INSIDE THE BLACK BOX is an occasional column providing insight into the FDA and its policies and procedures. In this installment, National Toxicology Program scientists Kembra L. Howdeshell, PhD, and Michael D. Shelby, PhD, discuss a recently completed monograph that reviews the published data on pregnancy outcomes in women who received chemotherapy for cancer during pregnancy. Dr. Howdeshell and Dr. Shelby (retired) are Health Scientists with the Office of Health Assessment and Translation, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health.
In May 2013, the National Toxicology Program completed a Monograph on Developmental Effects and Pregnancy Outcomes Associated With Cancer Chemotherapy Use During Pregnancy.1 The Monograph is intended as a resource for clinicians and their pregnant patients and provides a comprehensive literature review of the human data, including all available data on follow-up evaluations in gestationally exposed offspring. The Monograph does not provide medical advice or guidance.
Interagency Program
What are the National Toxicology Program and Office of Health Assessment and Translations?
Dr. Howdeshell: The National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying tools of modern toxicology and molecular biology. The NTP reports to the FDA, the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health.
The Office of Health Assessment and Translation (OHAT), which is located within the NTP, serves as an environmental health resource to the public and to regulatory and health agencies. The purpose of OHAT is to conduct technical literature–based assessments focused on understanding the potential for adverse effects on human health by agents, substances, or mixtures at various human exposure levels. OHAT assessments are published as NTP Monographs.
Assessment Origins
What initiated the NTP’s interest in chemotherapy use during pregnancy?
Dr. Howdeshell: As you know, many chemotherapy agents used to treat cancer are mutagens or carcinogens. Most chemotherapy agents for the treatment of cancer also induce birth defects in animal studies, and some of these agents have been associated with birth defects in humans. This topic was selected for evaluation by the NTP because of the paucity of comprehensive reviews on pregnancy outcomes following cancer chemotherapy use during pregnancy in humans, including the integration of the developmental animal toxicology literature with observational studies in humans, and growing public interest in the developmental effects of chemotherapy on offspring exposed to cancer chemotherapy during gestation.
The NTP Monograph includes data on 56 agents administered to 1,256 women during 1,261 pregnancies for which pregnancy outcomes were reported. The NTP Monograph also includes a review of the developmental toxicity of these agents in laboratory animals and any reports examining their transport via the placenta or breast milk.
Available Literature
What was the extent of the literature on cancer chemotherapy use during pregnancy?
Dr. Shelby: We identified 431 publications that reported pregnancy outcomes associated with chemotherapy for cancer during pregnancy. The published literature included reports from the 1950s through May 15, 2012. We made a concerted effort to avoid duplicate reporting of cases (eg, an infant reported in a case report and subsequently included in a case series was only counted once). We did not include the pregnancy outcomes of women who became pregnant after completing chemotherapy.
Overall Conclusions
What were the overall conclusions of the Monograph?
Dr. Howdeshell: The NTP Monograph focused on the following five health outcomes: major congenital malformations, spontaneous fetal loss, pregnancy complications, newborn weight and height, and growth and development of gestationally exposed children. Overall, the NTP evaluation found that chemotherapy for treatment of cancer appeared to be associated with a higher rate of major malformations following exposure during the first trimester compared to exposure in the second and/or third trimester only, and the rate of major malformations following exposure in the second and/or third trimester only was similar to the prevalence of major malformations reported in the general U.S. population by the CDC.
Other findings included a higher rate of stillbirth following exposure in the second and/or third trimester compared to the general population and a higher incidence of abnormally low levels of amniotic fluid, which was primarily attributable to trastuzumab (Herceptin). In addition, chemotherapy for treatment of cancer did not appear to increase spontaneous preterm birth and did not appear to impair normal growth and development of offspring during early life. Finally, the data were characterized as insufficient for an effect of chemotherapy on impaired fetal growth and myelosuppression.
