Multiple sclerosis (ms) is a chronic demyelinating neurological disease result-ing from the predominately T cell-mediated autoimmune destruction of oligodendrocytes which synthesise myelin.1 The disease affects women twice as often as men and symptoms usually present when patients are between 20 and 40 years old, which means that women of reproductive age are the most susceptible.1 Several disease-modifying drugs (DMDs) have been reported to reduce the frequency of clinical MS attacks and are prescribed with the intent of slowing disability progression; these medications include interferon (IFN)-β 1a and 1b, glatiramer acetate, natalizumab, mitoxantrone and fingolimod, with IFN-β and glatiramer acetate currently considered first-line therapies.1 Many newer agents are also being introduced, including tyrosine kinase inhibitors.2,3 Unfortunately, recent evidence has emerged regarding the potential pregnancy-related adverse effects of DMDs.4 In general, DMD therapy is discontinued during pregnancy, although the actual risk of adverse effects occurring due to IFN-β and glatiramer acetate appears to be low.5 This report describes a pregnant woman who took IFN-β throughout her first trimester and subsequently developed severe placental complications. Case Report A 30-year-old gravida 2 para 1 woman presented to the Tawam Hospital, Al Ain, United Arab Emirates, in 2013. She had been diagnosed with relapsing-remitting MS five years previously, after she had developed unilateral optic neuritis with frequent relapses. These symptoms had progressed two years later to epilepsy and left-sided haemiplegia and her MS was re-classified as secondary progressive MS. She was prescribed IFN-β 1a at a dose of 30 µg weekly as a lifelong 1Department of Pharmacy, Sheikh Zayed Hospital, Abu Dhabi, United Arab Emirates; 2Department of Obstetrics & Gynaecology, Tawam Hospital, Al Ain, United Arab Emirates *Corresponding Author e-mail: ssdocpharm@gmail.com األدوية املغرية للمرض قد تؤدي إىل قصور املشيمة مضاعفات حادة يف مشيمِة امرأٍة حامٍل ومصابٍة مبرض التصلب املتعدد �صلطان حممد �صالح الدين و موزيبوني�صا بيجام abstract: Disease-modifying drugs (DMDs) such as interferon (IFN)-β and glatiramer acetate are often prescribed to slow disability progression in patients with multiple sclerosis (MS). However, adverse pregnancy outcomes have been reported with these medications. We report the rare occurrence of severe placental complications in a 30-year- old pregnant woman with MS who continued to take IFN-β during her first trimester. She presented at the Tawam Hospital, Al Ain, United Arab Emirates, in 2013 with early-onset fetal growth restriction. At 30 gestational weeks, she developed severe pre-eclampsia. The baby was delivered via emergency Caesarean section and was discharged at the age of two months. Continuation of IFN-β during pregnancy may have contributed to the development of placental insufficiency in this patient. Increased education regarding the risks of DMDs for pregnant patients with MS is very important to ensure successful pregnancy outcomes. Keywords: Multiple Sclerosis; Interferon Beta; Pre-Eclampsia; Fetal Growth Retardation; Placental Insufficiency; Case Report; United Arab Emirates. امللخ�ص: يعترب عقاري البيتا انتريفريون وا�صيتات اجللتيمرات من االأدوية امل�صتخدمة الإبطاء االإعاقة يف مر�صى الت�صلب املتعدد، وهناك ت�صارب يف البيانات اخلا�صة بتاأثري هذه االأدوية علي احلمل، هذا تقرير حالة عن حدوث م�صاعفات �صديدة يف م�صيمة اأمراأة حامل يف 2013م عام املتحدة العربية االإمارات يف بالعني توام مل�صت�صفى املري�صة ح�رضت املتعدد، الت�صلب مبر�ض م�صابة العمر من الثالثني مع نق�ض مبكر يف منو اجلنني، يف االأ�صبوع الثالثني من احلمل تعر�صت املراأة مل�صاعفات احلمل ومت توليد الطفل ب�صكل طارئ عن طريق العملية القي�رضية، ومت ترخي�ض الطفل بعد �صهرين، اإن ا�صتمرار تعاطي عقاقري املر�ض يف الثالثة �صهور االأوىل من احلمل اأّدى ذلك اإىل حدوث ق�صور يف امل�صيمة، يجب االإهتمام بتثقيف وتوعية املر�صى امل�صابني بالت�صلب املتعدد عن هذه املخاطر من اأجل نتائج ناجحة للحمل. كلمات مفتاحية: الت�صلب املتعدد؛ انرتفريون بيتا؛ ا�صيتات اجللتيمرات؛ ت�صمم احلمل؛ تاأخر منو اجلنني؛ ق�صور امل�صيمة؛ تقرير حالة. Disease-Modifying Drug Possibly Linked to Placental Insufficiency Severe placental complications in a pregnant woman with multiple sclerosis *Sultan M. Salahudheen1 and Muzibunnisa A. Begam2 case report Sultan Qaboos University Med J, August 2016, Vol. 16, Iss. 3, pp. e368–370, Epub. 19 Aug 16 Submitted 8 Feb 16 Revision Req. 21 Mar 16; Revision Recd. 30 Mar 16 Accepted 7 Apr 16 doi: 10.18295/squmj.2016.16.03.019 Sultan M. Salahudheen and Muzibunnisa A. Begam Case Report | e369 prophylactic therapy as well as levetiracetam at a dose of 750 mg twice daily to control her epilepsy. In 2013, she conceived spontaneously; however, the medication was discontinued only at 13 gestational weeks after her first visit to an obstetrician. Levetiracetam was continued throughout her