==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 1805911610.5144/0256-4947.2007.448asm-6-448Case ReportSevere neonatal pulmonary hypertension secondary to antenatal maternal diclofenac ingestion reversed by inhaled nitric oxide and oral sildenafil Mersal Ali Attili Ihab Alkhotani Abdulaziz From the Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi ArabiaCorrespondence and reprint requests: Ali Mersal, MD, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, MBC 58-J, P.O. Box 40047, Jeddah 21499, Saudi Arabia, Tel: +966-2-607-0532, Fax: +966-2-667-7777 ext. 3508, alimersal@dr.comNov-Dec 2007 27 6 448 449 01 3 2007 Copyright © 2007, Annals of Saudi Medicine2007This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. ==== Body The nonsteroidal anti-inflammatory drugs (NSAID), which act as inhibitors of prostaglandin synthesis, are widely used in clinical practice as tocolytic agents.1 Administration of these agents in pregnancy, however, carries a potential risk to the fetus. Indomethacin can cause premature closure of the ductus arteriosus,1 which may lead to serious fetal and neonatal complications including oligohydramnios, hyperbilirubinemia, pulmonary hypertension, necrotizing enterocolitis and intraventricular hemorrhage.2,3 Diclofenac (Voltaren), closely related to indomethacin, is one of the group used to treat pain and fever, and it may cause the same fetal and neonatal complications. CASE A 37-year-old Saudi woman had an uneventful pregnancy until 38 weeks gestation when she was operated on for thrombosed hemorrhoids. She was given diclofenac sodium for pain, 50 mg orally three times a day. After 3 days she noticed decreased fetal movement. Subsequently, oligohydramnios and fetal distress developed, which led to cesarean section. The baby weighed 2 900g. Soon after birth the baby developed severe respiratory distress and cyanosis. After a trial of aggressive ventilation for severe hypoxemia at the referring hospital, she showed no improvement. Oxygen saturation was 60% on FiO2 of 100% and her oxygen index (OI) was 40. She was resuscitated and transferred to our institution at 20 hours of age. An echocardiogram done at the referral hospital and repeated in our center revealed right ventricular hypertrophy, moderate tricuspid regurgitation, closed ductus arteriosus and severe pulmonary hypertension. A high frequency oscillatory ventilator (HFOV), dopamine, dobutamine and milrinone all failed to improve oxygen saturation. Inhaled nitric oxide (iNO) at 20 ppm also resulted in no improvement. After 2 days, sildenafil was added as adjunctive therapy at 0.15 mg orally every eight hours. Within 24 hours oxygen saturation improved to 88% and the OI declined to 15 (Figure 1). iNO was weaned and then completely discontinued. Sildenafil was given for 2 weeks. The baby was discharged in excellent condition at 3 weeks of age. Two weeks later, the echocardiogram was normal. DISCUSSION The pathophysiology leading to pulmonary hypertension in our patient is most likely related to NSAID exposure in late gestation. The patency of the ductus arteriosus is maintained in utero with dilatatory prostaglandins such as (prostaglandin E). Closure of the fetal ductus arteriosus in utero can be either spontaneous or due to pharmacological agents such as NSAIDs.4 It usually begins with progressive constriction of the vessel walls, which initially leads to very high flow velocities from the pulmonary trunk towards the descending aorta.5 In cases with severe constriction or closure, the ductus arteriosus can no longer function as a conduit of right ventricular flow into the descending aorta. More blood is directed to the pulmonary arteries, which leads to pulmonary hypertension.1 Although most studies involved indomethacin in animal models, Mommas et al,6 who studied the effect of various NSAIDs on the ductus of fetal rats, demonstrated that diclofenac exerts an equally severe constrictive action as indomethacin. Thus, fetal exposure in late gestation provides the likely explanation for increased susceptibility to irreversible ductal constriction followed by severe pulmonary hypertension in our patient. Zenker et al reported a similar case where he used iNO alone. It required 22 days for pulmonary hypertension to be controlled and the patient subsequently developed papillary muscle necrosis. 6 Our patient was perfectly healthy at discharge and at follow up in 4 weeks. Our experience replicates those reported by Kendavello et al and Atz et al, where sildenafil had an augmentation effect and prevented a rebound pulmonary hypertension or hypertensive crisis during weaning of nitric oxide. The addition of sildenafil lead to a shorter duration of therapy and minimized the possible damaging effects of pulmonary hypertension and its complications.7,8 When pulmonary hypertension occurs, early transfer to a tertiary care center with the availability of nitric oxide should take place as soon as possible. In severe cases with pulmonary hypertension with suboptimal response to iNO, adjunctive therapy with sildenafil should be considered. Our experience and that of others8,9 should be confirmed by randomized double blind controlled studies to prove the safety and efficacy of sildenafil in neonates. Pregnant women should be instructed not to use NSAIDs during pregnancy. Figure 1 Average oxygen index and oxygen saturation in the neonate over first 2 weeks of life. ==== Refs REFERENCES 1 Auer M Brezinka C Eller P Luze K Schweigmann U Schwarzler P Prenatal diagnosis of intrauterine premature closure of the ductus arteriosus following maternal diclofenac application Ultrasound Obstetric and Gynecol 2004 23 513 516 2 Ostenesen M Optimisation of antirhumatic drug treatment in pregnancy Clin Pharmacokinet 1994 27 486 503 7882637 3 Mois KJ Huhta JC Sharif DS Indomethacin in the treatment of preterm labour N Eng J Med 1988 319 327 331 4 Hofstadler G Tulzer G Altmann R Schmitt K Danford D Huhta JC Spontaneous closure of the human fetal ductus arteriosus a cause of fetal congestive heart failure Am J Obstet Gynecol 1996 174 879 883 8633660 5 Tulzer G Gudmundsson S Tews G Wood DC Huhta JC Incidence of indomethacin-induced human fetal ductul constriction J Matern Fetal Invest 1992 1 267 269 6 Zinker M Klinge J Kruger C Singer H Scharf Severe pulmonary hypertension in a neonate caused by premature closure of ductus arteriosus following maternal treatment with diclofenac J Perinat Med 1998 26 231 234 9773385 7 Siu KL Lee WH Maternal diclofenac sodium ingestion and severe neonatal pulmonary hypertension J Pediatr Child Health 2004 40 152 153 8 Kandavello G Choo K Kalid F Samion H Alwi M Leman H The use of sildenafil during weaning of nitric oxide in severe pulmonary hypertension post cardiac surgery Pediatr Crit Care Med 2005 6 3 395 9 Atz AM Lefler AK Fairbrother DL Uber WE Sildenafil augments the effect of (iNO) for postoperative pulmonary hypertension crises Journal of Thoracic & Cardiovascular Surgery 2002 124 3 628 629 12202882