Breakthrough prenatal therapy saves children with congenital vascular malformations

Vascular malformations are congenital abnormalities of vascular development that can involve various vessels - lymphatic, venous, capillary and arterial. They often pose a serious threat to the health and life of fetuses and newborns. In Lynx, now 16 months old, and Gabrys, now 3 months old, doctors identified abnormalities of vascular development already in fetal life, during the second trimester of pregnancy. In both children, the malformations were very extensive and increased dynamically with each week of pregnancy, threatening dangerous pressure on the organs.

- After a prenatal MRI was performed on Lynx's mother, it became clear that the lesion involved the left lower limb and buttock, but also penetrated the pelvis and abdominal cavity. In addition, at the 32nd week of pregnancy, the boy was found to be bleeding into the malformation cyst. The fetus' condition was deteriorating dangerously, and prenatal Doppler ultrasound showed features indicative of progressive anemia. With mom's coexisting polycystic anemia, preterm labor was expected and there was concern that the baby would be born in poor condition...," says Prof. Ewa Bien, deputy head of the UCK Department of Pediatrics, Hematology and Oncology, who is also founder and chair of the Section on Vascular Anomalies of the Polish Society of Pediatric Oncology and Hematology and a consultant on rare tumors in children in Poland. - Gabrysi's mother came to UCK even a year later, in June 2024, with a huge, rapidly enlarging lymphovascular malformation of the thoracic region found on fetal ultrasound. A prenatal MRI scan also described features of a history of bleeding into the malformation. In the case of Mama Lynx, it was not possible to wait until delivery. We started looking in the literature and found only two reports of prenatal use of an antiangiogenic drug called Sirolimus (rapamycin). We have a lot of experience in treating tumors and vascular malformations with Sirolimus, but so far we have administered it in children after birth - newborns, older children and young adults.

After consulting teams of gynecologists, pediatricians and neonatologists, the team in Gdansk decided on an innovative solution: giving the baby's mother the drug Sirolimus. This is a therapy typically used for patients who have undergone transplants of vascular organs, mainly kidneys. The use of the drug in cases of lymphovascular malformation was expected to inhibit the growth of pathologically altered blood vessels and improve the health of the fetus. The drug in the form of pills is taken by the pregnant woman, and after passing through the placenta, it acts in the baby's body. The course of the therapy is monitored by rapamycin levels in the blood of mother and child. A year later, the same therapy was applied to Gabrysia's mother. For this innovative treatment, the first in Poland and one of the first in the world, the vascular team from UCK in Gdansk received approval from the Independent Commission for Scientific Research at the Medical University of Gdansk.

The parents of Rysia and Gabrysia, fully aware of the seriousness of the situation, signed consents for off-label treatment (outside the typical registration indication) with Sirolimus. In both patients, the therapy had a rapid effect - in Lynx, the bleeding into the malformations stopped and the lesions stopped growing, while in Gabrysia, a marked shrinking of the malformations was observed with each week of fetal life. The children were born in good health and are currently undergoing further therapy to reduce the size of the malformations. Thanks to modern imaging methods, doctors can precisely monitor the progress of treatment and adjust medical strategy on an ongoing basis.

- Without this therapy, extensive surgical interventions in the first days or weeks of the children's lives would have been necessary in Lynx and Gabrys, which always carries an increased risk. The results of such treatments can be unsatisfactory: lesions can grow back quickly, and it often takes multiple interventions to achieve the desired effect. We succeeded in reducing the size of malformations in both children already during fetal life, and then, as we continue treatment with Sirolimus after the children are born, we achieve a further therapeutic effect," emphasizes Anna Klosowska, an attending physician from the UCK Department of Pediatrics, Hematology and Oncology. - In Lynx's case, we did not avoid surgery, but it was a procedure performed on a several-month-old baby, not a newborn. The procedure was performed at Copernicus Hospital by Dr. Dariusz Wyrzykowski. We are on the right track for the child to be fit, developing motor skills like his peers. In Gabrysia's case we have a shorter observation period for now, but the lesions are slowly diminishing.

- Sirolimus treatment in fetal life is an incredible breakthrough, which opens new perspectives for families expecting a child with this type of defect, says Professor Ewa Bień. - However, it should be emphasized that this innovative therapy requires coordinated cooperation and experience of many specialists, close monitoring of the course of pregnancy and the effects, but also possible complications of Sirolimus treatment. I want to thank very much the team of doctors and nurses from the UCK Department of Obstetrics and Gynecology, Gynecologic Oncology and Gynecologic Endocrinology (headed by Prof. D. Wydra) and the UCK Department of Neonatology in Gdansk (headed by Dr. I. Domżalska-Popadiuk), as well as the teams from the clinics at the University Hospital in Krakow, taking care of Gabrysia and her mother. It is worth noting that both mothers were referred to the center in Gdansk by Dr. Magda Rybak-Krzyszkowska, a specialist in obstetrics and gynecology and clinical genetics from the Clinical Department of Obstetrics and Perinatology at the CM-UJ in Krakow, and the children are being cared for between hospitalizations in Gdansk by Dr. Anna Taczanowska-Niemczuk, a specialist in pediatric surgery and oncology from the Department of Pediatric Surgery at the CM-UJ in Krakow.

The UCK Department of Pediatrics, Hematology and Oncology (PCHiO), headed by Ninela Irga-Jaworska, MD, PhD, provides care for more than 100 patients from all over Poland with various vascular anomalies. The lesions treated are: tumors and vascular malformations - lymphatic, venous, arteriovenous, mixed, as well as hypertrophic syndromes. The KPHiO team co-organized the 1st National Conference "Tumors and Vascular Malformations in Children", held on 4-5.10.2024 in Lodz, Poland. The publication of the results of prenatal treatment with Sirolimus of children with vascular malformations is also in preparation, which may become the basis for the development of new therapeutic guidelines for other centers in Poland and abroad.

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