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Objective: We aimed to add to the limited outcome data on breast cancer during pregnancy (BCP), and compared disease-free survival (DFS), and overall survival (OS) between patients with BCP and breast cancer not diagnosed during pregnancy, adjusted for known prognostic factors. Methods: We analyzed a pro- and retrospectively compiled multi-centric registry of BCP patients (www.cancerinpregnancy.org and GBG/BIG 0203). Outcome was compared to a control group of patients who did not have associated pregnancies. The main analysis is a Cox proportional hazards regression of disease free survival (DFS) and overall survival (OS) on exposure (pregnant or not). The analysis was weighted by propensity score matching to correct for any bias that may have been associated with differences in baseline characteristics, with the following set of covariates: age, stage, grade, hormone receptor status, HER2 status, histology, type of chemotherapy and trastuzumab. Sensitivity analysis was also performed on age only, and also on chemotherapy only. Results: From April 2003-December 2011, 447 women with BCP were registered, 368 women with BCP were eligible for this analysis. The control group consisited of 2739 women (ratio 1:7.44). Median age was 33 years (interquartile range 30-36) for the cases and 41 years (interquartile range 37-43) for the controls. Median follow-up was 57 months. There were no statistically significant differences noted for DFS and OS studied after propensity-score matching, and sensitivity analysis.Conclusion: Patients diagnosed with breast cancer during pregnancy do not have a worse prognosis compared to patients who are not pregnant after matching for prognostic factors and treatment. This information is important when BCP patients are counseled regarding prognosis and adds to the possibility of treatment during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Platina and taxanes are frequently used chemotherapeutic agents to treat cancer, also when diagnosed during pregnancy. This report presents an interim analysis of the largest series of children prenatally exposed to platinum and/or taxane agents and aims to determine their physical health and neurocognitive outcomes., Methods: As part of a multicentre, prospective cohort study (ClinicalTrials.gov: NCT00330447), children born between 2000 and 2022 were assessed between 2005 and 2024 at ages 1.5-18 years (interim analysis; median length of follow-up, 3.2 years (IQR 3.0-6.4)) by a comprehensive neurocognitive test battery, parent-reported questionnaires, and a physical assessment. Mixed-effects regression and Type III Analysis of Variance models were used to investigate associations between these outcomes and platinum/taxane cumulative dose and agent type, with best-fit models corrected for age and covariates (gestational age at birth, chemotherapy timing, other chemotherapy, sex, parental education level, maternal death)., Findings: In total, 144 children were included (13% exposed to platinum, 62% to taxanes, 25% to both). Of these, 101 were assessed at age 1.5 years, 96 at age 3, 63 at age 6, 32 at age 9, 18 at age 12, 7 at age 15, and 2 at age 18 years. Neurocognitive outcomes were within normal ranges across all ages, compared with test-specific normative data. Eight children (6%) reported ototoxicity, seven (5%) reported chronic medical conditions, three (2%) had congenital malformations, and two (1%) were diagnosed with Attention-Deficit Hyperactivity Disorder. Thirty-three children (23%) needed extra neurocognitive support, of which 64% were born preterm. Children prenatally exposed to paclitaxel scored lower on visuospatial (β = 0.64 ± 0.21, p = 0.0052) and verbal memory (β = 0.68 ± 0.27, p = 0.015) than those exposed to docetaxel., Interpretation: In this interim analysis, we found normal neurocognitive outcomes and no increase in congenital malformations nor medical conditions after prenatal exposure to platinum/taxane-based chemotherapy. However, owed to the limited number of older children, further investigation regarding their potential neurotoxicity and its long term effects is necessary in follow-up studies with larger samples., Funding: Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Cooperatio program, Research Foundation Flanders., Competing Interests: CLL: Personal fellowship fundamental research contract with FWO (no. 1127523N). FA: Personal Senior Clinical Researcher grant with FWO. Participation in the MiMARK advisory board for early detection of endometrial cancer. Chair of the International Network on Cancer, Infertility, and Pregnancy (INCIP) of the European Society of Gynecologic Oncology (ESGO), and of the Advisory Board on Cancer, Infertility and Pregnancy (ABCIP). The remaining authors declare no conflict., (© 2024 The Author(s).)

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., (© 2024 John Wiley & Sons Ltd.)

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of interests FA is on the MiMARK advisory board for early detection of endometrial cancer and is Chair of the International Network on Cancer, Infertility, and Pregnancy of the European Society of Gynecologic Oncology, and of the Advisory Board on Cancer, Infertility and Pregnancy. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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/1.73m 2 . 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/1.73m 2 ). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy β=-1.030, post-pregnancy β=-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., (Copyright © 2024 International Society of Nephrology. All rights reserved.)