These pooled data were evaluated using descriptive—not inferential—statistics because of the limitations in using a largely case report–derived literature for quantitative analysis. Data were analyzed as apparent rates of occurrence, which were based on the published literature. The apparent rates of occurrence were compared to published population studies. While they were not statistically analyzed, the general population studies provided points of reference for interpreting the apparent rates of occurrence.
Illustrative Outcomes
Can you provide an example of an NTP recommendation for consideration of use of chemotherapy for treatment of cancer during pregnancy?
Dr. Howdeshell: First, I want to emphasize that the Monograph does not provide medical advice or guidance. The objective of the Monograph was to summarize the pregnancy outcomes reported in women receiving cancer chemotherapy during pregnancy. However, we did observe that some effects were specific to certain agents following exposure during certain periods of pregnancy.
For example, exposure to imatinib (Gleevec), a tyrosine kinase inhibitor, in the first trimester (ie, during the period of organogenesis) appeared to be associated with a combination of malformations, including exomphalos (umbilical hernia), skeletal malformations, and/or urogenital malformations (ie, kidney agenesis). Some of the same effects have been observed in developmental toxicity studies of imatinib in laboratory animals.
Another example was the high incidence of abnormally low levels of amniotic fluid that was reported with exposure to trastuzumab in the second and/or third trimester(s). This condition appeared to be reversible if administration of the agent was discontinued until birth.
Evaluation Limitations
What were the challenges in interpreting this literature?
Dr. Shelby: There were several limitations to the NTP’s interpretation of the published reports on pregnancy outcomes associated with cancer chemotherapy use during pregnancy, mostly stemming from the necessity of relying on case reports or case series, which limits the ability to reach conclusions with confidence. Some of these limitations included lack of a reference group for comparison (ie, few studies compared the data to nontreated pregnant cancer patients), a small number of cases reported for specific combination chemotherapy regimens, and a lack of data on the condition of the fetus from induced abortions, spontaneous miscarriages, or stillbirths.
Some larger case series lacked individual data on treatment and pregnancy outcomes and could not be added to our pooled analysis. There was also a lack of long-term follow-up examination of the offspring (ie, most reports examined the infant at ≤ 2 years of age), and the quality of the assessments among reports with long-term follow-up evaluation was variable. Finally, a high rate of premature birth among these pregnancies complicated the interpretation of whether adverse effects observed in offspring were due to gestational exposure to cancer chemotherapy or to prematurity.
Expert Panel
What was the composition of the expert panel that peer-reviewed the Monograph?
Dr. Howdeshell: The NTP convened a nine-member ad hoc expert panel to review the draft Monograph in a public meeting on October 1–2, 2012. The expert panel membership included oncologists, high-risk obstetrician/gynecologists, a developmental geneticist, an epidemiologist, and a developmental toxicologist. Two members of the panel had extensive experience in working with this patient population through their work on retrospective surveys and prospective studies of cancer diagnosed during pregnancy.
In addition, the NTP received feedback from our federal agency partners, including comments from Dr. Paul Howard, the FDA liaison to the NTP. The NTP also employed technical experts in the field of high-risk obstetrics/gynecology and clinical oncology to review early drafts of the Monograph.
Available for Download
How does one access the Monograph?
Dr. Howdeshell: The final edited version of the NTP Monograph is available as a downloadable file on the NTP/OHAT website (http://ntp.niehs.nih.gov/go/36495). In addition to the Monograph itself, the website includes an appendices file, which contains detailed tables of all the cases included in the Monograph, organized by chemotherapy agent. ■
Disclosure: Drs. Howdeshell and Shelby reported no potential conflicts of interest.
Reference
1. National Toxicology Program: NTP Monograph on Developmental Effects and Pregnancy Outcomes Associated With Cancer Chemotherapy Use During Pregnancy. May 13, 2013. NIH Publication No. 13-5956. U.S. Department of Health and Human Services, U.S. Health Service, National Institutes of Health, Research Triangle Park, North Carolina. Available at ntp.niehs.nih.gov/go/36495. Accessed on April 28, 2014.
