Impact of chemotherapy during pregnancy on fetal growth.

BACKGROUND: Chemotherapy crosses the placenta, however, it remains unclear to what extent it affects fetal growth. The current literature suggests up to 21% of the offspring of women receiving chemotherapy are small for gestational age (SGA, birth weight <10th percentile). Limiting research to birth weights only might misjudge fetal growth restriction (FGR) in this high-risk population with multiple risk factors for impaired fetal growth. Moreover, the role of the duration of chemotherapy and gestational age at initiation of chemotherapy in fetal growth is yet poorly understood. OBJECTIVE: This retrospective cohort study evaluates fetal growth and neonatal birthweights in pregnant women receiving chemotherapy. STUDY DESIGN: All pregnant patients, registered by the International Network of Cancer, Infertility and Pregnancy (INCIP), treated with chemotherapy with at least two ultrasounds reporting on fetal growth, were eligible for this study. Duration and gestational age at initiation of chemotherapy were our major determinants, followed by cancer type and stage, maternal characteristics (parity, BMI, ethnicity hypertension, and diabetes) and individual cytotoxic agents (anthracycline, taxanes, and platinum). Fetal growth outcomes were described using the following mutually exclusive groups (1) FGR, based on a Delphi consensus (2016); (2) "low risk SGA" (birth weight below the 10th percentile), but an estimated growth above the 10th percentile; (3) "fetal growth disturbance", which did not meet all FGR criteria; (4) "non-FGR". Obstetric and oncological characteristics were compared between the growth impaired groups and non-FGR group. We calculated estimated fetal weight (EFW) according to Hadlock's formula (1991) and birth weight percentile according to Nicolaides (2018). We used univariable and multivariable regression, and linear mixed effect models to investigate the effect of duration and gestational age at initiation of chemotherapy on birth weight, and fetal growth, respectively. RESULTS: We included 201 patients, diagnosed with cancer between March 2000 and March 2020. Most patients were diagnosed with breast cancer (n = 132, 66%). Regimens included anthracyclines (n = 121, 60%), (anthracyclines and) taxanes (n = 45, 22%) and platinum (n = 35, 17%). Fetal growth abnormalities were detected in 75 pregnancies: 43 (21%) FGR, 10 (5%) low risk SGA and 22 (8.5%) fetal growth disturbance. Chemotherapy prior to 20 weeks of gestation (47% vs. 25%, p = .04) and poor maternal gestational weight gain (median percentile 15 (range 0-97) vs. 8 (0-84), p = .03) were more frequent in the FGR group compared to the non-FGR group, whereas no difference was seen for specific chemotherapy or cancer types. Univariable regression identified gestational weight gain, hypertension, systemic disease, parity, neonatal sex and maternal BMI as confounders for birth weight percentiles. Multivariable regression revealed that each additional week of chemotherapy was associated with lower birth weight percentiles (-1.06; 95%CI -2.01; -0.04; p = .04), and that later initiation of chemotherapy was associated with an increase in birth weight percentile (1.10 per week; 95%CI 0.26; 1.95; p = .01). Each additional week of chemotherapy was associated with lower EFW and abdominal circumference (AC) percentiles (-1.77; 95%CI -2.21; -1.34, p < .001; -1.64; 95%CI -1.96; -1.32, p < .001, respectively). CONCLUSIONS: This study demonstrates that FGR is common after chemotherapy in pregnancy, and that the duration of chemotherapy has a negative impact. Sonographic follow-up of fetal growth and well-being is recommended.

Ten-year experience of a national multidisciplinary tumour board for cancer and pregnancy in the Netherlands.

BACKGROUND: Most physicians encounter pregnant women with cancer incidentally, leading to a lack of expertise or confidence to inform and treat these patients based on the most recent guidelines and expert opinions. In the Netherlands, a national multidisciplinary tumour board for cancer, infertility and pregnancy (CIP-MDT) was founded in December 2012, including 35 specialists from a variety of disciplines. This study evaluates the frequency of consultation of the CIP-MDT, the types of questions asked and the satisfaction of consulting physicians with its existence. METHODOLOGY: Of all requests to the CIP-MDT between December 2012 and June 2021, tumour type, stage, gestational age at diagnosis and recommendations were collected and analysed. For evaluating the methods of the CIP-MDT, a survey with questions regarding experiences with the CIP-MDT and its impact on treatment decisions was sent out to physicians that consulted the CIP-MDT. RESULTS: Recommendations (n = 213) concerned preferred and safest options for imaging, treatment options during pregnancy, possible effects on the child and fertility preserving options. Most frequently discussed malignancies were breast cancer (n = 66), cervical cancer (n = 34), haematological malignancies (n = 32) and melanoma (n = 21). The questionnaire was completed by 54% of the physicians (n = 50). Satisfaction with the recommendations of the CIP-MDT was high, and 94% of the physicians informed their patients about consulting the CIP-MDT and felt supported by the received recommendations. DISCUSSION: The national Dutch CIP-MDT contributes to a high level of satisfaction among physicians requesting advice. Further research should be executed to confirm that a CIP-MDT improves the outcomes for pregnant women and their children.