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., (© 2024. The Author(s).)

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., Competing Interests: Competing interests: K.A. is deputy editor in chief and A.S. an Editorial board member of the journal BMJ PO. P.A. is co-owner of the company BioNotus GCV. The remaining authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

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)., Competing Interests: Competing interests: TV is co-inventor on licensed patents WO/2011/157846 (Methods for haplotyping single cells), WO/2014/053664 (High-throughput genotyping by sequencing low amounts of genetic material) and WO/2015/028576 (Haplotyping and copy number typing using polymorphic variant allelic frequencies)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2024. The Author(s).)

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., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2023.)

Purpose: Patients with postpartum breast cancer diagnosed after cessation of breastfeeding (postweaning, PP-BCPW) have a particularly poor prognosis compared with patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, regardless of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth in the mammary gland. However, in women, the molecular mechanisms that underlie this poor prognosis of patients with PP-BCPW remain vastly underexplored, due to of lack of adequate patient numbers and outcome data., Experimental Design: We explored whether distinct prognostic features, common to all breast cancer molecular subtypes, exist in postpartum tumor tissue. Using detailed breastfeeding data, we delineated the postweaning period in PP-BC as a surrogate for mammary gland involution and performed whole transcriptome sequencing, immunohistochemical, and (multiplex) immunofluorescent analyses on tumor tissue of patients with PP-BCPW, PP-BCDL, Pr-BC, and NP-BC., Results: We found that patients with PP-BCPW having a low expression level of an immunoglobulin gene signature, but high infiltration of plasma B cells, have an increased risk for metastasis and death. Although PP-BCPW tumor tissue was also characterized by an increase in CD8+ cytotoxic T cells and reduced distance among these cell types, these parameters were not associated with differential clinical outcomes among groups., Conclusions: These data point to the importance of plasma B cells in the postweaning mammary tumor microenvironment regarding the poor prognosis of PP-BCPW patients. Future prospective and in-depth research needs to further explore the role of B-cell immunobiology in this specific group of young patients with breast cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objectives: To assess maternal characteristics and comorbidities in patients with persistent uninterpretable non-invasive prenatal testing (NIPT) and to evaluate the association with adverse pregnancy outcome in a general risk population., Methods: A retrospective cohort study (July 2017-December 2020) was conducted of patients with persistent uninterpretable NIPT samples. Maternal characteristics and pregnancy outcomes were compared with the general Belgian obstetric population., Results: Of the 148 patients with persistent uninterpretable NIPT, 37 cases were due to a low fetal fraction (LFF) and 111 due to a low quality score (LQS). Both groups (LFF, LQS) showed more obesity (60.6%, 42.4%), multiple pregnancies (18.9%, 4.5%) and more obstetrical complications. In the LQS group, a high rate of maternal auto-immune disorders (30.6%) was seen and hypertensive complications (17.6%), preterm birth (17.6%) and neonatal intensive care unit (NICU) admission (22%) were significantly increased. In the LFF group hypertensive complications (21.6%), gestational diabetes (20.6%), preterm birth (27%), SGA (25.6%), major congenital malformations (11.4%), c-section rate (51.4%) and NICU admission (34.9%) were significantly increased. Chromosomal abnormalities were not increased in both groups., Conclusions: Patients with persistent uninterpretable NIPT have significantly more maternal obesity, comorbidities and adverse pregnancy outcome than the general population and should receive high-risk pregnancy care. Distinguishing between LFF and LQS optimizes counseling because maternal characteristics and pregnancy outcome differ between these groups., (© 2023 John Wiley & Sons Ltd.)

Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. This multicenter cohort study reports on the long-term effects of prenatal exposure to maternal cancer and its treatment on cognitive and behavioral outcomes in 9-year-old children. In total, 151 children (mean age, 9.3 years; range, 7.8-10.6 years) were assessed using a neurocognitive test battery and parent-report behavioral questionnaires. During pregnancy, 109 children (72.2%) were exposed to chemotherapy (only or in combination with other treatment modalities), 18 (11.9%) to surgery only, 16 (10.6%) to radiotherapy, one to trastuzumab, and 16 (10.6%) were not exposed to oncologic treatment. Mean cognitive and behavioral outcomes were within normal ranges. Gestational age at birth showed a positive association with Full Scale Intelligence Quotient (FSIQ), with the average FSIQ score increasing by 1.6 points for each week increase in gestational age (95% CI, 0.7 to 2.5; P < .001). No difference in FSIQ was found between treatment types (F[4,140] = 0.45, P = .776). In children prenatally exposed to chemotherapy, no associations were found between FSIQ and chemotherapeutic agent, exposure level, or timing during pregnancy. These results indicate a reassuring follow-up during the critical maturational period of late childhood, when complex functions develop and rely on the integrity of early brain development. However, associations were observed with preterm birth, maternal death, and maternal education.

