Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study

doi:10.1016/S1470-2045(11)70363-1

The Lancet Oncology

Volume 13, Issue 3, March 2012, Pages 256-264

https://doi.org/10.1016/S1470-2045(11)70363-1 Get rights and content

Summary

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.

Findings

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.

Interpretation

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.

Funding

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.

Introduction

The unintended use of urethane to treat chronic myeloid leukaemia in a pregnant woman in 1948 was one of the first reports of chemotherapy use during pregnancy.¹ Since then, more experience has been gained and chemotherapy is now regularly given after the first trimester if cancer treatment is needed during pregnancy.2, 3 Investigators estimate that cancer complicates one in 1000–2000 pregnancies and the incidence increases by 2·5% per calendar year.4, 5, 6 However, the effect of the malignancy and its treatment on fetal health remains a serious concern.

Chemotherapy during the first trimester increases the risk of congenital malformations, whereas the effects of chemotherapy on the fetus beyond the first trimester could potentially affect the development of the brain and heart. Of concern is the potential effect on the front of the brain (attention, memory, and executive functions), because these are most affected by cytotoxic treatment in adults and children.⁷ These cognitive functions are also the most vulnerable in infants at risk, such as preterm neonates, children with periventricular leucomalacia, and children in utero exposed to toxic products such as cocaine, tobacco, or alcohol, or to maternal emotional disturbance and distress.8, 9, 10 A second concern is the potential cardiotoxic effect of anthracyclines, commonly used in the treatment of breast cancer and haematological malignancies—the most common cancer types during pregnancy.¹¹

So far, solely retrospective and restricted data exist on the long-term outcome of children exposed to chemotherapy in utero.12, 13, 14 We aimed to assess the general health, cardiac function, and neurodevelopmental outcomes, including intelligence, memory, attention, and executive functions, in children who were prenatally exposed to chemotherapy.

Section snippets

Participants

This multicentre cohort study was started on March 18, 2005 in three European countries and on the basis of a collaboration between national referral centres in Belgium (University Hospitals Leuven), the Netherlands (Radboud University Nijmegen Medical Centre), and the Czech Republic (Faculty Hospital Motol, Charles University, Prague). The study is still recruiting. Some children were enrolled and followed up prospectively; however, others were identified retrospectively (ie, were exposed to

Results

This interim analysis was done with a data cutoff at March 1, 2011. Figure 1 shows the study profile. 32 girls and 38 boys were exposed to chemotherapy in utero (236 cycles) during 68 pregnancies (two twin pregnancies). Distribution of children by country was 42 in Belgium, 20 in the Netherlands, and eight in the Czech Republic. Maternal disease, staging examinations, and drugs administered as supportive care are shown in the appendix. During pregnancy, 34 women received chemotherapy, one

Discussion

Despite prenatal exposure to chemotherapy, radiotherapy, staging examinations, and co-medications, the outcome for children in our study is not different from the general population. In particular, we noted age-adequate cognitive development and normal cardiac outcome in a cohort of children aged at least 18 months who were prenatally exposed to chemotherapy and tested at predefined ages. In our cohort, we confirmed the negative prognostic effect of prematurity on cognitive development (Bayley

References (37)

A Creskoff et al.
Urethane therapy in leukemia
Blood
(1948)
F Amant et al.
Breast cancer in pregnancy
Lancet
(2012)
A Aviles et al.
Hematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero
Clin Lymphoma
(2001)
A Aviles et al.
Long-term evaluation of cardiac function in children who received anthracyclines during pregnancy
Ann Oncol
(2006)
A Verrotti et al.
New trends in neuronal migration disorders
Eur J Paediatr Neurol
(2010)
J Isen
A meta-analytic assessment of Wechsler's P>V sign in antisocial populations
Clin Psychol Rev
(2010)
E Cardonick et al.
Use of chemotherapy during human pregnancy
Lancet Oncol
(2004)
K Van Calsteren et al.
Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model
Gynecol Oncol
(2010)
O Mir et al.
Emerging therapeutic options for breast cancer chemotherapy during pregnancy
Ann Oncol
(2008)
F Amant et al.
Gynecologic cancers in pregnancy: guidelines of an international consensus meeting
Int J Gynecol Cancer
(2009)

U Nieminen et al.

Malignancy during pregnancy

Acta Obstet Gynecol Scand

(1970)

JF Potter et al.

Metastasis of maternal cancer to the placenta and fetus

Cancer

(1970)

H Stensheim et al.

Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study

J Clin Oncol

(2009)

M Mennes et al.

Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Pediatr Blood Cancer

(2005)

GC Lohaugen et al.

Cognitive profile in young adults born preterm at very low birthweight

Dev Med Child Neurol

(2010)

AL van Baar et al.

Functioning at school age of moderately preterm children born at 32 to 36 weeks' gestational age

Pediatrics

(2009)

BR Van den Bergh et al.

Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood

Neuropsychopharmacology

(2008)

K Van Calsteren et al.

Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes

J Clin Oncol

(2010)

Cited by (206)

Breast cancer during pregnancy: epidemiology, phenotypes, presentation during pregnancy and therapeutic modalities
2022, Best Practice and Research: Clinical Obstetrics and Gynaecology
Although it is uncommon in general, breast cancer is the most commonly diagnosed cancer during pregnancy. While treatment for pregnant patients should adhere to treatment guidelines for non-pregnant patients, there exist specific considerations concerning diagnosis, staging, oncological treatment, and obstetrical care. Imaging and staging are preferably performed using breast ultrasound and mammography. Other ionizing radiation imaging modalities, including computed tomography (CT) and Positron Emission Tomography/ Computed Tomography (PET/CT), can be selectively performed when the estimated benefit for the mother outweighs the risks to the foetus, e.g., when the results will change clinical management. MRI is appropriate to stage for distant disease on the indication. Breast cancer during pregnancy is less often hormone receptor-positive and more frequently triple-negative breast cancer compared to age-matched controls. The basic principle is that women should receive state-of-the-art oncological treatment without delay if possible and that the pregnancy should be maintained as long as possible. Treatment strategy should be multidisciplinary defined, carefully weighing the selection, sequence, and timing of treatment modalities depending on patient-, tumour-, and pregnancy-related characteristics, as well as patient preferences. Initiating cancer treatment during pregnancy often decreases the risks of early delivery and prematurity. Breast cancer surgery is possible during all trimesters. Radiotherapy is possible during pregnancy in the first half of pregnancy. Chemotherapy can be safely administered starting from 12 weeks of gestational age, but endocrine and HER2 targeted therapy are contraindicated throughout the whole pregnancy. Importantly, foetal growth should be monitored and long-term follow-up of the children is encouraged in dedicated centres.
Prognosis of triple-negative breast cancer associated with pregnancy: A propensity score-matched analysis from the French CALG (Cancer Associé à la Grossesse) network
2022, Breast
Triple-negative (TN) breast cancer represents one third of pregnancy-associated breast cancers (PABC). The aims of the current study were to describe oncological and obstetrical outcomes of patients with TN-PABC and to compare their prognosis with TN-non-PABC patients using a propensity score.
Between January 2005 and December 2020, data of patients with histologically proven TN-PABC were collected and compared with data of TN-non-PABC patients under the age of 46 years diagnosed during the same period using a propensity score (PS).
After PS matching (tumor size and lymph node involvement),there were 59 patients in each group. The median follow-up was 14 months (IQR 4.8–40.1) for the TN-PABC group and 60 months (IQR 30.7–101.4) for the TN-non-PABC group. Eight recurrences occurred in the TN-PABC group and 10 in the TN-non-PABC group (adjusted OR (AOR) = 0.60 (0.21–1.60), HR (Cox adjusted model- AHR) = 1.25 (0.53–2.94)). Two patients died in the TN-PABC group, and six in the TN-non-PABC group with an AOR = 0.23 (0.03–1.01) and an AHR = 0.58 (0.12–2.69). All the patients diagnosed during the second (n = 17) and third trimesters (n = 28) continued their pregnancies, with a median term at delivery of 38 WG (IQR 36–39). All patients gave birth to healthy newborns.
Although the TN subtype is associated with poor prognosis in pregnant patients due to advanced stage at diagnosis and high lymph node involvement, our PS-matched case-control study showed that pregnancy per se does not worsen the prognosis in terms of recurrence-free and overall survival.
In-Hospital Complications in Pregnant Women With Current or Historical Cancer Diagnoses
2021, Mayo Clinic Proceedings
To assess the temporal trends, characteristics and comorbidities, and in-hospital cardiovascular and obstetric complications and outcomes of pregnant women with current or historical cancer diagnosis at the time of admission for delivery.
We analyzed delivery hospitalizations with or without current or historical cancer between January 1, 2004, and December 31, 2014, from the US National Inpatient Sample database.
We included 43,132,097 delivery hospitalizations with no cancer, 39,118 with current cancer, and 67,336 with historical diagnosis of cancer. The 5 most common types of current cancer were hematologic, thyroid, cervical, skin, and breast cancer. Women with current and historical cancer were older (29 years and 32 years vs 27 years) and incurred higher hospital costs ($4131 and $4078 vs $3521) compared with women without cancer. Most of the cancer types were associated with preterm birth (hematologic: adjusted odds ratio [aOR], 1.48 [95% CI, 1.35 to 1.62]; cervical: aOR, 1.47 [95% CI, 1.32 to 1.63]; breast: aOR, 1.93 [95% CI, 1.72 to 2.16]). Current hematologic cancer was associated with the highest risk of peripartum cardiomyopathy (aOR, 12.19 [95% CI, 7.75 to 19.19]), all-cause mortality (aOR, 6.50 [95% CI, 2.22 to 19.07]), arrhythmia (aOR, 3.82 [95% CI, 2.04 to 7.15]), and postpartum hemorrhage (aOR, 1.31 [95% CI, 1.11 to 1.54]). Having a current or historical cancer diagnosis did not confer additional risk for stillbirth; however, metastases increased the risk of maternal mortality and preterm birth.
Women with a current or historical diagnosis of cancer at delivery have more comorbidities compared with women without cancer. Clinicians should communicate the risks of multisystem complications to these complex patients.
Pregnancy associated breast cancer (PABC): Report from a gestational cancer registry from a tertiary cancer care centre, India
2021, Breast
Pregnancy associated breast cancer (PABC) is a rare entity and defined as breast cancer diagnosed during pregnancy or one-year post-partum. There is sparse data especially from low and middle-income countries (LMIC) and merits exploration.
The study (2013–2020) evaluated demographics, treatment patterns and outcomes of PABC.
There were 104 patients, median age of 31 years; 43 (41%) had triple-negative disease, 31(29.8%) had hormone-receptor (HR) positive and HER2 negative, 14 (13.5%) had HER2-positive and HR negative and 16(15.4%) had triple positive disease. 101(97%) had IDC grade III tumors and 74% had delayed diagnosis. 72% presented with early stage (24, EBC) or locally advanced breast cancer (53, LABC) and received either neoadjuvant (n = 49) or adjuvant (n = 26) chemotherapy and surgery. Trastuzumab, tamoxifen, and radiotherapy were administered post-delivery. At a median follow up of 27 (IQR:19–35) months, the estimated 3-year event-free survival (EFS) for EBC and LABC was 82% (95% CI: 65.2–100) and 56% (95% CI: 42–75.6%) and for metastatic 24% (95% CI: 10.1%–58.5%) respectively.
Of the 104 patients, 34 were diagnosed antepartum (AP) and 15 had termination, 2 had preterm and 16 had full-term deliveries(FTDs). Among postpartum cohort (n = 70), 2 had termination, 1 had preterm, 67 had FTDs. 83(including 17 from AP) children from both cohorts were experiencing normal milestones.
Data from the first Indian PABC registry showed that the majority had delayed diagnosis and aggressive features(TNBC, higher grade). Treatment was feasible in majority and stage matched outcomes were comparable to non-PABCs.
Survival in pregnancy-associated breast cancer patients compared to non-pregnant controls
2024, Reproductive Biology and Endocrinology
Long-term outcomes of children after prenatal exposure to maternal cancer and its treatment
2024, Acta Obstetricia et Gynecologica Scandinavica

View all citing articles on Scopus

View full text

ArticlesLong-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Participants

Results

Discussion

Blood

Lancet

Clin Lymphoma

Ann Oncol

Eur J Paediatr Neurol

Clin Psychol Rev

Lancet Oncol

Gynecol Oncol

Ann Oncol

Gynecologic cancers in pregnancy: guidelines of an international consensus meeting

Int J Gynecol Cancer

Malignancy during pregnancy

Acta Obstet Gynecol Scand

Metastasis of maternal cancer to the placenta and fetus

Cancer

Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study

J Clin Oncol

Attention and information processing in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Pediatr Blood Cancer

Cognitive profile in young adults born preterm at very low birthweight

Dev Med Child Neurol

Functioning at school age of moderately preterm children born at 32 to 36 weeks' gestational age

Pediatrics

Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: a prospective study on the fetal origins of depressed mood

Neuropsychopharmacology

Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes

J Clin Oncol

Articles
Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study