Risk of congenital anomalies in children who have a sibling with cancer: A matched cohort study.

PURPOSE: We assessed the risk of congenital anomalies in children who have a sibling with cancer. METHODS: We performed a matched cohort study of children born between 2006 and 2022 in Quebec. The exposure was having a sibling with cancer. Exposed children were matched to unexposed children based on sex, number of siblings, birth order, and year. The outcome included heart defects, orofacial clefts, and other anomalies. Using conditional logistic regression, we estimated odds ratios (OR) and 95 % confidence intervals (CI) for the association between having a sibling with cancer and the likelihood of having a congenital anomaly. RESULTS: A total of 2403 children who had a sibling with cancer were matched to 240,257 unexposed children. Congenital anomalies were more frequent in children who had a sibling with cancer compared with unexposed children (10.3 % vs 8.9 %). Overall, having a sibling with cancer was only weakly associated with congenital anomalies (OR 1.18, 95 % CI 1.04-1.35). Exposed children tended to have greater odds of polydactyly/syndactyly (OR 1.89, 95 % CI 1.11-3.21) and urinary defects (OR 1.50, 95 % CI 1.09-2.08) compared with unexposed children. CONCLUSIONS: Children who have a sibling with cancer have an only weakly elevated risk of congenital anomalies.

Burn Patients and Mental Health: A Matched Cohort Study.

OBJECTIVE: To determine the association between burns and hospitalization for mental health disorders up to three decades later. SUMMARY BACKGROUND DATA: Burns are associated with pain, disability, and scarring, but the long-term impact on mental health is unclear. METHODS: We analyzed a cohort of 23,726 burn patients aged ≥10 years who were matched to 223,626 controls from Quebec, Canada, between 1989 and 2022. The main exposure was admission for a burn. We followed patients during 3,642,206 person-years of follow-up to identify future hospitalizations for psychiatric disorders, substance use disorders, and suicide attempts. We estimated adjusted hazard ratios (HR) with 95% confidence intervals (CI) for the association between burns and subsequent mental health hospitalization using Cox proportional hazards regression. RESULTS: Burn patients had 1.76 times greater risk of mental health hospitalization over time (95% CI 1.72-1.81), compared with controls. Associations were present regardless of burn site, but were greatest for burns covering ≥50% of the body (HR 3.29, 95% CI 2.61-4.15), third degree burns (HR 2.04, 95% CI 1.94-2.14), and burns requiring skin grafts (HR 2.00, 95% CI 1.90-2.10). Compared with controls, burn patients had more than two times the risk of hospitalization for eating disorders (HR 3.14, 95% CI 2.50-3.95), psychoactive substance use disorders (HR 2.27, 95% CI 2.17-2.39), and suicide attempts (HR 2.42, 95% CI 2.23-2.62). Risks were particularly elevated within 5 years of the burn, but persisted throughout follow-up. CONCLUSIONS: Burns are associated with an increased risk of hospitalization for mental health disorders up to 30 years later.

Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients.

Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

Multisystem inflammatory syndrome in 1.2 million children: longitudinal cohort study of risk factors.

BACKGROUND: We identified patient characteristics associated with an increased risk of developing MIS-C. METHODS: We conducted a longitudinal cohort study of 1,195,327 patients aged 0-19 years between 2006 and 2021, including the first two waves of the pandemic (February 25-August 22, 2020 and August 23, 2020-March 31, 2021). Exposures included prepandemic morbidity, birth outcomes, and family history of maternal disorders. Outcomes included MIS-C, Kawasaki disease, and other Covid-19 complications during the pandemic. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for the association between patient exposures and these outcomes using log-binomial regression models adjusted for potential confounders. RESULTS: Among 1,195,327 children, 84 developed MIS-C, 107 Kawasaki disease, and 330 other Covid-19 complications during the first year of the pandemic. Prepandemic hospitalizations for metabolic disorders (RR 11.3, 95% CI 5.61-22.6), atopic conditions (RR 3.34, 95% CI 1.60-6.97), and cancer (RR 8.11, 95% CI 1.13-58.3) were strongly associated with the risk of MIS-C, compared with no exposure. These same exposures were also associated with Kawasaki disease and other Covid-19 complications. However, birth characteristics and history of maternal morbidity were not associated with MIS-C development. CONCLUSIONS: Children with pre-existing morbidity have a considerably elevated risk of MIS-C. IMPACT: Morbidities that predispose children to multisystem inflammatory syndrome (MIS-C) are unclear. In this study, prepandemic hospitalizations for metabolic disorders, atopic conditions, and cancer were associated with an elevated risk of MIS-C. Birth characteristics and family history of maternal morbidity were not, however, associated with MIS-C. Pediatric morbidities may play a greater role in MIS-C onset than maternal or perinatal characteristics, and may help clinicians better recognize children at risk for this complication.

