Maternal death by cancer in pregnancy: A descriptive study of the International Network on Cancer, Infertility and Pregnancy.

OBJECTIVE: To characterise pregnant women diagnosed with primary or recurrent cancer who died during pregnancy, during delivery or within 1 year postpartum. DESIGN: A descriptive study. SETTING: The registry of the International Network on Cancer, Infertility and Pregnancy (INCIP). POPULATION: Women diagnosed with cancer during pregnancy between 2000 and 2022. METHODS: Using the INCIP registry database, we compared the characteristics of all women with cancer who died during pregnancy, delivery or within 1 year postpartum with those of all women with cancer who survived the first year postpartum. MAIN OUTCOME MEASURES: Maternal and tumour characteristics and obstetrical and neonatal outcomes. RESULTS: Of the 2359 women registered in INCIP, there were 131 cases (5.6%) of maternal mortality. Lung cancer (9/14, 64.3% of all registered women with lung cancer), gastro-oesophageal cancer (13/21, 61.9%) and acute leukaemia (17/105, 16.2%) had the highest rates of maternal mortality. Maternal mortality was associated with fewer live births compared with the control group without maternal mortality (99/131, 75.6%, vs 1952/2163, 90.0%; P < 0.001), more elective caesarean sections (64/104, 60.4%, vs 756/1836, 41.2%; P < 0.001) and a lower gestational age at (induced) delivery (34.0 vs 37.1 weeks; P < 0.001), resulting in more preterm births. CONCLUSIONS: Maternal mortality occurred in 5.6% of cancer-in-pregnancy cases and is associated with adverse perinatal outcomes.

Interventional radiology for prevention and management of postpartum haemorrhage: a single centre retrospective cohort study.

PURPOSE: Postpartum haemorrhage (PPH) remains a leading cause of maternal death despite current medical management. Surgical interventions are still needed for refractory bleeding. Interventional radiology (IR) can be a successful intermediary that avoids the need for hysterectomy. Nevertheless, IR outcome data in a peripartum setting are limited. The objective of this study is to document the efficacy and safety of IR. METHODS: Retrospective study reviewed the records of consecutive patients who underwent peripartum IR from 01/01/2010 until 31/12/2020 in a tertiary academic centre. Patients were divided in a prophylactic and a therapeutic group. Information about interventions before and after IR, and IR specific complications was retrieved. Efficacy was defined by the number of transfusions and additional surgical interventions needed after IR, and safety was assessed by the incidence of IR related complications. RESULTS: Fifty-four patients, prophylactic group (n = 24) and therapeutic group (n = 30), were identified. In both groups, IR was successful with 1.5 ± 2.9 packed cells transfused post-IR (1.0 ± 2.1 prophylactic vs 1.9 ± 3.3 therapeutic; p = 0.261). Additional surgical interventions were required in n = 5 patients (9.2%), n = 1 (4.2%) in the prophylactic vs. n = 4 (13.3%) in the therapeutic group. Complications were reported in n = 12 patients (22.2%), n = 2 (8.3%) prophylactic vs. n = 10 (33.3%) in therapeutic group. Mostly minor complications, as puncture site hematoma or bleeding, were reported in n = 4 (7.4%). Severe complications as necrosis and metabolic complications were reported in n = 2 patients (3.9%). CONCLUSION: IR for prevention and treatment of PPH was highly successful and associated with minor complications.

Aorta pathology and pregnancy-related risks in adult congenital cardiac disease: does the aorta dilate during pregnancy?

Background: Aortic dilatation and pregnancy are major concerns in women with aortopathy (AOP). This single-centre retrospective analysis focuses on the evolution of aortic diameters during and after pregnancy in women with Marfan syndrome (MS), Turner syndrome (TS) and bicuspid aortic valve (BAV) aortopathy. Methods and results: Thirty-eight women who had one or more single pregnancies were included. The ascending aorta was measured during pregnancy and postpartum. During pregnancy, a significant increase of diameters of the sinus aortae (median 1.4 mm; [-1.3; 3.8]) and ascending aorta (median 2.1 mm; [0.0; 4.0]) was noted. Systemic hypertension gives dilation of the aorta, but it did not influence the overall trajectory during pregnancy. Conclusion: Significant aortic dilatation is noted during pregnancy in women with underlying AOP, even persisting in the long term. Pre-existing systemic hypertension is associated with larger aortic diameters prior to pregnancy. More research on a larger study population however is needed.

Urogenital cultures and preterm birth in women with cervical cerclage: a single center retrospective cohort study.