pregnancy. During her pregnancy, the patient remained stable; however, a fetal ultrasound at 22 gestational weeks indicated that all fetal growth parameters had decreased. Severe early-onset fetal growth restriction (FGR) was diagnosed. The results of a detailed anatomic survey, karyotyping by amniocentesis and a virology screening test were normal. However, prenatal ultrasonography revealed that the fetus had an echogenic mildly dilated bowel [Figure 1], most probably due to ischaemia. A uterine artery Doppler ultrasound revealed high-resistance flow with early diastolic notching [Figure 2A] and an umbilical artery Doppler ultrasound showed absent end-diastolic flow [Figure 2B]. Additionally, the patient suffered from oligohydramnios. These findings were suggestive of placental insufficiency as the cause for early-onset FGR. The patient was subsequently monitored with a series of biophysical tests. At 30 gestational weeks, the patient developed severe pre-eclampsia that was further complicated by HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome. As a result, an emergency Caesarean section was performed and the patient was given full high-intensive care to manage the pre- eclampsia, including magnesium sulphate infusions, serial monitoring of vitals and renal and respiratory function tests. Post-delivery, the patient had an uneventful recovery and was discharged eight days after the Caesarean section in stable condition with the advice to continue IFN-β as lifelong prophylactic therapy. In this case, the placenta was not sent for histopathology examination; it is recommended to do so in future cases. At birth, the female baby weighed 980 g and was admitted to the Neonatal Unit of Tawam Hospital. A physical examination did not reveal any malformations or abnormalities. The neonate required a postnatal course of surfactant for respiratory distress. She also required total parenteral nutrition initially but subsequently tolerated enteral feeds. She was discharged at the age of two months. Discussion There are four clinical types of MS, including relapsing-remitting MS, secondary progressive MS, primary progressive MS and progressive-relapsing MS. Generally, DMDs are recommended for patients who suffer from relapsing forms of MS, such as relapsing-remitting MS or secondary progressive MS with exacerbations; the prescription criteria include abnormal neurological examinations, several MS attacks and a high burden of disease as assessed by magnetic resonance imaging of the brain.1 The patient in the current case was an ideal candidate for DMDs as she was first diagnosed with relapsing-remitting MS, which then progressed to secondary progressive MS with permanent neurological complications. Hence, she was on lifelong prophylactic therapy with IFN-β 1a. Figure 1: Prenatal ultrasonography of a pregnant woman with multiple sclerosis showing a fetus with a mildly dilated echogenic bowel. Figure 2A & B: Doppler ultrasonography of (A) the uterine arteries revealing high-resistance flow with early diastolic notching (arrow) and (B) the umbilical artery showing absent end-diastolic flow in a pregnant woman with multiple sclerosis. EDN = early diastolic notching ; RT = right; AEDF = absent end-diastolic flow. Disease-Modifying Drug Possibly Linked to Placental Insufficiency Severe placental complications in a pregnant woman with multiple sclerosis e370 | SQU Medical Journal, August 2016, Volume 16, Issue 3 Conclusion This case describes severe placental complications in a pregnant woman with MS who continued taking IFN-β during her first trimester. The continuation of this DMD well into the period of full placental development may have contributed to the development of early-onset FGR and pre-eclampsia in this patient. However, further research into this issue is required to determine whether these factors are related. It is advisable that women who continue taking DMDs during their pregnancies should be followed-up closely to assess and prevent the development of fetal and maternal complications. References 1. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J. Harrison’s Principles of Internal Medicine, 18th ed. New York, USA: McGraw-Hill Professional, 2012. Pp. 3395–409. 2. Mirshafiey A, Ghalamfarsa G, Asghari B, Azizi G. Receptor tyrosine kinase and tyrosine kinase inhibitors: New hope for success in multiple sclerosis therapy. Innov Clin Neurosci 2014; 11:23–36. 3. Azizi G, Mirshafiey A. Imatinib mesylate: An innovation in treatment of autoimmune diseases. Recent Pat Inflamm Allergy Drug Discov 2013; 7:259–67. doi: 10.2174/1872213 X113079990021. 4. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy: A systematic review. Neurology 2012; 79:1130–5. doi: 10.1212/ WNL.0b013e3182698c64. 5. Cunningham FG, Leveno KJ, Bloom SL, Spong CY, Dashe JS, Hoffman BL, et al. Williams Obstetrics, 24th ed. New York, USA: McGraw-Hill Education/Medical, 2013. Pp. 1187–1203. 6. Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, et al. Levetiracetam in pregnancy: Results from the UK and Ireland epilepsy and pregnancy registers. Neurology 2013; 80:400–5. doi: 10.1212/WNL.0b013e31827f0874. 7. Hellwig K, Brune N, Haghikia A, Müller T, Schimrigk S, Schwödiauer V, et al. Reproductive counselling, treatment and course of pregnancy in 73 German MS patients. Acta Neurol Scand 2008; 118:24–8. doi: 10.1111/j.1600-0404.2007.00978.x. 8. Stuart M, Bergstrom L. Pregnancy and multiple sclerosis. J Midwifery Womens Health 2011; 56:41–7. doi: 10.1111/j.1542- 2011.2010.00008.x. 9. Parham P, Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat Rev Immunol 2013; 13:133–44. doi: 10.1038/nri3370. 10. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002; 2:656–63. doi: 10.1038/nri886. 11. Mifsud W, Sebire NJ. Placental pathology in early-onset and late-onset fetal growth restriction. Fetal Diagn Ther 2014; 36:117–28. doi: 10.1159/000359969. 12. Salafia CM, Minior VK, Pezzullo JC, Popek EJ, Rosenkrantz TS, Vintzileos AM. Intrauterine growth restriction in infants of less than thirty-two weeks’ gestation: Associated placental pathologic features. Am J Obstet Gynecol 1995; 173:1049–57. doi: 10.1016/0002-9378(95)91325-4. 13. Manaster I, Mandelboim O. The unique properties of uterine NK cells. Am J Reprod Immunol 2010; 63:434–44. doi: 10.11 11/j.1600-0897.2009.00794.x. In the current case, the patient was prescribed levetriacetam monotherapy to control her epilepsy during pregnancy. With levetriacetam, the risk of major congenital malformations is comparable with that of the non-epileptic population, indicating the relative safety of the drug.6 On the other hand, a systematic review reported that IFN-β exposure was associated with lower mean birth weight, shorter mean birth length and preterm birth, although the drug was not associated with increased risk of low birth weight infants (<2,500 g), Caesarean section delivery, congenital anomalies or spontaneous abortion.4 Due to the limited data regarding the effect of DMDs on pregnancy outcomes, women are advised to stop taking the drug either three months or at least one month prior to conception.7,8 Close follow-up is recommended for patients who continue taking DMDs during their pregnancies in order to assess and prevent the development of any fetal or maternal complications. Women with MS should be given more education regarding the risks of DMDs in pregnancy. Extra-villous trophoblast (EVT) cells are fetal cells that invade the mother’s uterus, where they transform the spiral arteries into large vessels capable of conducting sufficient blood to the placenta.9 Early trophoblast invasion is important for placental function and the extent of arterial transformation by the trophoblasts affects successful reproductive outcomes.9 Severe early-onset FGR overlapping with severe pre-eclampsia, as in the present case, is mainly associated with features of impaired maternal uteroplacental perfusion secondary to defective EVT invasion, which results in insufficient blood supply to the placenta.10,11 Placental histopathological findings generally reflect abnormal uteroplacental flow with secondary chronic fetal vasoconstriction and distal villous changes.11,12 Trophoblast invasion is controlled by the uterine natural killer cells (uNK cells), the most common uterine leukocyte.9,13 The efficacy of IFN-β in patients with MS is due to its immunomodulatory properties; the drug downregulates major histocompatibility molecules on antigen-presenting cells, inhibits proinflammatory cytokine levels, increases regulatory cytokine levels, inhibits T cell proliferation and limits the trafficking of inflammatory cells in the nervous system.1 These properties evidently oppose the effects of uNK cells.9,13 The patient in the current case took IFN-β until the 13th week of her pregnancy, which is when EVT invasion and placental development occurs.9 How- ever, further research is required to determine whether DMDs are related to placental insufficiency. Studies using experimental animal models are recommended to assess the relationship between IFN-β and EVT invasion or placental development. http://dx.doi.org/10.2174/1872213X113079990021 http://dx.doi.org/10.2174/1872213X113079990021 http://dx.doi.org/10.1212/WNL.0b013e3182698c64 http://dx.doi.org/10.1212/WNL.0b013e3182698c64 http://dx.doi.org/10.1212/WNL.0b013e31827f0874 http://dx.doi.org/10.1111/j.1600-0404.2007.00978.x http://dx.doi.org/10.1111/j.1542-2011.2010.00008.x http://dx.doi.org/10.1111/j.1542-2011.2010.00008.x http://dx.doi.org/10.1038/nri3370 http://dx.doi.org/10.1038/nri886 http://dx.doi.org/10.1159/000359969 http://dx.doi.org/10.1016/0002-9378%2895%2991325-4 http://dx.doi.org/10.1111/j.1600-0897.2009.00794.x http://dx.doi.org/10.1111/j.1600-0897.2009.00794.x