Embryogenesis is a complex process and is divided between pre-implantation, embryo, and fetal period. This process is highly susceptible to various external factors such as teratogenic drugs, alcohol, smoking, radiation, and even the lack of appropriate nutrition. Ionizing radiation way more than non-ionizing has known effects in developing fetus with fatal outcomes.
Malignancy is relatively uncommon during pregnancy, with a low incidence of 0.02 to 0.1%. The most common malignancies found are breast, skin including melanoma, gynecological (uterine, cervix, and ovarian), and hematological (Hodgkin and non-Hodgkin lymphoma (NHL)). Generally, when rivaled with patients who received surgical monotherapy, survivors who underwent abdominopelvic radiation with or without surgery were more likely to have infants that were premature, low–birth weight, and even associated with perinatal mortality in few cases. Various studies have demonstrated an increased risk of unfavorable pregnancy and neonatal outcomes with prior history of abdominopelvic irradiation, possibly due to radiation-induced uterine damage. Since high-dose uterine irradiation can restrict the pregnant uterus' growth and cause vascular changes that impair uterine blood flow, preterm birth, fetal growth restriction, and stillbirth are common. Signorello et al. observed that infants of patients treated with high-dose radiotherapy (>5 Gy) to the uterus were at a heightened risk of preterm delivery, low birth weight, and small for gestational age when compared with offspring of patients who did not receive radiotherapy. Green et al. observed that the incidence of fetal malposition, early or threatened labor, low birth weight, and prematurity were higher with elevated radiation doses.
When compared to radiotherapy, chemotherapy does not appear to have harmful effects on the uterus. Hence it generally has favorable pregnancy outcomes in patients treated only with chemotherapy. Those who conceived ≥one year after post-chemotherapy without radiation or ≥two years after chemotherapy with radiation displayed no elevated risks to pregnancy outcomes.
Significant potential harmful effects of ionizing radiation can be summarised into four main categories:
While treating cancer in pregnant patients with radiotherapy, the goal is to improve the mother overall survival; however, specific considerations are vital to reduce the fetus's possible adverse implications. Earlier, the norm was to terminate the ongoing pregnancy, regardless of the trimesters. Fortunately, because of the advent of the latest developments of evidence and technology in the last two decades, we have steered away from this blanket policy. Since the 1990s, various technological and technical advancements in modern radiotherapies, such as 3D-conformal radiotherapy, intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy, have made it possible to give high doses to the tumor while sparing the surrounding healthy tissues or organs in the vicinity, hence improving radiotherapy in terms of effectiveness and tolerability. Furthermore, IMRT techniques using on-board cone-beam computed tomography have evolved to ensure a precise dose delivery. The detrimental principle of all radiation is that it should be "as low as reasonably achievable" (ALARA) as the effects of radiation are linearly cumulative. In practice, even though the fetus is excluded from the direct radiation field, the fetus gets radiation leaking from the accelerator and collimator dispersions. To cut down this radiation, we use lead blocks and shields to achieve ALARA.
Childhood malignancy in the context of prenatal diagnostic and assessment X-ray was first reported by Giles et al. in 1956. Their survey of childhood cancers established that the risk increased linearly with the number of films exposed. The relative risk of developing a childhood cancer-associated was significantly higher if the exposure was during the first trimester, about 2.5 times greater than the third trimester. This study became the working model of various radiation-induced teratogenesis studies. A defining study was by Kato et al., where they followed up the survivors of the Hiroshima and Nagasaki atomic bombs. It was the most extensive cohort study of intrauterine radiation exposure; interestingly, only 2 cases had childhood cancer before the 14th birthday out of 1630 children exposed without a single case of leukemia.
Broadly, radiation effects are expressed as being either deterministic or stochastic.
Ionizing radiation induces these effects by causing structural changes at the cellular and molecular levels. Non-ionizing radiation (which is not associated with medical imaging or radiotherapy) causes damage through heat transfer, such as microwave heating. Furthermore, by producing free radicals, ionizing radiation causes cellular damage by interfering with chemical bonds between molecules regulating critical cellular processes and events. This process generally leads to DNA mutation or cell death and sometimes causes damage to essential cellular enzymes. Susceptibility to radiation injury depends on the rate of cellular proliferation and differentiation of exposed tissues. Hence lymphoproliferative tissues with rapid cell turnover are the most susceptible, while nervous tissue with little or no cell turnover is the least affected.
The American Association of Physicists in Medicine and the International Commission on Radiological Protection described guidelines for assessing the potential fetal radiation exposure during maternal radiotherapy. They recognized three possible radiation sources that need to be evaluated: first, the photon leakage from the machine head; second, the scatter and leakage from the collimators and beam modifiers; and lastly, scattered radiation emerging from the treatment beams of the volume treated within the patient. To reduce the leakage and scatter from the treatment head, beam modifiers, and collimators, lead shielding is placed on the pregnant mother's abdomen and pelvis. Shielding is possible earlier in the pregnancy, but as the gravid uterus grows, it is difficult for adequate shielding. Also, as the abdominal size increases, the distance between the field and fetus reduces, thus increasing the risk of exposure while treating supradiaphragmatic areas. In this circumstance, the fetus receives 10 to 15 times more radiation dose for the same treatment field.
The developing fetus is most sensitive to ionizing radiation harmful effects during the first 14 days post-conception. In this period, either the pregnancy withstands the radiation exposure unharmed or is resorbed, often termed as an "all or none" phenomenon. However, significant consequential damage is seen when exposed during the period of organogenesis (approximately 2 to 8 weeks post-conception or 4 to 10 weeks after the last menstrual period). The embryo may sustain damage due to radiation-induced cell death leading to irregularities in cell migration and proliferation or mitotic delay. Significant sequelae of radiation-induced damage are fetal growth restriction and congenital malformations, particularly of the central nervous system seen as microcephaly and ocular abnormalities, often associated with intellectual disability. Microcephaly is the most frequently seen manifestation of radiation injury in utero.
Diagnostic radiology imaging is essential. It is noted that the risks to the pregnant woman of not having imaging or a particular procedure are far greater than the speculated potential harm to the fetus. The fetal radiation dose from various conventional radiograph examinations is below 0.01 Gy. For fluoroscopic examinations, the dose resulting from barium enema might exceed 0.01 Gy, which can be further reduced by proper pre-requisites of the procedure. For a computed tomographic (CT) scan of the pelvis and abdomen, the fetal radiation dose is typically about 0.01–0.04 Gy, well below the threshold, which never exposes the fetus to dangerous radiation levels. In general, the doses involved in diagnostic radiology are much lower than the threshold dose for deterministic effects and present no substantial risk of causing fetal death, malformation, or mental development impairment.
Potential consequences of fetal radiation
Potential effects seen from fetal radiation exposure:
An insight into the radiation effects on the developing fetus serves to deliver better care to the expecting mother who is concomitantly undergoing radiotherapy. It helps curate a pre-conceptional, gestational, and post-conceptional radiotherapy planning to provide maximum care to the pregnant mother malignancy while maintaining minimum risk to fetal life.
Fertility issues in Radiotherapy Patients
Cranial or head/neck radiation can damage the hypothalamic-pituitary axis affecting patient fertility since head and neck cancers require high doses in the 40 to 70 Gy range. Direct radiation to ovaries can also cause early ovarian failure. As described earlier, pelvis radiation may cause structural changes such as reduced uterine volume, lack of endometrial response to estrogen, or impaired uterine artery blood flow, impeding successful embryonal implantation or development.
Cancer-Specific Radiotherapy Management
Head and Neck Cancer
Managing radiotherapy in pregnancy:
Important considerations for team planning of radiotherapy in pregnant patients:
Informed consent and understanding by the patient are pivotal components before proceeding with the treatment:
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