Effects of Radiation Exposure on the Developing Fetus Hannah Connolly, Janessa Gioia, Gillian Reid, Nadine Savoie, Suzanne Taylor University of New Brunswick

Problem Statement Pregnant women may be denied diagnostic and therapeutic radiation procedures because physicians fear the radiation will cause harm to the developing fetus. Thus, fewer options are available for improving the health of pregnant women when they require medical attention. Understanding the effects of radiation on the developing fetus may help physicians better counsel their patients on the risks involved. This education would allow for an informed decision to be made on whether to proceed with radiation procedures. http://www.math.cmu.edu/~handron/problems/

Research Question Are diagnostic and therapeutic radiation procedures harmful to the developing fetus? http://sites.mckesson.com/mprs/images/page/mprs_home.jpg

Harmful Teratogenic- causing congenital malformations (CNS abnormalities, mental retardation, microencephaly, growth retardation) Carcinogenic- cancer causing (developing childhood cancer) Mutagenic- causing genetic changes (embryonic loss, fertility) (Whitt, 2010) http://www.biomol.de/wiki/index.php/DNA_Damage_and_Repair_Antibodies feed://www.blogger.com/feeds/4105934082939383122/posts/default http://health-e-waste.blogspot.com/

Related Diseases Harmful radiation exposure to the fetus include: prenatal or neonatal death, congenital anomalies and malformations, severe mental retardation, temporary or permanent growth retardation, carcinogenesis, increased occurrence of seizures, neurological effects, sterility and germ cell mutations (seen in Japanese victim of the atomic bombs at the end of WWII in Hiroshima and Nagasaki doses higher then 250 mGy). Other abnormalities include: small birth weight, stunned growth, microcephaly, microphthalmus, pigmentary degeneration of the retina, genital and skeletal malformation, cataracts and heredity effects, include stunted growth, deformities, abnormal brain function, tumors in a variety of sites including the brain, breast, nasopharynx and knee. (Greskovich & Macklis, 2000; Dekaban, 1968; Osei & Faulkner, 2000; Pavlidis & Penteroudakis, 2005; Kal & Struikmans, 2005; Tutty, 2001, Brent, 1999, Departement of Health and Human Services, 2005, Bednarz, B., & Xu, G. X., 2008, Whitt, 2010) The major risk is of course, embryonic loss. (Brent 1999). http://www.sci-art.com/image.asp?id=2689&search=1&pagename=DNA_radiation_damage

Radiation: DNA Damage http://www.windows2universe.org/earth/Life/images/radiation_dna_damage_big_jpg_image.html

History of why these studies emerged In 1956, researchers found that prenatal exposure to radiation from diagnostic X rays was associated with an increased risk of leukemia and solid tumors during childhood. This report and others contributed to major changed in medical practice. The consensus because that low-dose fetal exposure might be harmful and x-ray doses started to decrease over time and ultrasound replaced fetal x-ray examinations (Naumburg et al. 2001; Doll & Wakeford, 1997) http://awesometalks.files.wordpress.com/2008/08/ng30.jpg http://www.belarusguide.com/chernobyl1/chernobyl.htm

Fetal Stages and Radiation Sensitivity (1) Preimplantation (days 0 to ~14): The number of cells in the embryo is relatively small. The pre-implantation phase of the embryo has the greatest sensitivity to the lethal effects of ionizing radiation. radiation can either be lethal or have no apparent effect (“all or none” response) . (Osei & Faulkner, 2000, Pavlidis & Penteroudakis, 2005, , Klieger-Grossmann, 2009,) Retrieved from: http://www.scienceagogo.com/news/20080427022113data_trunc_sys.shtml

Fetal Stages and Radiation Sensitivity (2) Organogenesis (week 2 to week 8), or (2 to 7 weeks) During the early stage of organogenesis, the embryo is sensitive to the growth-retarding, teratogenic and lethal effects of irradiation, but it may re-cover from the growth-retarding effects in the post-partum period. Malformations may result from cells killing during the active phase of cell proliferation and differentiation during organogenesis. This stage is where the embryo is most susceptible to the effects of radiation (and also during early fetal period) (Osei & Faulkner, 2000;Williams & Fletcher, 2010, Klieger-Grossmann, 2009, Jaffe, 2007) http://microrespuestas.com/que-es-la-organogenesis

