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Numerous studies have demonstrated that assisted reproductive technology (ART: defined here as including only

STUDY QUESTION Do women with polycystic ovary syndrome (PCOS) have a greater risk of adverse pregnancy complications (gestational diabetes, preeclampsia, cesarean section, placental abnormalities) and neonatal outcomes (preterm birth, small for gestational age, prolonged delivery hospitalization) compared to women without a PCOS diagnosis and does this risk vary by BMI, subfertility and fertility treatment utilization? SUMMARY ANSWER Deliveries to women with a history of PCOS were at greater risk of complications associated with cardiometabolic function, including gestational diabetes and preeclampsia, as well as preterm birth and prolonged length of delivery hospitalization. WHAT IS KNOWN ALREADY Prior research has suggested that women with PCOS may be at increased risk of adverse pregnancy outcomes. However, findings have been inconsistent possibly due to lack of consistent adjustment for confounding factors, small samples size and other sources of bias. STUDY DESIGN, SIZE, DURATION Massachusetts deliveries among women ≥18 years old during 2013–2017 from state vital records linked to hospital discharges, observational stays and emergency department visits were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) and the Massachusetts All-Payers Claims Database (APCD). PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS was identified by ICD9 and ICD10 codes in APCD prior to index delivery. Relative risks (RRs) and 95% CI for pregnancy and delivery complications were modeled using generalized estimating equations with a log link and a Poisson distribution to take multiple cycles into account and were adjusted a priori for maternal age, BMI, race/ethnicity, education, plurality, birth year, chronic hypertension and chronic diabetes. Tests for homogeneity investigated differences between maternal pre-pregnancy BMI categories ( MAIN RESULTS AND THE ROLE OF CHANCE Among 91 825 deliveries, 3.9% had a history of PCOS. Women with a history of PCOS had a 51% greater risk of gestational diabetes (CI: 1.38–1.65) and a 25% greater risk of preeclampsia (CI: 1.15–1.35) compared to women without a diagnosis of PCOS. Neonates born to women with a history of PCOS were more likely to be born preterm (RR: 1.17, CI: 1.06–1.29) and more likely to have a prolonged delivery hospitalization after additionally adjusting for gestational age (RR: 1.23, CI: 1.09–1.40) compared to those of women without a diagnosis of PCOS. The risk for gestational diabetes for women with PCOS was greater among women with a pre-pregnancy BMI LIMITATIONS, REASONS FOR CAUTION PCOS was defined by ICD documentation prior to delivery so there may be women with undiagnosed PCOS or PCOS diagnosed after delivery included in the unexposed group. The study population is limited to deliveries within Massachusetts among most private insurance payers and inpatient or observational hospitalization in Massachusetts during the follow-up window, therefore there may be diagnoses and or deliveries outside of the state or outside of our sample that were not captured. WIDER IMPLICATIONS OF THE FINDINGS In this population-based study, women with a history of PCOS were at greater risk of pregnancy complications associated with cardiometabolic function and preterm birth. Obstetricians should be aware of patients’ PCOS status and closely monitor for potential pregnancy complications to improve maternal and infant perinatal health outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the NIH (R01HD067270). S.A.M. receives grant funding from NIH, AbbVie and the Marriot Family Foundation; payment/honoraria from the University of British Columbia, World Endometriosis Research Foundation and Huilun Shanghai; travel support for attending meetings for ESHRE 2019, IASP 2019, National Endometriosis Network UK meeting 2019; SRI 2022, ESHRE 2022; participates on the data safety monitoring board/advisory board for AbbVie, Roche, Frontiers in Reproductive Health; and has a leadership role in the Society for Women’s Health Research, World Endometriosis Research Foundation, World Endometriosis Society, American Society for Reproductive Medicine and ESHRE. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

To compare the obstetric and perinatal outcomes of deliveries conceived with embryos from single-step vs. sequential culture media systems.Historical cohort of Massachusetts vital records linked to assisted reproductive technology clinic data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System and laboratory embryology data from two large academic hospital fertility centers.Not applicable.Patients with singleton live birth deliveries between 2004 and 2017 conceived with autologous assisted reproductive technology cycles with fresh blastocyst transfer using either single-step (n = 1,058) or sequential (n = 474) culture media systems.None.Associations of single-step vs. sequential culture with obstetric outcomes (mode of delivery, placental abnormalities, pregnancy-induced hypertension, and gestational diabetes) and perinatal outcomes (preterm birth, low birthweight, small-for-gestational-age, and large-for-gestational-age [LGA]) were assessed with multivariate logistic modeling, adjusted for maternal age, race/ethnicity, education, parity, insurance type, protein supplementation, oxygen concentration, fertilization method, and number of transferred embryos.Compared with sequential culture, single-step culture was associated with increased odds of LGA (adjusted odds ratio 2.1, 95% confidence interval 1.04-4.22). There were no statistically significant differences between single-step and sequential culture media systems in the odds of placental abnormalities, pregnancy-induced hypertension, gestational diabetes, prematurity, small-for-gestational-age, or low birthweight.Single-step culture is associated with increased odds of LGA, indicating that embryo culture media systems may affect perinatal outcomes.