Background: The Netherlands and Belgium have been among the first countries to offer non-invasive prenatal testing (NIPT) as a first-tier screening test. Despite similarities, differences exist in counseling modalities and test uptake. This study explored decision-making and perspectives of pregnant women who opted for NIPT in both countries., Methods: A questionnaire study was performed among pregnant women in the Netherlands (NL) (n = 587) and Belgium (BE) (n = 444) opting for NIPT, including measures on informed choice, personal and societal perspectives on trisomy 21, 18 and 13 and pregnancy termination., Results: Differences between Dutch and Belgian women were shown in the level of informed choice (NL: 83% vs. BE: 59%, p < 0.001), intention to terminate the pregnancy in case of confirmed trisomy 21 (NL: 51% vs. BE: 62%, p = 0.003) and trisomy 13/18 (NL: 80% vs. BE: 73%, p = 0.020). More Belgian women considered trisomy 21 a severe condition (NL: 64% vs. BE: 81%, p < 0.001). Belgian women more frequently indicated that they believed parents are judged for having a child with trisomy 21 (BE: 42% vs. NL: 16%, p < 0.001) and were less positive about quality of care and support for children with trisomy 21 (BE: 23% vs. NL: 62%, p < 0.001)., Conclusion: Differences in women's decision-making regarding NIPT and the conditions screened for may be influenced by counseling aspects and country-specific societal and cultural contexts., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

The hormone hepcidin plays an important role in intestinal iron absorption and cellular release. Cord blood hepcidin values reflect fetal hepcidin status, at least at the time of delivery, but are not available for the Belgian population. Therefore, we aimed (1) to provide the first data on cord blood hepcidin levels in a Belgian cohort and (2) to determine variables associated with cord blood hepcidin concentrations. A cross-sectional, observational study was performed at the University Hospital Leuven, Belgium. Cord blood samples were analyzed using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry. Descriptive statistics, Spearman correlation tests, and Mann-Whitney U tests were performed. In total, 61 nonhemolyzed cord blood samples were analyzed. The median hepcidin level was 17.6 μg/L (IQR: 18.1; min-max: 3.9-54.7). A moderate correlation was observed between cord blood hepcidin and cord blood ferritin (r = 0.493) and hemoglobin (r = -0.342). Cord blood hepcidin was also associated with mode of delivery ( p = 0.01), with higher hepcidin levels for vaginal deliveries. Nonetheless, larger studies are needed to provide more evidence on the actual clinical value and benefit of cord blood hepcidin measurements.

Non-invasive prenatal testing has been introduced for the detection of Trisomy 13, 18, and 21. Using genome-wide screening also other "rare" autosomal trisomies (RATs) can be detected with a frequency about half the frequency of the common trisomies in the large population-based studies. Large prospective studies and clear clinical guidelines are lacking to provide adequate counseling and management to those who are confronted with a RAT as a healthcare professional or patient. In this review we reviewed the current knowledge of the most common RATs. We compiled clinical relevant parameters such as incidence, meiotic or mitotic origin, the risk of fetal (mosaic) aneuploidy, clinical manifestations of fetal mosaicism for a RAT, the effect of confined placental mosaicism on placental function and the risk of uniparental disomy (UPD). Finally, we identified gaps in the knowledge on RATs and highlight areas of future research. This overview may serve as a first guide for prenatal management for each of these RATs., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Competing Interests: We declare no competing interests.

