mmHg diastolic pr. - 90~100 mmHg preg. with end-organ damage below 140/90 mmHg, go as low as 120/80 mmHg.

methyldopa : most widely used in preg. and long-term safety hydralazine : safe and used frequently Beta-blocker : generally safe labetalol is the preferred agent. atenolol - impair fetal growth early in preg non selective BB – not used d/t risk of uterine contraction

ACEi and angiotensin receptor antagonists : serious adversed effects – oligohydroamnios, neonatal anuria, renal failure, death Calcium channel blocker : no incresed congenital anomalies

First choice : methyldopa or labetalol. 2nd or 3rd line : long acting calcium channel blocker (nifedipine or amlodipine) normal fall in BP during 2nd trimester reduction in dose or cessation

Breastfeeding mothers Beta blockers and calcium channel blockers : enter breast milk; safe during lactation labetalol & propranolol preferred for initial choice SR nifedipine or verapamil alternatives ACE inhibitors and angiotensin receptor : avoided in the neonatal period, but considered after time. Diuretics reduce milk volume and should be avoided.