Chemotherapy During Pregnancy Appears Safe for Offspring

Roxanne Nelson

February 09, 2012

February 9, 2012 — Chemotherapy given during pregnancy does not appear to interfere with normal childhood development, according to the results of a study published online February 9 in the Lancet Oncology.

The data, which were first presented at the 2011 European Multidisciplinary Cancer Congress (EMCC), showed that children born to women exposed to chemotherapy while pregnant develop as well as children in the general population, and do not appear to suffer any detrimental effects.

Fetal exposure to chemotherapy was not associated with increased central nervous system, cardiac, or auditory morbidity, note the researchers. Nor was it associated with impairments to general health and growth. In particular, in children at least 18 months of age who were prenatally exposed to chemotherapy and tested at predefined ages, cognitive development was age-adequate, they report.

This study has the potential to affect clinical practice, writes Elyce Cardonick, MD, from Cooper Medical School of Rowan University, Camden, New Jersey, in an accompanying editorial.

"If we can present these reassuring data to pregnant women with cancer, women might be more likely to accept treatment during pregnancy when indicated," she writes. "This report might encourage oncologists and obstetricians to recognize the advantages of collaboration when the subject under study, such as cancer in pregnancy, is rare."

The study can also reassure pregnant women and their physicians that the benefits of maternal treatment do not appear to be outweighed by any long-term cardiac or neurologic consequences for the exposed fetus, Dr. Cardonick writes.

Prematurity Worsens Outcome

Although neurocognitive outcomes were within normal ranges, cognitive development scores were lower for children who were born preterm. Developmental delay is common in children who are born premature, explained lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium. However, they are unable to tell if these issues are related to chemotherapy exposure or to the preterm delivery.

"We can't exclude the effects of chemotherapy in preterm children," Dr. Amant told Medscape Medical News when the data were presented at the EMCC meeting. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."

When confounders, including age, sex, and country, were controlled for, IQ score increased by 11.6 points, on average, for each additional month of gestation (P < .0001).

Premature birth is very common in this population; 66% of the cohort was born before 37 weeks of gestation. The high rate of prematurity seen in this study was also not caused by chemotherapy, but was related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.

In 38 pregnancies (56%), a decision was made to induce the delivery for nonobstetric reasons, primarily to begin cancer treatment or, in a few cases, because of the mother's deteriorating health. Of this group, 28 infants (74%) were delivered preterm iatrogenically, at a median gestational age of 35.3 weeks (range, 31.3 to 36.3).

"Our message is that we prefer to give chemotherapy until the baby is mature, and then after the baby is delivered, we continue maternal treatment," said Dr. Amant. "We think that the baby has less trauma from chemotherapy than from prematurity, and in our setting, this changes how we treat patients."

"Fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," he explained.

Longer Follow-Up Needed

There were subtle changes in cardiac and neurocognitive measurements, despite the fact that the general neurodevelopmental assessment was within the normal range, the researchers emphasize. Therefore, it is necessary to remain prudent until a larger cohort of children has been assessed, with a longer follow-up period.

For example, in 23 children older than 6 years of age who did a Wechsler intelligence test, a disharmonic intelligence profile (a discrepancy between verbal and performance IQ values) was observed in 39%; in the normal population, the rate is 15%. Even though this does not directly suggest that these children have neuropsychological impairment, "verbal and performance IQ discrepancies have been associated with several neurological disorders and learning," note the researchers.

A severe neurodevelopmental delay was observed in both members of a twin pregnancy. A cortical malformation with multiple dysmorphic characteristics was identified in one of the children, suggesting a syndromal entity, although a specific clinical syndrome could not be diagnosed. The strong suggestion of a syndrome makes a causal relation to chemotherapy less probable, they note.

Study Details

In their study, Dr. Amant and colleagues assessed the general health, cardiac function, and neurodevelopmental outcomes of children who were exposed to chemotherapy in the prenatal period. They evaluated 68 pregnancies (70 children), during which 236 cycles of chemotherapy were administered.

Median maternal age was 32.9 years, and gestational age at cancer diagnosis was 18.1 weeks. Median gestational age at birth was 35.7 weeks; 7 children were born at 28.0 to 31.9 weeks, 9 at 32.0 to 33.9 weeks, 31 at 34.0 to 36.9 weeks, and 23 at term (37.0 or more weeks).

Congenital malformations in this cohort were similar to those in the general population. During the study period, the children ranged in age from 1.5 to 18.0 years. Assessments were conducted at birth, at 18 months, and at age 5/6, 8/9, 11/12, 14/15, and 18 years. Testing included clinical neurologic examinations, tests of the general level of cognitive functioning (Bayley or IQ test), and electrocardiography and echocardiography. In addition, a questionnaire was completed on general health and development.

Audiometry, the Auditory Verbal Learning Test, subtasks of the Children's Memory Scale, and the Test of Everyday Attention for Children were administered to children who were at least 5 years of age. Parents completed the Child Behavior Checklist.

During pregnancy, 19 different regimens of chemotherapy were administered; anthracyclines were the most common agents (given to 53 patients). In children exposed to anthracyclines, the variables for systolic and diastolic function were all within normal ranges. A higher heart rate was observed in the study participants, but an analysis of the electrocardiography measurements revealed no arrhythmia or conduction abnormalities. In addition, echocardiographic examination did not reveal any structural cardiac defects.

The researchers conclude that 3 important factors contributed to the "overall reassuring outcome" of this trial. One is that chemotherapy was administered only after the first trimester, which is the most vulnerable time for toxic effects. Second, in contrast to the "belief that the fetal blood–brain barrier is immature and leaky," recent data suggest that, in fact, the fetal brain is well protected. Third, they note, even though human data are anecdotal, the placenta filters cytotoxic drugs and shields a proportion from the fetus.

Recruitment for this study is ongoing; the researchers hope to follow-up with a larger number of children over a longer period of time. In the meantime, "only time will inform us of the full consequences, including fertility and secondary malignancies (especially if DNA-damaging drugs are used), of fetal exposure to chemotherapy," the researchers write.

The editorialist adds that there are key questions that remain unanswered about the pharmacokinetics of chemotherapy during pregnancy. It is not known how pregnancy affects chemotherapy metabolism, and pregnancy does affect the metabolism of a number of drugs.

"Lower survival for pregnant women undergoing chemotherapy than for matched nonpregnant women has not been shown, but the relative number of pregnant women treated for cancer has been small," Dr. Cardonick explains. "If lower free drug, because of pregnancy-induced changes in blood volume, protein binding, or drug metabolism affected the efficacy of chemotherapy, it would be important for oncologists to recognize and allow for dose adjustments."

The study was funded by Research Foundation Flanders; Research Fund KU Leuven; the Agency for Innovation by Science and Technology; Stichting tegen Kanker; Clinical Research Fund University Hospitals Leuven; and Belgian Cancer Plan, Ministry of Health. The authors and the editorialist have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 10, 2012. Abstract, Editorial


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