Fetal Stages and Radiation Sensitivity (3) Fetal (week 9 to term) – undergoes organ cellular growth (except the central nervous system, which is in the early and mid-fetal stages) (Greskovich & Macklis, 2000; Williams & Fletcher, 2010, Klieger-Grossmann, 2009). During the fetal period, the fetus is less sensitive to multiple organ teratogenesis, but irradiation of the central nervous system could result in post-natal behavior disturbances and lowered intelligence. During later stages, irradiation of the fetus does not result in gross deformation (Osei & Faulkner, 2000). Radiation at the late fetal stage was found to induce sterility malignancies and genetic defects. Kal & Struikmans, (2005) found that the CNS is sensitive to radiation 8-15 weeks after conception. The CNS is less sensitive after 25 weeks. (Klieger-Grossmann, 2009) http://www.webmd.com/baby/slideshow-fetal-development

Methods Quantitative Experimental Non Experimental Time frames Retrospective Prospective Surveys Time frames Longitudinal http://www.faqs.org/photo-dict/photofiles/list/664/1074test_tubes.jpg

Health Concerns From our studies these are some health concerns that would bring pregnant woman to our departments (Diagnostic imaging, Oncology Dept). Pulmonary Embolism Loss of bone density Cancer (cervical cancer, breast cancer, lymphoma, leukemia and melanoma). Abdominal/Pelvic issues (renal, GI, trauma, appendix) http://rochesterchiro.files.wordpress.com/2008/06/chiropractor-patient.jpg

Pulmonary Embolism Pulmonary embolism is a leading cause of maternal mortality. It is reported to occur in approximately 3 in every 1000 pregnancies The two methods of diagnosis for PE are CT and Ventilation Perfusion imaging (Nuclear Medicine) Studies found in all three trimesters, the mean fetal dose delivered with helical CT is less than that delivered with V/P scanning Researches compared the mean exposure at all three trimesters for both CT and V/P (Winner-Muram et al., 2002; Tutty, 2001) A UK survey showed lack of knowledge involving fetal dose delivered while imaging pregnant women suspected of having PE > only half of specialists directly involved in diagnosing PE’s knew that ventilation perfusion imaging resulted in higher radiation doses to the fetus than CT imaging. (Groves et al. 2006) http://jenniferashe.com/thrombophilia/images/lungs-pulmonary-embolism-PU.jpg

Pulmonary Embolism The combination of a chest radiograph (10 uGy), V-P scanning (370 uGy), helical CT scanning (131 uGy) and pulmonary angiography with a brachial approach (500uGy) exposes the fetus to ~ 1000 uGy. This dose is approximately the same dose received from background during the 9 months of pregnancy. Winner-Muram et al., 2002; If the dose to the fetus exceeds 10 cGy, the probability that a child will be born with a congenital defect rises 10%. 10cGy does is 200 times the does received from a perfusion lung scan. (Tutty, 2001) Another reason why CT is better…Ventilation perfusion scans are usually not definitive in the diagnosis of acute PE, the presence and absence of PE is inconclusive in up to 80% of these scans. And prior episodes of PE may cause a false-positive result. One review stated that a regular chest CT radiography resulted in higher radiation exposure compared to V/Q scan. (Brent, 2006)

Bone Density There is evidence that some pre-existing disorders as well as heparin treatments may lead to significant diminution of bone mass during pregnancy. These women may benefit from a bone density examination during pregnancy. This examination consists of dual x-ray absorptometry (DXA) generally of the spine and hip. Treatment with antiresorptive drugs and supplimentation with calcium and vitamin D would be administered to patients who demonstrate rapid bone lose during the first postconception months. Emryo/fetus doses due to DXA estimates were found to be lower than the average daily natural background in the United States of 8 uGy. The max was 3.4uGy from a proximal femur scan.  Therefore for the above circumstances...Benefits Outweigh Risks! Wrist*** Damilakis, 2002 http://www.tappmedical.com/page_images/dexa_femur.jpg