Outcome of breast cancer patients treated with chemotherapy during pregnancy compared with non-pregnant controls.

BACKGROUND: A diagnosis of breast cancer during pregnancy (PrBC) does not impact prognosis if standard treatment is offered. However, caution is warranted as gestational changes in pharmacokinetics may lead to reduced chemotherapy concentration. METHODS: Survival of PrBC patients treated with chemotherapy during pregnancy was compared to non-pregnant breast cancer patients treated with chemotherapy, diagnosed after 2000, excluding patients older than 45 years or with a postpartum diagnosis. The data was registered in two multicenter registries (the International Network of Cancer, Infertility and Pregnancy and the German Breast Group). Cox proportional hazards regression was used to compare disease-free (DFS) and overall survival (OS) between both groups, adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status and histology, weighted by propensity scoring to account for the differences in baseline characteristics between pregnant patients and controls. RESULTS: In total, 662 pregnant and 2081 non-pregnant patients were selected. Pregnant patients were more likely to have stage II breast cancer (60.1% vs 56.1%, p = 0.035), grade 3 tumors (74.0% vs 62.2%, p < 0.001), hormone receptor-negative tumors (48.4% vs 34.0%, p < 0.001) or triple-negative breast cancer (38.9% vs 26.9%, p < 0.001). Median follow-up was 66 months. In multivariable analysis, DFS and OS were comparable for pregnant and non-pregnant patients (DFS: HR 1.02, 95% CI 0.82-1.27, p = 0.83; OS: HR 1.08, 95% CI 0.81-1.45, p = 0.59). CONCLUSION: Outcome of women with breast cancer treated with chemotherapy during pregnancy is comparable to young non-pregnant women. These results support chemotherapy for PrBC when indicated.

Data describing child development at 6 years after maternal cancer diagnosis and treatment during pregnancy.

This manuscript is an accompanying resource of the original research article entitled "Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy" and present data that compare the outcome of 6-year-old-children born to women diagnosed with cancer during pregnancy (with or without treatment during pregnancy) (study group) with children born after an uncomplicated pregnancy (control group). Oncological, obstetrical and neonatal data were collected. Neurodevelopment was examined by clinical evaluation and neuropsychological testing (including intelligence, attention and memory tests) and by general health and behavior questionnaires. Cardiac evaluation included electro- and echocardiography. Univariate analyses of covariance were used to investigate between-group differences. A subgroup analysis was performed in chemotherapy-exposed children versus controls and anthracycline-exposed versus controls. Additionally, the incidence of behaviour problems was compared to matched controls for children whose mothers died and for those with surviving mothers.

Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy.

BACKGROUND: Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. METHODS: In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. RESULTS: In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5-101.8, versus 104.4, 95% CI: 100.4-108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6-4.3, versus 4.5, 95% CI: 4.1-4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). CONCLUSIONS: Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. CLINICAL TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, NCT00330447.

Pregnancy and Cancer: the INCIP Project.

PURPOSE OF REVIEW: Cancer diagnosis in young pregnant women challenges oncological decision-making. The International Network on Cancer, Infertility and Pregnancy (INCIP) aims to build on clinical recommendations based on worldwide collaborative research. RECENT FINDINGS: A pregnancy may complicate diagnostic and therapeutic oncological options, as the unborn child must be protected from potentially hazardous exposures. Pregnant patients should as much as possible be treated as non-pregnant patients, in order to preserve maternal prognosis. Some approaches need adaptations when compared with standard treatment for fetal reasons. Depending on the gestational age, surgery, radiotherapy, and chemotherapy are possible during pregnancy. A multidisciplinary approach is the best guarantee for experience-driven decisions. A setting with a high-risk obstetrical unit is strongly advised to safeguard fetal growth and health. Research wise, the INCIP invests in clinical follow-up of children, as cardiac function, neurodevelopment, cancer occurrence, and fertility theoretically may be affected. Furthermore, parental psychological coping strategies, (epi)genetic alterations, and pathophysiological placental changes secondary to cancer (treatment) are topics of ongoing research. Further international research is needed to provide patients diagnosed with cancer during pregnancy with the best individualized management plan to optimize obstetrical and oncological care.

Severe Adverse Reaction to Vemurafenib in a Pregnant Woman with Metastatic Melanoma.

Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction.

Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients.

BACKGROUND: Awareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes. METHODS: This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log-binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing. FINDINGS: 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1·10, 95% CI 1·05-1·15), mainly related to an increase of chemotherapeutic treatment (1·31, 1·20-1·43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1·04, 95% CI 1·01-1·06) and fewer iatrogenic preterm deliveries (0·91, 0·84-0·98). Our data suggest a relationship between platinum-based chemotherapy and small for gestational age (odds ratio [OR] 3·12, 95% CI 1·45-6·70), and between taxane chemotherapy and NICU admission (OR 2·37, 95% CI 1·31-4·28). NICU admission seemed to depend on cancer type, with gastrointestinal cancers having highest risk (OR 7·13, 95% CI 2·86-17·7) and thyroid cancers having lowest risk (0·14, 0·02-0·90) when compared with breast cancer. Unexpectedly, the data suggested that abdominal or cervical surgery was associated with a reduced likelihood of NICU admission (OR 0·30, 95% CI 0·17-0·55). Other associations between treatment or cancer type and outcomes were less clear. INTERPRETATION: Over the years, the proportion of patients with cancer during pregnancy who received antenatal treatment increased, especially treatment with chemotherapy. Our data indicate that babies exposed to antenatal chemotherapy might be more likely to develop complications, specifically small for gestational age and NICU admission, than babies not exposed. We therefore recommend involving hospitals with obstetric high-care units in the management of these patients. FUNDING: Research Foundation-Flanders, European Research Council, Charles University, Ministry of Health of the Czech Republic.

Cancer related maternal mortality and delay in diagnosis and treatment: a case series on 26 cases.

BACKGROUND: Cancer during pregnancy is relatively rare but may lead to maternal mortality. We aimed to assess the incidence of cancer related maternal mortality and the neonatal outcome in these patients. Also, doctor- and patient-related delay in cancer diagnosis and therapy among patients with cancer related maternal mortality is assessed. METHODS: Maternal mortality was defined as death during pregnancy or within 1 year after delivery. Data of the Dutch Maternal Mortality Committee was used to calculate the cancer related maternal mortality rate and to assess neonatal outcome in the Netherlands. Delay was scored by ten medical specialist based on case descriptions. RESULTS: Cancer related maternal mortality rate was 1.23 per 100,000 live births. Delay in either diagnosis or treatment occurred in 65%. Delay in diagnosis was more frequent then delay in treatment, and was mainly caused by health care providers. Only 77% of pregnancies were ongoing, and 65% ended preterm of which 85% was induced. CONCLUSIONS: Avoiding delay in diagnosis and therapy in case of pregnancy related cancer could potentially improve maternal and neonatal outcome. It is therefore essential to increase awareness among health care providers about the occurrence and recurrence of cancer in pregnancy and the possibilities of diagnostic and therapeutic interventions in these women.

Maternal and obstetrical outcome in 35 cases of well-differentiated thyroid carcinoma during pregnancy.

OBJECTIVES/HYPOTHESIS: Thyroid cancer, with 6% to 10% of cancer diagnoses, is one of the most common malignancies during pregnancy. Its treatment poses a risk for the pregnancy, as the thyroid gland plays a crucial role in the evolution of pregnancy. The aim of this study is to evaluate treatment of primary well-differentiated thyroid carcinoma during pregnancy and fetal and maternal outcomes. STUDY DESIGN: This is an international cohort study. METHODS: Primary thyroid cancer patients were identified from the database of the International Network on Cancer, Infertility, and Pregnancy registration study. Data on histopathological characteristics, diagnostic and therapeutic interventions, outcome (obstetrical, neonatal, and maternal) and maternal follow-up were analyzed. RESULTS: Thirty-five patients with well-differentiated thyroid carcinoma were eligible. All 35 patients underwent surgery, 29 (83%) of which during pregnancy. Procedures during pregnancy were mainly total thyroidectomies (n = 24). The median number of days between diagnosis and surgical treatment was different between the groups with surgery during and after pregnancy (27 vs. 139 days, P < .001). Both maternal and neonatal outcomes were uncomplicated, regardless of gestational age during surgery. CONCLUSIONS: Well-differentiated thyroid carcinoma diagnosed during pregnancy has a favorable outcome for both mother and child. Surgical management during pregnancy has no negative impact on the pregnancy regardless of the trimester at the time of surgery. However, the potential negative effects of thyroid surgery early in pregnancy demand management of these patients in an experienced multidisciplinary team to provide the best possible care for these patients and their unborn babies. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1493-1500, 2018.

Melanoma during pregnancy: a report of 60 pregnancies complicated by melanoma.

The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.

Ovarian cancer in pregnancy.

Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non-epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor.