Radiation Effects On The Fetus

Excerpt

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.

Fetal Risks From Ionizing Radiation

Significant potential harmful effects of ionizing radiation can be summarised into four main categories:

1. Pregnancy loss (miscarriage, stillbirth)

2. Malformation

3. Disturbances of growth or development

4. Mutagenic and carcinogenic effects

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.

1. Deterministic effects have a cause and effect relationship such that below a certain threshold, the effect will not occur. However, once the threshold has been crossed, the effect of significance will increases linearly with every next dose. Deterministic effects on a fetus range from congenital malformations, lower intelligence quotient (IQ), mental retardation, microcephaly, various neurobehavioral dysfunctions leading to increased risk of seizures and growth retardation, fetal death, and increased cancer risk. A threshold dose of 0.1Gy has been reported on several occasions. The risks are uncertain between 0.05 Gy to 0.1Gy and deemed negligible when below 0.05Gy. Pathologically, these effects occur when a large number of cells are irradiated during a critical developmental stage of organogenesis.

2. The stochastic effect represents the radiation effects that may occur by chance, such as cancer induction. For this to occur, there is no threshold dose observed, and the risk manifolds in a linear-quadratic manner of the dose. Childhood cancers are primarily the result of the stochastic effect, as seen in the post-Chernobyl disaster with the increased thyroid cancer occurrence.

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.