Abdominal and Pelvic Procedures Medical imaging such as CT may be required of the abdominal/trunk/pelvic area due to trauma, acute abdominal pain, appendicitis, or renal issues in a pregnant patient. Ultrasound may be the primary imaging modality of choice for these patients but in the case of the ultrasound being non-diagnostic other modalities may be required. Respondents are more likely to choose CT for trauma in all three trimesters. For acute abdominal indications such as appendicitis, abscess, kidney stone or small-bowel obstruction they were more likely to choose CT in the second and third trimester, and MRI in the first trimester because of the concern about the potential teratogenic effects of ionizing radiation in the first trimester. The trend found in radiology literature that CT is fast, is readily available and allows immediate surgical intervention if needed. Concern about radiation to the fetus in this setting is outweighed by the necessity to intervene for the preservation of both maternal and fetal health. Literature suggests that for most radiologic procedures, the risk of fetal demise in the first 2 weeks after conception is less than 1% Radiologists may also opt for a modified CT protocol to reduce the exposure but reducing the power of the x-rays (kVp or mAs). (Jaffe, 2007). http://www.lakeridgehealth.on.ca/patient_care/interventional_radiology/presentations/radiology/slide25.htm http://www.lakeridgehealth.on.ca/patient_care/interventional_radiology/presentations/radiology/slide25.htm

Abdominal and Pelvic Procedures Hurtwitz et al. (2006) used female anthropomorphic phantoms (160cm height, 55kg). Placed MOSFET dosimeters at fetal locations to determine the radiation dose. Dosimeters were placed at 5 different locations (representing the uterus at 0 and 3 months). Hurtwitz et al. (2006) found: Dose was 0.8-1.2 (0 months) and 0.4- 0.7 cGy (3 months) for renal protocol, 1.2-1.68 cGy (0 months) and 2-4 cGy (3 months) for appendicitis protocol and 0.024-0.047 cGy (0 months) and 0.061-0.066cGy (3 months) (Hurtwitz et al. 2006). There was no direct radiation to the fetus. It was from internal scatter, scatter from the collimators, leakage, and from the tube head of the linear accelerator involved. Therefore planning is necessary. (Hurtwitz et al. 2006, Kal & Struikmans, 2005)

Cancer Diagnosis & Treatment when Pregnant Cancer complicates approximately 1 per 1000 pregnancies (Pavlidis & Penteroudakis, 2005; Kal & Struikmans, 2005). Most common cancer types being cervical cancer, breast cancer, lymphoma, leukemia and melanoma. (Greskovich & Macklis, 2000, Pavlidis & Penteroudakis, 2005). Greskovich & Macklis (2000) state that carcinoma of the cervix is the most common cancer diagnosed during pregnancy, (1 in 2,200 pregnancies). Breast cancer pregnant patient 1 in 3000 (Berry et al. 1999, Greskovich & Macklis, 2000; Kal & Struikmans, 2005, Pandit-Taskar et al. 2006) Radiation therapy is not usually offered during pregnancy because of the risks of teratogenicity and induction of malignant disorders in the fetus or child (Pavlidis & Penteroudakis, 2005; Kal & Struikmans, 2005) http://www.oregonlive.com/kiddo/index.ssf/2008/08/31-week/

Diagnosing Oncology Patients To diagnose: first do fine-needle biopsy (gold standard), ultrasound, and mammography with abdominal shielding (lead), MRI, as they are accurate and safe imaging techniques before CT (avoids ionizing radiation exposure). (Berry et al. 1999, Greskovich & Macklis, 2000, Pavlidis & Penteroudakis, 2005; Kal & Struikmans, 2005, Hurtwitz et al., 2006, Doll, R., Wakeford, R. (1997) Nicklas, A.H., Baker, M.E. (2000), . http://drlindagalloway.wordpress.com/2009/12/14/why-pregnant-women-need-more-than-one-ultrasound/ http://medicineworld.org/news/news-archives/breast-cancer-blog/April-4-2006.html http://thetyee.ca/News/2009/09/29/HaltClinics/

Delaying Radiation All chemotherapy drugs are capable of crossing the placenta. The first trimester is the period where severe damage leads to spontaneous abortion. If performing radiotherapy, it must be given safely and an ethical balance must be achieved (Pavlidis & Penteroudakis, 2005; Kal & Struikmans, 2005). Studies recommend delaying treatment until the second and third trimester. Mastectomy remains the standard managements with stages I and III of breast cancer for pregnant woman. (Greskovich & Macklis, 2000; Pavlidis & Penteroudakis, 2005, Doll, R., Wakeford, R.1997, Departement of Health and Human Services (2005). http://www.soc.ucsb.edu/sexinfo/article/effects-of-drugs-taken-during-pregnancy

Staging for Oncology Patients The benefits of radiation therapy as part of treatment must be weighed again the potential risk to the harm of the patient and developing fetus. (Greskovich & Macklis, 2000, Osei & Faulkner, 2000). Main concerns of doctors is to save the mothers life, protect the fetus and keep the woman’s reproductive system intact, cure the mother and deliver a healthy baby (Pavlidis & Penteroudakis, 2005). The medical staff and patient need to decide as a team whether to begin treatment or to postpone it (Kal & Struikmans, 2005). http://www.4dbabyscan.com/3d-ultrasound-houston-tx.htm

How much radiation is to much? It is concluded that radiation doses of the order of 10 mGy received by the fetus in utero produce a consequent increase in the risk of childhood cancer. (Doll, R. & Wakeford, R., 1997 ) Childhood cancer has been estimated to be approximately 0.28 at 1.0mGy in the first trimester, 0.03 at 1.0 mGy in the third trimester and overall 0.037 at 1.0mGy during pregnancy. Doses 2.5 Gy or more can be associated with fetal malformations. (Pavlidis & Penteroudakis, 2005). Therapeutic abortion is induced to pregnant woman to receive 360 to 55 cGy to the pelvis. (Greskovich & Macklis, 2000). Lymphoscintigraphy for sentinel lymph node mapping (SLN) led to a neglible dose to the fetus (0.014 mGy or less) (Pandit-Taskar, 2006). Exposure of 5 rads (0.05 Gy, 0.0 Sv) or less present a low risk to the embryo and the pregnancies should not be interrupted because of the risk or radiation exposure, and physicians should support the patients decision to continue the pregnancy. Ionizing radiation above 50 rads (0.050 Gy) present a significant risk to the embryo, regardless of gestation stage. There is a increase of malformation at approximately 20 rads (0.2 Gy) (Brent, 1999) http://www.aboutcancer.com/sentinel.htm http://www.aboutcancer.com/sentinel.htm

Oncology Studies Relative risk are higher when the exposure occurs in the first trimester and is highest when it occurs in the first 8 weeks after conception. (Greskovich & Macklis, 2000; Pavlidis & Penteroudakis, 2005; Doll, R., & Wakeford, R. 1997; Department of Health and Human Services (2005). Many patients may first undergo a radical or segmented mastectomy with postpartum radiation (Berry et al. 1999) Patients received a median of four cycles of chemotherapy during pregnancy during the second and third trimester of pregnancy. Shown minimal complications of labor and delivery. (Berry et al. 1999; Doll, R., & Wakeford, R.1997; Departement of Health and Human Services, 2005). Neonates experienced no unusual complications. None of the 24 infants was congenitally malformed. Only one infant had a birth weight lower than the 10th percentile. (Berry et al. 1999) Pandit-Taskar et al. (2006) found lower organ dose estimates than conservative references models and found fetal dose was much less than the NCRP limit.(National Council of Radiation Protection and Measurement) http://wardray-premise.com/images/products/large/aprons/claire_hugo.jpg http://blog.elekta.com/tag/radiation-therapy/ http://www.elekta.com

Oncology- Thyroid Cancer Radioiodine (131I) Therapy Features reported: Induced abortion, Miscarriage, Stillbirth, Prematurity (<37 weeks), Birth weight below the 10th percentile for the gestational age, Congenital abnormality, Death during the first year of life Live born babies: Later deaths, Thyroid disease, Tumors Indirect exposure to the uterus, 131I uptake in the Blood, Bladder, Gut, kidneys Results: Within a year after the therapy there were numerous miscarriages and induced abortions. Discussion. A number of stillbirths after radioiodine therapy are relatively high. An abnormal thyroid hormone status after therapy may be a factor. We recommend not to conceive one month prior the therapy and postponing conception until the thyroid hormone status has been verified. http://www.qatarpark.com/park/2010/01/dr-abdul-azim-hussain/ http://ahmadnour.maktoobblog.com/category/thyroid-cancer/ (Garsi, J-P., et al. 2008, Bohuslavizki, 1999)