BACKGROUND: The leading hypothesis of the pathogenesis of cervical insufficiency suggests a role of cervical inflammation. Urogenital tract infections could play a causative role in this process. To test this hypothesis in women with a cervical cerclage, we aimed to retrospectively examine the relationship between gestational age (GA) at delivery and positive urogenital cultures. METHODS: This single center retrospective study reviewed the records of all women with a singleton pregnancy that underwent cervical cerclage (n = 203) between 2010 and 2020 at the University Hospital of Leuven, Belgium. Transvaginal cerclages were categorized as history indicated (TVC I, n = 94), ultrasound indicated (TVC II, n = 79) and clinically indicated (TVC III, n = 20). Additionally, ten women received transabdominal cerclage (TAC). Urogenital cultures (vaginal and urine) were taken before and after cerclage with 4-week intervals. Urogenital cultures were reported 'positive' if urine and/or vaginal cultures showed significant growth of a microorganism. Treatment decision depended on culture growth and clinical presentation. The primary aim was to evaluate the association between the urogenital culture results and the GA at delivery, for each of the cerclage groups. Secondarily, to investigate the effect of antibiotic treatment of positive cultures on GA at delivery. RESULTS: Positive pre-cerclage urogenital cultures were associated with lower GA at delivery in TVC III (positive culture 26w4d ± 40d vs. negative 29w6d ± 54d, p = 0.036). For TVC I, GA at delivery was longer when pre-cerclage urogenital cultures were positive (positive culture 38w0d ± 26d vs. negative 35w4d ± 42d, p = 0.035). Overall post-cerclage urogenital cultures status was not associated with a different GA at delivery. Treating patients with pre- or post-cerclage positive urogenital cultures did also not change GA at delivery. CONCLUSION: Positive urogenital cultures taken before clinically indicated cerclage intervention may be associated with lower GA at delivery. However, there seems to be no benefit of antibiotic treatment or routine urogenital cultures during follow-up of asymptomatic women after cerclage placement.

Long-term neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy: a multicentre cohort study of the International Network on Cancer, Infertility, and Pregnancy.

BACKGROUND: The main data available on the safety of radiation during pregnancy originate from animal studies and from studies of survivors of atomic or nuclear disasters. The effect of radiotherapy to treat maternal cancer on fetal development is uncertain. This report presents a unique cohort and aims to determine the long-term neurocognitive, psychosocial and physical outcomes of offspring of mothers treated with radiotherapy during pregnancy. METHODS: In this international, multicentre, mixed retrospective-prospective cohort study, we recruited participants between Aug 5, 2006, and Aug 24, 2023, aged between 1·5 and 46 years, at three referral centres in Belgium, the Netherlands, and the USA. Participants were eligible if they were born from mothers treated with radiotherapy during pregnancy. Fetal radiation doses were obtained from medical records and participants were followed up at predefined ages (1·5, 3, 6, 9, 12, 15, and 18 years) and 5-yearly in adulthood, based on age at enrolment, using a neurocognitive test battery (measuring intelligence, attention, and memory), parent-reported executive function and psychosocial questionnaires, and a medical assessment. Results were compared with test-specific normative data. Linear regression models investigated associations between radiotherapy factors (fetal radiation dose, gestational age at the start and end of radiotherapy, and radiotherapy duration) and outcomes. FINDINGS: 68 maternal cases of radiotherapy during pregnancy were registered by the three participating centres, of which 61 resulted in a livebirth and were therefore eligible to participate in the child follow-up study. After excluding those who did not give consent, 43 participants born from 42 mothers treated with radiotherapy during pregnancy were included in the study (median age at first assessment 3 years [IQR 2-11]; median age at last assessment 12 years [9-18]; median number of assessments two [1-4]). 18 (42%) of the included participants were female and 25 (58%) male, and 37 (86%) were of White ethnicity. Mean neurocognitive outcomes of the entire cohort were within normal ranges. No associations were found with fetal radiation dose or timing of radiotherapy during pregnancy. Six (16%) of 38 participants with neurocognitive outcomes scored lower than one SD on at least one neurocognitive outcome, three (7%) reported chronic medical conditions (spasmophilia, spastic diplegia, and IgG deficiency), and three (7%) were diagnosed with attention-deficit hyperactivity disorder (of whom two scored lower on attention). Of ten (23%) participants with lower neurocognitive score(s), a chronic medical condition, or attention-deficit hyperactivity disorder, eight were born preterm. The remaining 33 (77%) participants showed no neurocognitive, psychosocial, or chronic physical problems. INTERPRETATION: We show on average normal neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy. Differences in outcomes could not be explained by exposure to radiotherapy during pregnancy. These results suggest that extra-abdomino-pelvic radiotherapy exposure during pregnancy in general does not adversely affect outcomes of liveborn children. Further research with a larger sample is necessary to confirm these findings. FUNDING: Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Research Foundation Flanders.

Determining the exposure of maternal medicines through breastfeeding: the UmbrelLACT study protocol-a contribution from the ConcePTION project.

INTRODUCTION: Breastfeeding is beneficial for the health of the mother and child. However, at least 50% of postpartum women need pharmacotherapy, and this number is rising due to the increasing prevalence of chronic diseases and pregnancies at a later age. Making informed decisions on medicine use while breastfeeding is often challenging, considering the extensive information gap on medicine exposure and safety during lactation. This can result in the unnecessary cessation of breastfeeding, the avoidance of pharmacotherapy or the off-label use of medicines. The UmbrelLACT study aims to collect data on human milk transfer of maternal medicines, child exposure and general health outcomes. Additionally, the predictive performance of lactation and paediatric physiologically based pharmacokinetic (PBPK) models, a promising tool to predict medicine exposure in special populations, will be evaluated. METHODS AND ANALYSIS: Each year, we expect to recruit 5-15 breastfeeding mothers using pharmacotherapy via the University Hospitals Leuven, the BELpREG project (pregnancy registry in Belgium) or external health facilities. Each request and compound will be evaluated on relevance (ie, added value to available scientific evidence) and feasibility (including access to analytical assays). Participants will be requested to complete at least one questionnaire on maternal and child's general health and collect human milk samples over 24 hours. Optionally, two maternal and one child's blood samples can be collected. The maternal medicine concentration in human milk will be determined along with the estimation of the medicine intake (eg, daily infant dose and relative infant dose) and systemic exposure of the breastfed child. The predictive performance of PBPK models will be assessed by comparing the observed concentrations in human milk and plasma to the PBPK predictions. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee Research UZ/KU Leuven (internal study number S67204). Results will be published in peer-reviewed journals and presented at (inter)national scientific meetings. TRIAL REGISTRATION NUMBER: NCT06042803.

Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.

Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.

Evaluating offspring Genomic and Epigenomic alterations after prenatal exposure to Cancer treatment In Pregnancy (GE-CIP): a multicentric observational study.

INTRODUCTION: Around 1 in 1000-2000 pregnancies are affected by a cancer diagnosis. Previous studies have shown that chemotherapy during pregnancy has reassuring cognitive and cardiac neonatal outcomes, and hence has been proposed as standard of care. However, although these children perform within normal ranges for their age, subtle differences have been identified. Given that chemotherapeutic compounds can cross the placenta, the possibility that prenatal chemotherapy exposure mutates the offspring's genome and/or epigenome, with potential deleterious effects later in life, urges to be investigated. METHODS AND ANALYSES: This multicentric observational study aims to collect cord blood, meconium and neonatal buccal cells at birth, as well as peripheral blood, buccal cells and urine from infants when 6, 18 and/or 36 months of age. Using bulk and single-cell approaches, we will compare samples from chemotherapy-treated pregnant patients with cancer, pregnant patients with cancer not treated with chemotherapy and healthy pregnant women. Potential chemotherapy-related newborn genomic and/or epigenomic alterations, such as single nucleotide variants, copy number variants and DNA-methylation alterations, will be identified in mononuclear and epithelial cells, isolated from blood, buccal swabs and urine. DNA from maternal peripheral blood and paternal buccal cells will be used to determine de novo somatic mutations in the neonatal blood and epithelial cells. Additionally, the accumulated exposure of the fetus, and biological effective dose of alkylating agents, will be assessed in meconium and cord blood via mass spectrometry approaches. ETHICS AND DISSEMINATION: The Ethics Committee Research of UZ/KU Leuven (EC Research) and the Medical Ethical Review Committee of University Medical Center Amsterdam have approved the study. Results of this study will be disseminated via presentations at (inter)national conferences, through peer-reviewed, open-access publications, via social media platforms aimed to inform patients and healthcare workers, and through the website of the International Network on Cancer, Infertility and Pregnancy (www.cancerinpregnancy.org).

Results of an international survey on the current organization of care for pregnant women with cancer.

The global incidence of cancer is increasing, including its incidence in women of reproductive age. Still, physicians encounter this situation rarely, which could lead to substandard care. This research sought to explore opportunities to improve future care for pregnant women with cancer, by describing the outcomes of a survey distributed to physicians all over the world focusing on clinical experience with pregnant women with cancer, the organization of care and current gaps in knowledge. We included 249 responses from physicians working across 36 countries. Responses demonstrate a wide variation in the organization of care - generally lacking centralization, and the physicians' acknowledgement of insufficient knowledge on the management of pregnant women with cancer. There is a need for improvement through national centralization and/or establishing advisory boards for cancer in pregnancy. Seeing the paucity of cancer in pregnancy experience, the importance of global multidisciplinary collaboration is emphasized.

Reassuring pregnancy outcomes in women with mild COL4A3-5-related disease (Alport syndrome) and genetic type of disease can aid personalized counseling.

Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.