Cancer during pregnancy threatens the lives of mother and foetus and its incidence is rising, making it an emerging medical challenge. Evidence on the direct impact of cancer therapies on neonatal outcomes resulted in general guidelines for maternal treatment that safeguards foetal development. Less focus has been placed on indirect factors, in pre- and postnatal periods, that may exert long-term impacts specifically on child neurocognition. Foetal development, in the context of maternal cancer during pregnancy, may be influenced directly by exposure to cancer diagnostics and (co-)treatment, or indirectly through maternal inflammation, malnutrition, hormonal fluctuations, prematurity, and psycho-biological stress. Maternal stress and insecure mother-infant bonding related to postpartum cancer treatment may further impact child cognitive-behavioural development. Understanding the independent and synergistic effects of the factors impacting neurocognitive development creates the opportunity to intervene during the oncological treatment to improve the child's long-term outcome, both by medical and psychosocial care and support., Competing Interests: Conflict of Interest The authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The early detection of tissue and organ damage associated with autoimmune diseases (AID) has been identified as key to improve long-term survival, but non-invasive biomarkers are lacking. Elevated cell-free DNA (cfDNA) levels have been observed in AID and inflammatory bowel disease (IBD), prompting interest to use cfDNA as a potential non-invasive diagnostic and prognostic biomarker. Despite these known disease-related changes in concentration, it remains impossible to identify AID and IBD patients through cfDNA analysis alone. By using unsupervised clustering on large sets of shallow whole-genome sequencing (sWGS) cfDNA data, we uncover AID- and IBD-specific genome-wide patterns in plasma cfDNA in both the obstetric and general AID and IBD populations. We demonstrate that pregnant women with AID and IBD have higher odds of receiving inconclusive non-invasive prenatal screening (NIPS) results. Supervised learning of the genome-wide patterns allows AID prediction with 50% sensitivity at 95% specificity. Importantly, the method has the potential to identify pregnant women with AID during routine NIPS. Since AID pregnancies have an increased risk of severe complications, early recognition or detection of new-onset AID can redirect pregnancy management and limit potential adverse events. This method opens up new avenues for screening, diagnosis and monitoring of AID and IBD., (© 2022. The Author(s).)

Knowledge of the impact of in utero exposure to lithium during the postnatal period is limited. Besides a possible teratogenic effect during the first trimester, exposure during the second and third trimesters might lead to neonatal effects. Uniform guidelines for postnatal management of these neonates are lacking. The aim was to retrospectively describe all neonates admitted to the University Hospitals Leuven after in utero exposure to lithium (January 2010 to April 2020), and to propose a postnatal care protocol. Descriptive statistics were performed. For continuous parameters with serial measurements, median population values were calculated. In total, 10 mother-neonate pairs were included. The median gestational age was 37 (interquartile range, IQR, 36-39) weeks. Neonatal plasma lithium concentration at birth was 0.65 (IQR 0.56-0.83) mmol/L with a median neonate/mother ratio of 1.02 (IQR 0.87-1.08). Three neonates needed respiratory support, 7/10 started full enteral (formula) feeding on day 1. The median length of neonatal stay was 8.5 (IQR 8-12) days. One neonate developed nephrogenic diabetes insipidus. This study reported in detail the postnatal characteristics and short-term neonatal outcomes. A postnatal care protocol was proposed, to enhance the quality of care for future neonates, and to guide parental counselling. Future prospective protocol evaluation is needed.

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., Competing Interests: Conflict of interest None declared, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A Teratology Information Service (TIS) does not exist in Belgium yet but will hopefully be established soon. To prepare for this, we aimed to provide insight into the information needs and counseling preferences of the Belgian public and healthcare professionals (HCPs) regarding medication use in pregnancy and breastfeeding. A cross-sectional study using two anonymous, online surveys disseminated via social media, websites, and newsletters addressing Dutch and French-speaking individuals (≥18 years) and licensed HCPs was performed between June and September 2020. Ethics approval and informed consent were obtained. In total, 1508 public survey respondents (98% women) and 702 HCPs participated. Information needs on perinatal medication use were ubiquitous among both groups, and for which they often relied on patient information leaflets or the product information and online fora. Conflicting information on this topic regularly occurs and complicates HCPs' duties. Women and HCPs assigned an important role to a TIS, both in terms of providing evidence-based information (via a website or app) and being accessible to be contacted in case of questions (by phone or via e-mail or chat). In conclusion, a TIS would be warmly welcomed by women and HCPs in Belgium and should ideally be established soon to address current information needs regarding perinatal medication use and to contribute to research in this field.