Childhood Development Research showed no statistical difference in physical, neurological, and developmental parameters between preschool aged children born to mothers who had abdominal or pelvic x-rays, x-rays to other areas, or controls. This implies that there is no damaging effects of diagnostic, low dose x radiation on human fetal brain. Therefore during the first trimester of pregnancy only high doses if irradiation may affect the developing brain. (Ornoy et al., 1996) Large radiation doses (which is equivalent to the dose of over 500 chest x-rays) to the fetus can cause birth defects during the stages of development of week 2-15 of pregnancy. (Department of Health and Human Services, 2005) http://photos.ibibo.com/photo/5598752/cute-child http://www.topnews.in/files/baby-girls.jpg

Childhood Cancer Another concern is that radiation exposure during pregnancy might be associated with a carcinogenic effect, which can include an increased risk of childhood solid tumors or leukemia. (CS#2) The United States National Council on Radiation Protection states that the risk of induced miscarriages, malignancies or major congenital malformations in embryos or fetuses exposed to doses of 50 mGy or less is negligible compared with the spontaneous risk in the non-exposed. Spontaneous risk includes a 15% chance of having a spontaneous abortion, a 3% risk for a major malformation, and a 4% possibility of restricted fetal growth Leukemia: Leukemia is the most common malignancy among children. The incidence peaks at 2-4 years of age suggesting that events early in life, including the intrauterine period, are causally related to childhood leukemia. One study looked at all children born in Sweden between 73- 89. For each case of Leukemia, one control was selected randomly from the Swedish birth register (included all data on more than 99% of all births in Sweden) The control subjects were matched individually to case subjects on sex, birth year and month. Controls had to be alive and without leukemia. This study did not reveal a significant association between x-ray exposure to the fetus and leukemia. Therefore this suggests that the fraction of children who developed leukemia that is possibly attributable to diagnostic x-rays is likely to be small today.

Childhood Cancer Cancer: There has been a substantial increase in the utilization of CT and nuclear medicine radiodiagnostic procedures, with about 1 in 160 term pregnancies now being exposed,  making them a common source of radiation to patients. Since these tests are often ordered under emergency circumstances, inadvertent exposure in early pregnancy may occur, since half of all pregnancies are unplanned. One study in particular was a retrospective population-based cohort study of women who delivered a live born infant in Ontario between April 1, 1992 and march 31, 2008. They then looked at the incidence of malignancy in the children born to mothers that were exposed to radiation and those who were unexposed in an effort to provide clinicians and mothers with better estimates of the risk of pediatric malignancy in their offspring. The offspring of women exposed to major radiodiagnostic testing in pregnancy do not appear to be  at a higher risk of childhood malignancy then the children of unexposed mothers. Moreover, the overall prevalence of pediatric malignancy following exposure to CT or radionuclide imaging in pregnancy was under 0.07% http://www.casperwyoming.info/dining.php?sort=Family

Childhood Cancer A comparison between the current and previous studies : Many studies lacked statistical power because of the small sample size. (This study was a big sample size with 624 children with leukemia each with a controlled matched-pair) Also there was no adjustment made for potential confounders, such as concomitant disease in the mother and/or the fetus Recall bias was possible (exposure info was based on interviews of parents of affected and nonaffected children). The largest study, the Oxford Survey of Childhood Cancers, included over 4000 cases of leukemia and reported a 50% increase in risk after prenatal exposure to X-rays for both myeloid and lymphatic leukemia.  Possible explanations for these findings are Recall bias (exposure data was based on maternal interviews) Higher prenatal X-ray doses for examinations preformed in the 40’s and 50’s Unidentified characteristics that select women predestinated to have a child with leukemia (confounding factors) there was no adjustment made for potential confounders, such as concomitant disease in the mother and/or the fetus

