Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study.
BACKGROUND
Chemotherapy for the treatment of maternal cancers during pregnancy has become more acceptable in the past decade; however, the effect of prenatal exposure to chemotherapy on cardiac and neurodevelopmental outcomes of the offspring is still uncertain. We aimed to record the general health, cardiac function, and neurodevelopmental outcomes of children who were prenatally exposed to chemotherapy.


METHODS
We did an interim analysis of a multicentre observational cohort study assessing children who were prenatally exposed to maternal cancer staging and treatment, including chemotherapy. We assessed children at birth, at age 18 months, and at age 5-6, 8-9, 11-12, 14-15, or 18 years. We did clinical neurological examinations, tests of the general level of cognitive functioning (Bayley or intelligence quotient [IQ] test), electrocardiography and echocardiography, and administered a questionnaire on general health and development. From age 5 years, we also did audiometry, the Auditory Verbal Learning Test, and subtasks of the Children's Memory Scale, and the Test of Everyday Attention for Children, and we also completed the Child Behavior Checklist. This study is registered with ClinicalTrials.gov, number NCT00330447.


RESULTS
236 cycles of chemotherapy were administered in 68 pregnancies. We assessed 70 children, born at a median gestational age of 35·7 weeks (range 28·3-41·0; IQR 3·3; 47 women at <37 weeks), with a median follow-up period of 22·3 months (range 16·8-211·6; IQR 54·9). Although neurocognitive outcomes were within normal ranges, cognitive development scores were lower for children who were born preterm than for those born at full term. When controlling for age, sex, and country, the score for IQ increased by an average 11·6 points (95% CI 6·0-17·1) for each additional month of gestation (p<0·0001). Our measurements of the children's behaviour, general health, hearing, and growth corresponded with those of the general population. Cardiac dimensions and functions were within normal ranges. We identified a severe neurodevelopmental delay in both members of one twin pregnancy.


CONCLUSIONS
Fetal exposure to chemotherapy was not associated with increased CNS, cardiac or auditory morbidity, or with impairments to general health and growth compared with the general population. However, subtle changes in cardiac and neurocognitive measurements emphasise the need for longer follow-up. Prematurity was common and was associated with impaired cognitive development. Therefore, iatrogenic preterm delivery should be avoided when possible.


BACKGROUND
Research Foundation-Flanders; Research Fund-K U Leuven; Agency for Innovation by Science and Technology; Stichting tegen Kanker; Clinical Research Fund-University Hospitals Leuven; and Belgian Cancer Plan, Ministery of Health.
Leuven Cancer Institute, Gynaecologic Oncology, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium. frederic.amant@uzleuven.be
Frédéric
F
Amant
Kristel
K
Van Calsteren
Michael J
MJ
Halaska
Mina Mhallem
MM
Gziri
Wei
W
Hui
Lieven
L
Lagae
Michèl A
MA
Willemsen
Livia
L
Kapusta
Ben
B
Van Calster
Heidi
H
Wouters
Liesbeth
L
Heyns
Sileny N
SN
Han
Viktor
V
Tomek
Luc
L
Mertens
Petronella B
PB
Ottevanger
D000293:Adolescent; D041923:Adolescent Development / Q000187:drug effects; D000367:Age Factors; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001288:Attention / Q000187:drug effects; D057189:Checklist; D002648:Child; D002657:Child Development / Q000187:drug effects; D002675:Child, Preschool; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000523:psychology; D004452:Echocardiography; D004562:Electrocardiography; D005060:Europe; D005260:Female; D005865:Gestational Age; D006331:Heart Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D007361:Intelligence Tests; D016014:Linear Models; D008297:Male; D008568:Memory / Q000187:drug effects; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic / Q000188:drug therapy*; D047928:Premature Birth; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D011795:Surveys and Questionnaires
D000970:Antineoplastic Agents