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., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: SL reports grants from AbbVie, Celgene, AstraZeneca, Amgen, Novartis, Pfizer, Daiichi-Sankyo, Immunomedics, and Roche; advisory board honoraria paid to the institution from AbbVie, Celgene, AstraZeneca, Amgen, Novartis, Pfizer, Lilly, Bristol Myers Squibb, Puma, Pierre Fabre, Merck Sharp and Dohme, and EirGenix; speaker honoraria paid to their institution from AbbVie, Celgene, AstraZeneca, Amgen, Novartis, Pfizer, and PriME/Medscape; personal fees from Chugai and Daiichi-Sankyo; honoraria for advisory board participation and speaking fees paid to the institution from Daiichi-Sankyo, Roche, and SeaGen; and has a patent (EP18209682.7). AS reports grants from Celgene, Roche, AbbVie; personal fees from Celgene, Roche, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly. IB reports grants from GSK and support from AstraZeneca. SS reports support from Novartis, personal fees from Roche, Mundipharma, Amgen, Abbvie. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the economic impact of introducing the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test into clinical practice in Belgium for the prediction of preeclampsia (PE)., Study Design: We developed a one-year time-horizon decision tree model to evaluate the short-term costs associated with the introduction of the sFlt-1/PlGF test for guiding the management of women with suspected PE from the Belgian public healthcare payers' perspective. The model estimated the costs associated with the diagnosis and management of PE in pregnant women managed in either a test scenario, in which the sFlt-1/PlGF test is used in addition to current clinical practice, or a no test scenario, in which clinical decisions are based on current practice alone. Test characteristics were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of PE. Unit costs were obtained from Belgian-specific sources. The main model outcome was the total cost per patient., Results: Introduction of the sFlt-1/PlGF ratio test is expected to result in a cost saving of €712 per patient compared with the no test scenario. These savings are generated mainly due to a reduction in unnecessary hospitalizations., Conclusions: The sFlt-1/PlGF test is projected to result in substantial cost savings for the Belgian public healthcare payers through reduction of unnecessary hospitalization of women with clinical suspicion of PE that ultimately do not develop the condition. The test also has the potential to ensure that women at high risk of developing PE are identified and appropriately managed., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure., Competing Interests: AD is an employee of Bayer AG and uses Open Systems Pharmacology software, tools, and models in his professional role. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mian, Nolan, van den Anker, van Calsteren, Allegaert, Lakhi and Dallmann.)

Cancer is diagnosed in one in 1000 to 1500 pregnancies. Most frequently encountered malignancies during pregnancy are breast cancer, hematological cancer, cervical cancer and malignant melanoma. Maternal cancer is associated with an increased risk of IUGR and preterm labor, especially in patients with systemic disease or those receiving chemotherapy during pregnancy, requiring a high-risk obstetrical follow-up. Fetal aneuploidy screening by non-invasive prenatal testing (NIPT) can lead to the incidental identification of copy number alterations derived from non-fetal cell-free DNA (cfDNA), as seen in certain cases of maternal malignancy. The identification of tumor-derived cfDNA requires further clinical, biochemical, radiographic and histological investigations to confirm the diagnosis. In such cases, reliable risk estimation for fetal trisomy 21, 18 and 13 is impossible. Therefore, invasive testing should be offered when ultrasonographic screening reveals an increased risk for chromosomal anomalies, or when a more accurate test is desired. When the fetal karyotype is normal, long term implications for the fetus refer to the consequences of the maternal disease and treatment during pregnancy. This manuscript addresses parental questions when NIPT suggests a maternal malignancy. Based on current evidence and our own experience, a clinical management scheme in a multidisciplinary setting is proposed., (© 2021 John Wiley & Sons Ltd.)

There is almost no experience with concentrated ginger extracts during pregnancy. The purpose of this trial was to include 50 pregnant women in a clinical feasibility study with EXT.GR10, a 10 × concentrated ethanolic extract of ginger root. The primary objective was to detect complications in the mother during pregnancy and malformations or complications in the newborn at delivery. The secondary purpose was to evaluate the satisfaction of the patients. In total, 51 pregnant women were included in this observational study. They could freely use ginger tablets with a maximum of 2 tablets of 50 mg EXT.GR10 a day in case of gastrointestinal discomfort. Tablets were taken by 44 patients. Stillbirth, prematurity, hypertension, and gestational diabetes occurred. There were no serious complications at birth. In the newborn, 4 cases of dysplasia of the hip were seen and 2 minor malformations. There was no relation between events affecting mother and child and the number of EXT.GR10 tablets taken. About ⅔ of patients appreciated the effects of ginger. This is the first clinical study with the EXT.GR10 extract. Based on this feasibility study, a follow-up clinical trial is planned with a fixed minimum of exposure to EXT.GR10 during the first trimester of pregnancy., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Community pharmacists acknowledge to have an important role in providing pharmaceutical care during preconception, pregnancy and lactation. However, pharmacists' knowledge and counseling regarding this topic is still insufficient. Hence, educational initiatives are urgently needed., Objectives: To assess the impact of a blended learning program ('intervention') on community pharmacists' barriers, knowledge, and counseling practice with regard to preconception, pregnancy and lactation., Methods: A pre-post study was performed in collaboration with 40 randomly selected pharmacies belonging to a large pharmacy chain in Belgium. All pharmacists employed in these pharmacies were eligible to participate in a blended learning program consisting of an e-learning and an on-site training day. Data were collected using online surveys, mystery shopping visits and pharmacy records. Pharmacy conversations were assessed on information gathering, dispensed product, and case-specific information. A retention knowledge test was completed 3-6 months after the intervention., Results: In total, 60 pharmacists completed the post-intervention surveys (response rate: 95%). The total number of barriers decreased after the intervention, while organizational barriers such as lack of privacy (73%) and lack of time (67%) became more prevalent. Pharmacists' short and long-term knowledge improved after the intervention (p ≤ 0.001), although knowledge declined again over time (p ≤ 0.001). During counseling, pharmacists more often spontaneously provided information about folic acid when dispensing a pregnancy test, and more often suggested the correct dose/dosage for the dispensed OTC-product against pregnancy-related nausea. However, poor information gathering, dosing errors and incomplete information were still observed., Conclusion: The blended learning decreased pharmacists' barriers and improved their short- and long-term knowledge, while counseling practice only partially improved. Hence, the blended learning was insufficient to enhance pharmacists' information gathering competences and to fully implement pharmaceutical care services with regard to preconception, pregnancy and lactation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy., Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women., Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates., Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients., Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

Importance: Chemotherapy during the first trimester of pregnancy should be avoided owing to the risk of congenital malformations. However, the precise gestational age at which chemotherapy can be initiated safely remains unclear., Objective: To assess congenital malformation rates associated with gestational age at initiation of chemotherapy among pregnant women with cancer., Design, Setting, and Participants: This multicenter cohort study evaluated all pregnant women who received chemotherapy between 1977 and 2019 registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. Data were analyzed from February 15 to June 2, 2020., Exposures: Cancer treatment with chemotherapy during pregnancy., Main Outcomes and Measures: Analysis was focused on major and minor structural malformations in offspring, defined by EUROCAT, detected during pregnancy or at birth., Results: A total of 755 women in the INCIP database who underwent cancer treatment with chemotherapy during pregnancy were included in analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Among offspring, the major congenital malformation rate was 3.6% (95% CI, 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%). Chemotherapy exposure prior to 12 weeks gestational age was associated with a high rate of major congenital malformations, at 21.7% (95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after gestational age 12 weeks, the frequency of major congenital malformations was 3.0% (95% CI, 1.9%-4.6%), which was similar to the expected rates in the general population. Minor malformations were comparable when exposure occurred before or after gestational age 12 weeks (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy prior to 12 weeks gestation, 17 (58.6%) were not aware of pregnancy, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate their pregnancy (3 women [10.3%])., Conclusions and Relevance: This cohort study found that chemotherapy was associated with an increased risk of major congenital malformations only in the first 12 weeks of pregnancy. The risk of congenital malformations when chemotherapy was administered during the first trimester and the high number of incidental pregnancies during cancer treatment in the INCIP registry underscore the importance of contraceptive advice and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer.

Background: Implausible false positive results in non-invasive prenatal testing (NIPT) have been occasionally associated with the detection of occult maternal malignancies. Hence, there is a need for approaches allowing accurate prediction of whether the NIPT result is pointing to an underlying malignancy, as well as for organized programs ensuring efficient downstream clinical management of these cases., Methods: Using a data set of 88,294 NIPT performed at University Hospital Leuven (Belgium) between November 2013 and March 2020, we retrospectively evaluated the positive predictive value (PPV) of our NIPT approach for cancer detection. In this approach, whole-genome cell-free DNA (cfDNA) data from NIPT were scrutinized for the presence of (sub)chromosomal copy number alterations (CNAs) predictive for a malignancy, using an unbiased NIPT analysis pipeline coined GIPSeq. For suspected cases, the presence of a maternal cancer was evaluated via subsequent multidisciplinary clinical follow-up examinations. The cancer-specificity of the identified CNAs in cfDNA was assessed through genetic analyses of a tumor biopsy., Findings: Fifteen women without a cancer history were identified with a GIPSeq result suggestive of a malignant process. Their cfDNA profiles showed either genome-wide aberrations or a single trisomy 8. Upon clinical examinations, a solid or hematological cancer was identified in 4 and 7 cases, respectively. Three women were identified as having a clonal mosaicism. For one case no underlying condition was found. These numbers add to a PPV of 73%. Based on this experience, we presented a multidisciplinary care path for efficient clinical management of these cases., Interpretation: The presented approach for analysing NIPT results has a high PPV, yet unknown sensitivity, for detecting asymptomatic malignancies upon routine NIPT. Given the complexity of diagnosing a pregnant woman with cancer, clinical follow-up should occur in a well-designed multidisciplinary setting, such as via the care model that we presented here., Funding: This work was supported by Research Foundation Flanders and KU Leuven funding., Competing Interests: EL reports personal fees from Springworks Therapeutics outside the submitted work. All other authors declare no competing interests., (© 2021 The Author(s).)

This cohort study of the International Network on Cancer, Infertility and Pregnancy (INCIP) reports the maternal and neonatal outcomes of 80 pregnant patients diagnosed with non-Hodgkin lymphoma (NHL) between 1986 and 2019, focussing on 57 (71%) patients with diffuse large B-cell lymphoma (DLBCL). Of all 80 patients, 54 (68%) pregnant patients received chemotherapy; mostly (89%) CHOP-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens. Four early pregnancies were terminated. Among 76 ongoing pregnancies, there was one stillbirth (1·3%). Overall, there was a high incidence of small for gestational age neonates (39%), preterm delivery (52%), obstetric (41%) and neonatal complications (12·5%), and this could not exclusively be explained by the receipt of antenatal chemotherapy. Half of preterm deliveries (46%) were planned in order to tailor oncological treatment. The 3-year progression-free and overall survival for patients with DLBCL treated with rituximab-CHOP was 83·4% and 95·7% for limited stage (n = 29) and 60·6% and 73·3% for advanced stage (n = 15). Of 36 pregnant patients who received rituximab, five (13%) cases with neonatal complications and three (8%) with maternal infections were reported. In conclusion, standard treatment for DLBCL can be offered to pregnant patients in obstetric centres that cater for high-risk patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Data on the use of Granulocyte colony-stimulating factor (G-CSF) in pregnant cancer patients are scarce. The International Network of Cancer, Infertility and Pregnancy (INCIP) reviewed data of pregnant patients treated with chemotherapy and G-CSF, and their offspring. Among 2083 registered patients, 42 pregnant patients received G-CSF for the following indications: recent chemotherapy induced febrile neutropenia (5; 12%), dose dense chemotherapy (28, 67%), poly chemotherapy (7, 17%), or prevention of neutropenia at delivery (2; 5%). Among 24 women receiving dose dense chemotherapy, three (13%) patients recovered from asymptomatic neutropenia within 5 days. One patient developed pancytopenia following polychemotherapy after which the pregnancy was complicated by chorioamnionitis and intrauterine death. Nineteen singleton livebirths (49%) were born preterm. Sixteen neonates (41%) were admitted to the Neonatal Intensive care Unit (NICU). No neonatal neutropenia occurred. Two neonates had congenital malformations. Out of 21 children in follow-up, there were four children with a motor development delay and two premature infants had a delay in cognitive development. In conclusion, the rate of maternal and neonatal complications are similar to those described in (pregnant) women treated with chemotherapy. Due to small numbers and limited follow-up, rare or delayed effects among offspring exposed to G-CSF in utero cannot be ruled out yet.

Cancer during pregnancy is increasingly diagnosed due to the trend of delaying pregnancy to a later age and probably also because of increased use of non-invasive prenatal testing for fetal aneuploidy screening with incidental finding of maternal cancer. Pregnant women pose higher challenges in imaging, diagnosis, and staging of cancer. Physiological tissue changes related to pregnancy makes image interpretation more difficult. Moreover, uncertainty about the safety of imaging modalities, fear of (unnecessary) fetal radiation, and lack of standardized imaging protocols may result in underutilization of the necessary imaging tests resulting in suboptimal staging. Due to the absence of radiation exposure, ultrasound and MRI are obvious first-line imaging modalities for detailed locoregional disease assessment. MRI has the added advantage of a more reproducible comprehensive organ or body region assessment, the ability of distant staging through whole-body evaluation, and the combination of anatomical and functional information by diffusion-weighted imaging which obviates the need for a gadolinium-based contrast-agent. Imaging modalities with inherent radiation exposure such as CT and nuclear imaging should only be performed when the maternal benefit outweighs fetal risk. The cumulative radiation exposure should not exceed the fetal radiation threshold of 100 mGy. Imaging should only be performed when necessary for diagnosis and likely to guide or change management. Radiologists play an important role in the multidisciplinary team in order to select the most optimal imaging strategies that balance maternal benefit with fetal risk and that are most likely to guide treatment decisions. Our aim is to provide an overview of possibilities and concerns in current clinical applications and developments in the imaging of patients with cancer during pregnancy., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Pregnancy in women with congenital heart disease (CHD) is associated with increased risk for maternal cardiac complications. Several risk stratification models are used to predict adverse cardiac outcome in women with CHD who become pregnant. This study was set up as an exploratory study to provide a head-to-head comparison of the 4 most commonly used models: CARPREG, CARPREG II and ZAHARA risk scores and mWHO risk classification., Methods and Results: We randomly selected 100 women from the database of paediatric and congenital heart disease of the University Hospitals Leuven. Individual pregnancy risk scores were retrospectively calculated and summarized in a weighted average risk for each risk stratification model. To evaluate accuracy of each model, the weighted average risk was plotted against the actual observed number of "cardiac events" as defined in the respective risk models. Maternal adverse cardiac events occurred in 8% of our study population. Weighted average risks were plotted versus the observed number of events for each model: 10.1% versus 4.0% for CARPREG, 8.6% versus 5.0% for CARPREG II, 11.1% versus 8.0% for ZAHARA and 12.4% versus 8.0% for the mWHO classification., Conclusion: All risk models overestimated maternal cardiac risk. The ZAHARA risk model appeared to be a closer reflection of maternal risk in our cohort of CHD patients. More research on a larger study population is needed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the UK, mortality rate during pregnancy/in the peripartal period is 14.1 per 100,000 maternities with heart disease being the leading cause of non-obstetric maternal mortality (10% to 15% of all maternal deaths). Owing to the advances in the treatment of congenital heart disease (CHD), an increasing percentage of women has reached childbearing age, making CHD nowadays the most frequent cardiovascular disease during pregnancy in the Western world. In the pregnant woman, several adaptive changes occur in the cardiovascular and pulmonary system that in the worst case can lead to cardiovascular collapse in women with pre-existing heart disease. If medical management is not sufficient, cardiac interventions have to be considered, including percutaneous endovascular interventions, cardiac surgery, the use of extracorporeal membrane oxygenation or the placement of assist devices. While all these interventions seem to be relatively safe for the mother, fetal mortality remains considerably high. A thorough understanding of maternal physiology during pregnancy and of the perfusion of the feto-maternal unit is mandatory for the successful management of pregnant patients in need of cardiac (surgical) interventions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cancer treatment during pregnancy imposes a dilemma. Maternal advantage should be weighed against the potential impact of chemotherapy on child development. Recent studies in cancer survivors have shown that exposure to chemotherapeutic agents can have late adverse effects on cognitive functioning and executive functioning (EF). It is still unclear whether these late adverse effects also arise if a child is exposed to chemotherapy in utero., Aim: To compare the development of executive functioning in 6 year old children prenatally exposed to chemotherapy (study group) and children born to healthy women after an uncomplicated pregnancy (control group)., Methods and Study Design: In a multicenter cohort study, the outcome on a measure of EF was compared. Study and control children were prospectively examined by means of the Behavior Rating Inventory of Executive Function (BRIEF), a health questionnaire and an intelligence test., Results: In total 37 study children and 37 matched controls were included. In the study group, 11 children (29.7%) were exposed to chemotherapy alone, 22 children (59.5%) were exposed to chemotherapy and surgery and 4 children (10.8%) were exposed to chemotherapy, surgery and radiotherapy during pregnancy. All outcome scales of the BRIEF were within normal ranges. However, a significant between-group difference in emotional control was found., Conclusion: Overall outcomes of EF were reassuring. However, children prenatally exposed to chemotherapy have weaker emotion regulation skills compared to their matched controls. The results underscore the need for long-term follow-up of these children., (Copyright © 2020. Published by Elsevier B.V.)

COVID-19 also affects pregnant and breastfeeding women. Hence, clinicians and policymakers require reliable evidence on COVID-19 epidemiology and consequences in this population. We aimed to assess the susceptibility of pregnant women to SARS-CoV-2 and women's perceived impact of the pandemic on their breastfeeding practices, medical counseling and social support. We performed a cross-sectional study using an online survey in primary care in Belgium. Pregnant and breastfeeding women and women who breastfed in the preceding four weeks were eligible to participate. The survey was distributed through social media in April 2020. In total, 6470 women participated (i.e., 2647 pregnant and 3823 breastfeeding women). Overall, 0.3% of all respondents reported to have tested positive for SARS-CoV-2, not indicating a higher susceptibility of pregnant women to contracting COVID-19. More than 90% refuted that the pandemic affected their breastfeeding practices, nor indicated that the coronavirus was responsible for breastfeeding cessation. Half of the women even considered giving longer breastmilk because of the coronavirus. In contrast, women's medical counseling and social support were negatively affected by the lockdown. Women without previous breastfeeding experience and in the early postpartum period experienced a higher burden in terms of reduced medical counseling and support. In the future, more consideration and alternative supportive measures such as tele-visits by midwives or perinatal organizations are required for these women.