First successful case of in-utero medical management of fetal cervical lymphatic malformation using sirolimus in Singapore

Dear Sir, Prenatal ultrasonography allows the diagnosis of lymphatic malformations (LMs) during prenatal life. Recent evidence suggests that somatic genetic mutations and upregulation in the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)/mTOR pathway may contribute to their aetiopathogenesis.[1] Sirolimus, an immunosuppressant that inhibits the mTOR pathway and decreases cell proliferation and lymphangiogenesis, is a new medical therapy for vascular malformations.[2,3,4] We report Singapore’s first successful case of fetal treatment using sirolimus for a rapidly enlarging cervical LM that was causing tracheal deviation and polyhydramnios. Our patient is a 38-year-old Vietnamese woman with her third pregnancy. Routine screening ultrasonography at 20.2 weeks revealed an avascular multilocular lesion measuring 4.1 × 2.3 × 2.9 cm on the left side of the neck extending from the ear to the upper thorax in the fetus, likely a cervical lymphatic malformation (CLM) [Figure 1]. Chromosomal microarray showed a female profile. Fetal magnetic resonance imaging (MRI) confirmed the diagnosis [Figure 2a & b]. There was a slight retropharyngeal extension and a possible extension between some facial muscles, with tracheal deviation. The fetal head was tilted to the right side due to the mass effect. Small pleural effusions and ascites were noted, raising concern for the development of hydrops.Figure 1: Prenatal ultrasound images show (a) length and width and (b) depth of cervical lymphatic malformation (arrows).Figure 2: Fetal MR images show cervical lymphatic malformations (a & b) before sirolimus initiation (22.9 weeks) and (c) during sirolimus (32 weeks) treatment.Weekly ultrasonography follow-up demonstrated a significant size increase of the CLM, reaching 148 cm3 at 24 weeks’ gestation. Despite the rarity of reported CLM cases treated prenatally, we decided to offer sirolimus treatment to our patient after multidisciplinary discussion. After informed consent was obtained, the mother was started on oral sirolimus at 25.2 weeks with a loading dose of 6 mg for 2 days, followed by 2 mg daily. Five days later, the maternal serum level of sirolimus was <2 mcg/L, which led to a decision to increase the dose to 2.5 mg to reach the target serum level of between 10–15 mcg/L. The mother was monitored clinically weekly and by laboratory tests, including blood count, hepatic enzymes, electrolytes, creatinine, lipids and sirolimus trough levels. Dose was uptitrated to 3.5 mg twice daily. A follow-up scan showed an initial increase of CLM to 262 cm3 and a subsequent decrease in volume after 6 weeks, reaching 67.4 cm3 at 31 weeks [Figure 2c], resulting in a 75% volume reduction, as well as a reduction in amniotic fluid [Figure 3]. Repeat MRI at 32 weeks showed a smaller multiloculated lesion and resolution of fetal pleural effusion/ascites. There were no maternal or fetal side effects from the sirolimus treatment.Figure 3: Graph shows the evolution of lymphatic malformations under sirolimus treatment. Antenatal follow-up of cervical mass volume and deep vertical pool (DVP) of amniotic fluid was performed using ultrasonography.The case was presented at a multidisciplinary high-risk consultation to decide on the timing and mode of delivery at 34 weeks. Sirolimus was discontinued one week before delivery. Seeing the evolution, the ex-utero intrapartum treatment procedure was cancelled, and the mother underwent elective caesarean section at 37+6 weeks. A baby girl weighing 3185 g was delivered with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. The neonate was pink and comfortable in room air, and no stridor or wheezing was noted. No resuscitation was required, and she was transferred to the Special Care Nursery. A left neck ovoid mass, centrally firm and extending from the supraclavicular region to the back, pushing against the ear, was reported. She was discharged home on Day 3 of life [Figure 4].Figure 4: Postnatal evolution of lymphatic malformations (LM). (a) Photo shows the left cervical LM; and (b & c) coronal T2-weighted MR images at birth show the LM (arrows).In conclusion, transplacental sirolimus may be a promising approach for managing large fetal LMs and improving peripartum outcomes. Financial support and sponsorship Nil. Conflict of interest Thain SPT is a member of the SMJ Editorial Board and was thus not involved in the peer review and publication decisions of this article.