Infant Patient Exposed to Chemotherapy and Radiotherapy in the Womb: Letter to Editor

Dear Editor, Exposure to chemotherapy (CT) and radiotherapy (RT) during pregnancy is a complex clinical scenario with limited literature, particularly concerning infants exposed in utero. Potential fetal risks associated with CT include intrauterine growth restriction, congenital malformations, spontaneous abortion, and intrauterine fetal demise. Prenatal radiation exposure has been linked to growth retardation, microcephaly, intellectual disabilities, neocortical ectopia, agenesis of the corpus callosum, and an increased risk of brain tumors. This letter highlights a rare and challenging case of an infant exposed to both chemotherapy and radiotherapy in utero due to the mother’s diagnosis of glioblastoma multiforme (GBM) during pregnancy, raising critical questions about fetal risks and long-term outcomes. Background The incidence of cancer during pregnancy is approximately 1 in 1,000 pregnancies. Chemotherapeutic agents used in cancer treatment typically have molecular weights less than 400 kDa, allowing them to cross the placenta and potentially affect the fetus. Exposure to CT during the first trimester, a critical period of organogenesis, can result in malformations, spontaneous abortions, and intrauterine fetal death. In the second and third trimesters, CT exposure is associated with intrauterine growth restriction, low birth weight, preterm delivery, or stillbirth. Recent studies have reported that infants exposed to prenatal CT may have lower birth weights and lengths. Additionally, intrauterine CT exposure may directly impact the maturation and differentiation of neurons and oligodendrocytes, with oxidative stress and neuroinflammation contributing to neurotoxic effects. Prenatal radiation exposure, particularly between 8 and 15 weeks of gestation, has been associated with growth retardation, microcephaly, intellectual disabilities, neocortical ectopia, agenesis of the corpus callosum, and an increased risk of brain tumors. The exact mechanisms underlying these effects remain unclear. GBM is one of the most common and aggressive primary brain tumors in adults. Standard treatment involves radical surgery followed by concurrent temozolomide-based CT and RT. Managing GBM during pregnancy presents unique challenges due to potential fetal risks. Treatment planning must balance maternal benefits with fetal risks, and there is limited evidence guiding the timing of surgery and the use of RT and CT during pregnancy. Additional considerations include the teratogenic effects of anticonvulsant medications and the management of peritumoral edema during pregnancy. A 2.5-month-old male infant presented to our pediatric hematology and oncology outpatient clinic. He was born spontaneously at 36 weeks' gestation, weighing 1,560 grams. The mother was diagnosed with stage IV GBM and discovered her pregnancy four days before delivery. She did not undergo surgery but received RT during the second month of pregnancy and temozolomide-based CT from the second month until delivery. At presentation, the infant's weight was 2,540 grams (<0.02 percentile), length 42 cm (<0.02 percentile), and head circumference 30 cm (<0.02 percentile); both anterior and posterior fontanelles were closed. Physical examination revealed macrocornea, low-set ears, high-arched palate, skeletal dysplasia, short limbs, hand and foot deformities (clinodactyly, pes equinovarus), bilateral cryptorchidism, and micropenis. Neurological assessment showed hypotonia with normal deep tendon reflexes. Laboratory evaluations, including complete blood count and metabolic screening, were unremarkable. Ophthalmologic examination was normal, but hearing loss was detected. Cardiac evaluation, including echocardiography, was unremarkable. Imaging studies revealed a 24x15 mm hemangioma in the right hepatic lobe on abdominal ultrasonography and a neurenteric cyst on cranial magnetic resonance imaging. Endocrine evaluations were within normal limits. The infant was hospitalized for sepsis the day after the initial outpatient visit and discharged after 30 days. At 4.5 months, follow-up revealed a disproportionately small head circumference relative to body size, consistent with premature fontanelle closure. Outpatient follow-up is ongoing. GBM accounts for approximately 1% of all new cancer cases worldwide. The occurrence of GBM during pregnancy is rare, with tumors detected in approximately 0.1% of all pregnancies. Literature on GBM management during pregnancy is limited to case reports and small case series. Treatment decisions must balance maternal survival benefits against potential fetal risks, with considerations derived from animal studies, epidemiological data, and observational studies. Studies suggest that CT with agents such as anthracyclines, taxanes, or platinum derivatives may be feasible during the second and third trimesters. The fetus is most sensitive to radiation effects between 8 and 15 weeks of gestation. Fetal sensitivity to radiation is related to gestational age and is highly dependent on the dose received. Exposure to radiation doses less than 1.0 Gray during early gestation has been associated with carcinogenic effects in animal studies. During RT, it is recommended that fetal exposure does not exceed 100 mGy to minimize the risk of fetal cancer development. Management of pregnant patients with GBM requires a multidisciplinary approach involving neurosurgeons, neurologists, oncologists, obstetricians, gynecologists, anesthesiologists, pediatric oncologists, and neonatologists. Calculating the potential fetal dose during CT and considering early delivery if the fetus has reached viability are important considerations. Counseling patients about treatment risks is challenging due to limited data, but it is essential for informed decision-making. Data on short- and long-term neurodevelopmental outcomes in children exposed to prenatal CT are limited. Administering CT after 14 weeks' gestation is recommended to avoid affecting organogenesis. Reporting outcomes of pregnant patients exposed to CT and RT is crucial to guide future clinical practice. CONCLUSION This case highlights the significant challenges associated with managing glioblastoma multiforme (GBM) during pregnancy and underscores the potential adverse effects of in utero exposure to chemotherapy (CT) and radiotherapy (RT). While maternal cancer treatment remains a clinical priority, its impact on fetal development must be carefully considered. The observed congenital anomalies and neurodevelopmental concerns in the infant suggest a need for ongoing evaluation of long-term outcomes in children exposed to CT and RT during gestation. Due to the rarity of such cases, data on the safety and long-term effects of prenatal CT and RT exposure are limited. This underscores the necessity for multidisciplinary collaboration between oncologists, obstetricians, neonatologists, and pediatric specialists to optimize both maternal and fetal health outcomes. Further research, including prospective studies and long-term follow-up of affected infants, is essential to develop evidence-based guidelines for managing cancer during pregnancy. Reporting similar cases and aggregating clinical data will provide valuable insights into risk assessment, treatment strategies, and neonatal outcomes. As advancements in cancer therapeutics continue, refining approaches to maternal treatment while mitigating fetal risks will remain a critical area of investigation in oncologic and perinatal care.