Association of maternal cancer with congenital anomalies in offspring.

BACKGROUND: Congenital anomalies are common, but the possibility that maternal cancer increases the chance of having a child with a birth defect is not fully understood. OBJECTIVES: To examine the association between maternal cancer before or during pregnancy and the risk of birth defects in offspring. METHODS: We conducted a retrospective cohort study of live births in Quebec, Canada, between 1989 and 2022 using hospital data. The main exposure measure was maternal cancer before or during pregnancy. The outcome included birth defects detected in offspring during gestation or at birth. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association of maternal cancer with birth defects using log-binomial regression models adjusted for potential confounders. RESULTS: In this study of 2,568,120 newborns, birth defects were present in 6.0% and 6.7% of infants whose mothers had cancer before or during pregnancy, respectively, compared with 5.7% of infants whose mothers never had cancer. Cancer during pregnancy was associated with heart (RR 1.58, 95% CI 1.03, 2.44), nervous system (RR 4.05, 95% CI 2.20, 7.46) and urinary defects (RR 1.72, 95% CI 1.01, 2.95). Among specific types of malignancies during pregnancy, breast cancer was the most prominent risk factor for birth defects (RR 1.55, 95% CI 1.02, 2.37). Cancer before pregnancy was not associated with any type of birth defect or with defects overall (RR 1.01, 95% CI 0.92, 1.11). Moreover, no specific type of cancer before pregnancy was associated with an increased risk of birth defects. CONCLUSIONS: Maternal cancer during pregnancy is associated with the risk of congenital anomalies in offspring, however, cancer before pregnancy is not associated with this outcome.

Cytogenetics in the management of myelodysplastic neoplasms (myelodysplastic syndromes, MDS): Guidelines from the groupe francophone de cytogénétique hématologique (GFCH).

Myelodysplastic neoplasms (MDS) are clonal hematopoietic neoplasms. Chromosomal abnormalities (CAs) are detected in 40-45% of de novo MDS and up to 80% of post-cytotoxic therapy MDS (MDS-pCT). Lately, several changes appeared in World Health Organization (WHO) classification and International Consensus Classification (ICC). The novel 'biallelic TP53 inactivation' (also called 'multi-hit TP53') MDS entity requires systematic investigation of TP53 locus (17p13.1). The ICC maintains CA allowing the diagnosis of MDS without dysplasia (del(5q), del(7q), -7 and complex karyotype). Deletion 5q is the only CA, still representing a low blast class of its own, if isolated or associated with one additional CA other than -7 or del(7q) and without multi-hit TP53. It represents one of the most frequent aberrations in adults' MDS, with chromosome 7 aberrations, and trisomy 8. Conversely, translocations are rarer in MDS. In children, del(5q) is very rare while -7 and del(7q) are predominant. Identification of a germline predisposition is key in childhood MDS. Aberrations of chromosomes 5, 7 and 17 are the most frequent in MDS-pCT, grouped in complex karyotypes. Despite the ever-increasing importance of molecular features, cytogenetics remains a major part of diagnosis and prognosis. In 2022, a molecular international prognostic score (IPSS-M) was proposed, combining the prognostic value of mutated genes to the previous scoring parameters (IPSS-R) including cytogenetics, still essential. A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations.

Cytogenetics in the management of bone marrow failure syndromes: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.

Cytogenetics in the management of hematologic neoplasms with germline predisposition: guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

The number of predisposing genes is continuously growing with the widespread availability of DNA sequencing, increasing the prevalence of hematologic malignancies with germline predisposition. Cytogenetic analyses provide an effective approach for the recognition of these malignancies with germline predisposition, which is critical for proper diagnosis, optimal treatment and genetic counseling. Based on the World Health Organization and the international consensus classifications as well as the European LeukemiaNet recommendations, this review first presents an advanced classification of neoplasms with germline predisposition focused on the acquired cytogenetic alterations during leukemogenesis. The various genetic rescue mechanisms and the progression to transformation are then explained. The review also outlines the specific constitutional and somatic cytogenetic aberrations indicative of germline predisposition disorders in B-acute lymphoblastic leukemia (ALL), T-ALL, bone marrow failure syndrome and myeloid neoplasms. An emphasis is made on monosomy 7 in the predisposition field, its frequency and diagnosis impact as well as its various circumstances of occurrence. Lastly, we propose cytogenetic technical recommendations and guidelines for clinical reporting of these specific aberrations.

Clinical utility of plasma ctDNA sequencing in metastatic urothelial cancer.

BACKGROUND: Genomic stratification may help improve the management of patients with metastatic urothelial cancer (mUC), given the recent identification of targetable alterations. However, the collection of tissue samples remains challenging. Here, we assessed the clinical utility of plasma circulating tumour DNA (ctDNA) sequencing in these patients. METHODS: Patients with mUC were prospectively enroled in the STING trial (NCT04932525), in which ctDNA was profiled using the Foundation One Liquid CDx Assay (324 genes, blood tumour mutational burden [bTMB], microsatellite instability status). Each genomic report was reviewed by a multidisciplinary tumor board (MTB). RESULTS: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. The median time to obtain the assay results was 20 days ((confidence interval) CI95%: [20,21]). The ctDNA analysis reproduced the somatic genomic landscape of previous tissue-based cohorts. Concordance for serial ctDNA samples was strong (r = 0.843 CI95%: [0.631-0.938], p < 0.001). At least one actionable target was detected in 63 patients (45%) with a total of 35 actionable alterations, including bTMB high (≥10 mutations/Mb) (N = 39, 21.1%), FGFR3 (N = 20, 10.8%), and Homologous recombination deficiency (HRD) alterations (N = 14, 7.6%). MTB recommended matched therapy in 63 patients (45.0%). Eight patients (5.7%) were treated, with an overall response rate of 50% (CI95%: 15.70-84.30) and a median progression-free survival (PFS) of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with a shorter PFS in patients treated with immunotherapy. CONCLUSION: Overall, we demonstrated that genomic profiling with ctDNAs in mUC is a reliable and feasible approach for the timely initiation of genotype-matched therapies.

Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia.

Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.

Multisystem inflammatory syndrome in adults: Comparison with other inflammatory conditions during the Covid-19 pandemic.

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) is an increasingly recognized complication of Covid-19. We assessed risk factors, clinical characteristics, and outcomes of patients with MIS-A compared with other inflammatory conditions. METHODS: We analyzed a cohort of patients ≥21 years hospitalized with MIS-A in Quebec, Canada between February 2020 and March 2021. We included comparison groups that share symptomatology or pathophysiology with MIS-A, including Kawasaki disease, toxic shock syndrome, and other Covid-19 complications. We examined characteristics of men and women at admission, and identified preexisting factors associated with MIS-A through odds ratios (OR) and 95% confidence intervals (CI) from adjusted logistic regression models. RESULTS: Among 22,251 patients in this study, 52 had MIS-A, 90 Kawasaki disease, 500 toxic shock syndrome, and 21,609 other Covid-19 complications. MIS-A was associated with an elevated risk of respiratory failure compared with Kawasaki disease (OR 7.22, 95% CI 1.26-41.24), toxic shock syndrome (OR 4.41, 95% CI 1.73-11.23), and other Covid-19 complications (OR 3.03, 95% CI 1.67-5.50). Patients with MIS-A had a greater risk of cardiac involvement, renal failure, and mortality. The data pointed towards sex-specific differences in presentation, with more respiratory involvement in women and cardiac involvement in men compared with patients that had other Covid-19 complications. Except for allergic disorders and cancer, prior medical risk factors were not associated with a greater likelihood of MIS-A. CONCLUSIONS: Patients with MIS-A have an elevated risk of mortality compared with other inflammatory conditions, with women having a predominance of respiratory complications and men cardiovascular complications.

Association between caesarean birth and childhood cancer: An age-lagged approach.

AIM: We assessed the association between caesarean birth and age-specific risks of childhood cancer. METHODS: We followed a cohort of 1 034 049 children between 2006 and 2020 in Quebec, Canada, from birth until age 14 years. The exposure was caesarean, operative vaginal, or spontaneous vaginal birth. The outcome included haematopoietic or solid tumours. We calculated hazard ratios (HR) and 95% confidence intervals (CI) for the association between mode of delivery and childhood cancer in age-lagged analyses, adjusted for potential confounders. RESULTS: A total of 249 415 (24.1%) children were born by caesarean and 97 411 (9.4%) by operative vaginal delivery. Compared with spontaneous vaginal birth, caesarean was associated with 1.16 times the risk of any cancer (95% CI 1.04-1.30), 1.12 times the risk of haematopoietic cancer (95% CI 0.92-1.36) and 1.21 times the risk of solid tumours (95% 1.06-1.39). Associations strengthened at 2 years of age and were greatest for lymphoma and sarcoma. Operative vaginal birth was not significantly associated with the risk of cancer. CONCLUSION: Caesarean birth may be associated with selected childhood cancers, including lymphoma and sarcoma early in childhood. The underlying reasons for the associations require further investigation, including whether mucosal dysbiosis or labour hormone exposure explain the excess risk.

Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience.

PURPOSE: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). EXPERIMENTAL DESIGN: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. RESULTS: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. CONCLUSIONS: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.

BACKGROUND: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. METHODS: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. FINDINGS: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. INTERPRETATION: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. FUNDING: Université Paris Saclay, Agence Nationale de Biomédecine.

Relationship between suicide attempt and medical morbidity in adolescent girls.

This study assessed whether suicide attempts before 20 years of age were associated with medical morbidity later in life. We carried out a cohort study of 169,806 girls under age 20 years between 1989 and 2019 in Quebec, Canada. The cohort included 8086 girls admitted for suicide attempts, matched on age and year with 161,720 girls with no attempt. Outcomes included hospitalization for medical conditions, such as infection, allergic disorders, autoimmune disease, cardiovascular disease, cancer, and death from nonpsychiatric causes during 31 years of follow-up. We computed hazard ratios (HR) and 95% confidence intervals (CI) for the association of adolescent suicide attempt with these health outcomes using Cox regression models adjusted for preexisting mental illness, substance use disorders, and socioeconomic deprivation. Compared with matched controls, adolescent girls with suicide attempts had a greater risk of hospitalization for infection (HR 1.55, 95% CI 1.44-1.68), allergic disorders (HR 1.72, 95% CI 1.45-2.05), cardiovascular disease (HR 1.31, 95% CI 1.12-1.52), and mortality (HR 3.11, 95% CI 1.69-5.70). Associations were present regardless of the age at the time of the suicide attempt, but were stronger for girls with repeated attempts. Associations were also more pronounced within the first 5 years of the attempt, although suicide attempts remained strongly associated with mortality throughout the 31-year follow-up period. The findings suggest that adolescent girls with suicide attempts have an elevated risk of medical morbidity and mortality and may benefit from closer clinical management to prevent adverse health outcomes.

Hyperemesis Gravidarum and the Potential for Cancer: A Longitudinal Cohort Study over Three Decades.

BACKGROUND: Our objective was to assess whether hyperemesis gravidarum is associated with the risk of endodermal, mesodermal, and ectodermal human chorionic gonadotropin (hCG) receptor+ cancer in women. METHODS: We performed a longitudinal cohort study of 1,343,040 women who were pregnant between 1989 and 2019 in Quebec, Canada. We identified women with and without hyperemesis gravidarum and followed them over time to capture incident cancers, grouped by embryonic germ cell layer of origin and organ hCG receptor positivity. We used time-varying Cox regression to model hazard ratios (HR) and 95% confidence intervals (CI) for the association between hyperemesis gravidarum and cancer onset, adjusted for maternal age, comorbidity, multiple gestation, fetal congenital anomaly, socioeconomic deprivation, and time period. RESULTS: Women with hyperemesis gravidarum had a greater risk of endodermal cancer compared with no hyperemesis gravidarum (5.8 vs. 4.8 per 10,000 person-years; HR, 1.36; 95% CI, 1.17-1.57), but not mesodermal or ectodermal cancer. Severe hyperemesis with metabolic disturbance was more strongly associated with cancer from the endodermal germ layer (HR, 1.97; 95% CI, 1.51-2.58). The association between hyperemesis gravidarum and endodermal cancer was driven by bladder (HR, 2.49; 95% CI, 1.37-4.53), colorectal (HR, 1.41; 95% CI, 1.08-1.84), and thyroid (HR, 1.43; 95% CI, 1.09-1.64) cancer. CONCLUSIONS: Women with hyperemesis gravidarum have an increased risk of cancers arising from the endodermal germ cell layer, particularly bladder, colorectal, and thyroid cancers. IMPACT: Future studies identifying the pathways linking hyperemesis gravidarum with endodermal tumors may help improve the detection and management of cancer in women.

Association of PCOS with offspring morbidity: a longitudinal cohort study.

STUDY QUESTION: Do children whose mothers have polycystic ovary syndrome (PCOS) have an increased risk of morbidity? SUMMARY ANSWER: Maternal PCOS is associated with an increased risk of infection, allergy and other childhood morbidity. WHAT IS KNOWN ALREADY: PCOS is associated with higher rates of gestational diabetes, pre-eclampsia and preterm delivery, but the long-term impact on child health is poorly understood. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective longitudinal cohort study of 1 038 375 children in Quebec between 2006 and 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 7160 children whose mothers had PCOS and 1 031 215 unexposed children. Outcomes included child hospitalization for infectious, allergic, malignant and other diseases before 13 years of age. We estimated hazard ratios (HRs) and 95% CI for the association of PCOS with childhood morbidity in adjusted Cox proportional hazards regression models. MAIN RESULTS AND THE ROLE OF CHANCE: Children exposed to PCOS were hospitalized at a rate of 68.9 (95% CI 66.2-71.8) per 1000 person-years, whereas unexposed children were hospitalized at a rate of 45.3 (95% CI 45.1-45.5) per 1000 person-years. Compared with no exposure, maternal PCOS was associated with 1.32 times the risk of any childhood hospitalization (95% CI 1.26-1.40), 1.31 times the risk of infectious disease hospitalization (95% CI 1.25-1.38) and 1.47 times the risk of allergy-related hospitalization (95% CI 1.31-1.66). Risk of hospitalization was also elevated for childhood metabolic (HR 1.59, 95% CI 1.16-2.18), gastrointestinal (HR 1.72, 95% CI 1.53-1.92), central nervous system (HR 1.74, 95% CI 1.46-2.07) and otologic disorders (HR 1.34, 95% CI 1.26-1.43). Subgroup analyses suggested that there was little difference in the association of PCOS with hospitalization among boys (HR 1.31, 95% CI 1.24-1.39) and girls (HR 1.34, 95% CI 1.26-1.43). LIMITATIONS, REASONS FOR CAUTION: We analyzed severe childhood morbidity requiring hospitalization, not mild diseases treated in ambulatory clinics. We lacked data on ethnicity, education and physical activity, and cannot rule out residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that maternal PCOS is associated with an increased risk of childhood morbidity. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grant PJT-162300 from the Canadian Institutes of Health Research. N.A. acknowledges a career award from the Fonds de recherche du Québec-Santé (296785). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.