Recommendations & Precautions A longitudinal study showed that many women do not have a typical 28 day cycle, and therefore our “10-day rule” may not be appropriate for all women - a 8 or 9 day rule would be safer. Procedures can be modified to reduce exposure to the patient and the fetus for example: Modifying CT scans by adjusting the kVp or mAs (Damilkis, 2000) The ventilation procedure may be unnecessary when perfusion scan is normal (ref) ALARA- as low as reasonably achievable Radiation Therapy- Simple techniques have been used to reduce the dose outside the treatment field by adjusting the gantry angle, field size, treatment beam energy, and patient position. The study demonstrates the feasibility to accurately determine the absorbed organ doses in the mother and fetus as part of the treatment planning and eventually in risk management. (PS#1) Do treatment planning and risk management. (Bednarz, B., & Xu, G. X., 2008). The use a lead shield can be used to protect the uterus from external radiation ( including scatter the exposed tissue or imaging equipment). A lead shield may offer the patient a sense of protection and reassurance. It was found that the presence of the 1mm lead shield decreased radiation levels substantially, introducing the possibility of lowering the dose to the fetus further. (R#3) (Sechopoulos et al. 2008)

Recommendations & Precautions However potentially small that risk may be, beta hCG testing should continue to be done in all potentially pregnant woman before undergoing a major radiodiagnostic testing, and lead apron shielding used in a woman of reproductive age, whether or not pregnant. Furthermore, nonradiation-emitting imaging (E.g. MRI and ultrasonography) should be considered first when appropriate. Some pregnant women will nevertheless be faced with the decision to undergo CT or nuclear medicine imaging because the test is clinically warranted. Unfortunately, some health care providers may be unwilling to counsel a woman about the related fetal risks or may provide misinformation. This issue seems more pressing than ever, given that we and others have noted that CT testing is on the rise, and has become the mainstay for the investigation of PE, stroke, appendicitis and other common conditions encountered in emergency situations. Delaying the diagnosis of such conditions may postpone therapy, in turn, jeopardizing both mother and child. Therefore when indicated, major radiodiagnostic testing in pregnancy should be carried out along with brief counseling. The latter will hopefully lessen the level of anxiety experienced by an expectant mother (and her family), not only at the time of illness but after her child is born.

Recommendations & Precautions When performing bone densitometry on a pregnant patient, there is the option of doing a wrist scan to avoid direct exposure to the fetus by performing the spine or femur scan. Pregnant nuclear workers should always take precautions by wearing two TLD’s, wearing lead aprons if available etc.  Implementation of a radiation protection program should be put in place if there is not already one in the facility. (Damilakis et al. 2005) http://www.life123.com/career-money/small-business/small-business-insurance/health-insurance-options-for-the-self-employed.shtml

Limitations No randomization, very small sample size, the use of simulated patients instead of real-life subjects.( Bednarz, B., & Xu, G. X., 2008) The main limitation in the study is the use of a mathematical phantom (anthropomorphic phantom) with simplified organ distribution and shapes. This could result in both under and over estimates in the order of 15- 40%. This error, although substantial, still allows assessment of the importance of the dose to the organs and other tissues outside the primary x-ray field receive from DBCT imaging. The Monte Carlo dosimetry method should be used only as a guideline. (Sechopoulos et al., 2008) The study was limited by its retrospective design and by the possibility that some pregnant patients were not known to be pregnant at imagine, and thus, not included in the database. As well, the method of basing the total pregnant population on the number of deliveries does not account for elective or spontaneous termination of pregnancies. Results were also limited because they were accumulated from a single academic institution, which may not reflect practice patterns throughout the country. (Lazarus et al., 2009) Tutty, (2001) states that since the values do not take into account placental crossover, the levels may be an underestimate of fetal Doses... so use shielding, and precautions. Results are only approximations. Obtaining data from a phantom simulating a single body habitus. Researchers recognize that radiation doses vary depending on the size of the individual. (Pandit-Taskar, 2006; Hurtwitz et al. 2006).

Conclusion 2 most important determining factors : dose & stage of gestation

References