To determine whether assisted reproductive technology (ART) treatment adds obstetric and neonatal risks over and above that of underlying infertility-related diagnoses.Retrospective study of linked ART, birth certificate, hospital discharge data, and outpatient insurance claims data in Massachusetts (2013-2017).Database.Singleton deliveries in women with and without diagnoses of tubal disease, polycystic ovarian syndrome (PCOS), other ovulatory conditions, or endometriosis, identified from the insurance claims and ART data.None.ART and non-ART pregnancy and delivery outcomes were compared with each other and with women with no history of infertility or usage of fertility treatment (fertile group). Generalizing estimating equations with Poisson distribution and exchangeable correlation structure were used to obtain adjusted relative risk ratios (aRRs) and 95% confidence intervals (CIs).Infertility-related diagnoses significantly increased the risks of pregnancy hypertension (PCOS: aRR, 1.13, 95% CI 1.00-1.27), preeclampsia/eclampsia (tubal: aRR 1.28, 95% CI 1.02-1.61; PCOS: aRR 1.23, 95% CI 1.06-1.43; other ovulatory: aRR 1.11, 95% CI 1.02-1.20), gestational diabetes (tubal: aRR 1.28, 95% CI 1.08-1.50; PCOS: aRR 1.58, 95% CI 1.42-1.75; other ovulatory: aRR 1.19, 95% CI 1.12-1.26), and placental problems (tubal aRR 1.47, 95% CI 1.11-1.94), as well as low birthweight and prematurity, compared with deliveries from the fertile group. Within each diagnosis, the use of ART consistently increased the risk of placental problems (aRR 1.49-2.86) but varied for other conditions.Our study demonstrated that compared with the fertile group, risk was elevated in pregnancies and deliveries from women with tubal, PCOS, other ovulatory, and endometriosis diagnoses who did/did not undergo ART treatment. Placental abnormalities were particularly elevated in ART compared to non-ART deliveries having the same diagnosis.

OBJECTIVE: To investigate hospitalizations up to 8 years after livebirth among women who utilized ART or who were subfertile, compared to women who conceived naturally. DESIGN: Retrospective cohort SETTING: Massachusetts deliveries among privately insured women ≥18 years old between 2004–2017 from state vital records were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), and hospital observational/inpatient stays. PATIENTS: We compared patients with ART, medically assisted reproduction, and unassisted subfertile delivery to fertile delivery. INTERVENTION: NA MAIN OUTCOME MEASURED: Post-delivery hospitalization information was derived from ICD codes for discharges and were combined by type. The relative risks (RR) and 95% confidence intervals (CI) of hospitalization for up to the first 8 years post-delivery were modeled. RESULTS: Among 492,515 deliveries, 5.6% used ART, 1.6% used medically assisted reproduction, and 1.8% were unassisted subfertile. Compared to fertile deliveries, deliveries that utilized ART, medically assisted reproduction or were unassisted subfertile were more likely to have hospital utilization (inpatient or observational stay) for any reason for up to 8 years of follow-up (unassisted subfertile aRR:1.18 (1.12–1.25); medically assisted reproduction:1.20 (1.13–1.27); ART aRR:1.29 (1.25–1.34)). ART deliveries had an increased risk of hospitalization for conditions of the cardiovascular system(aRR: 1.31 (1.20–1.41)), overweight/obesity(aRR:1.30 (1.17–1.44)), diabetes(aRR:1.25 (1.05–1.49)), reproductive tract(aRR:1.62 (1.47–1.79)), digestive tract(aRR:1.39 (1.30–1.49), thyroid(aRR:2.02 (1.80–2.26)), respiratory system(aRR: 1.13 (1.03–1.24)), and cancer(aRR:1.40 (1.18–1.65)) up to 8 years after delivery. Deliveries with medically assisted reproduction and subfertility had similar patterns of hospitalization as ART deliveries. CONCLUSION: Women who conceived through fertility treatment or who experienced subfertility were at an increased risk for subsequent hospitalization resulting from a variety of chronic and acute conditions. FUNDING: NIH R01HD067270

Objective: This study evaluates differences in child healthcare utilization by maternal fertility status in the first four years of life. Study Design: The retrospective cohort evaluated Massachusetts (MA) live born infants using data linked from clinical assisted reproductive technology (ART) data, birth certificates, and hospital discharge records. Hospital records of infants born 2004-2017 to mothers of fertile (no infertility treatments or indicators of infertility), unassisted subfertile (UF, indicators of infertility but no fertility treatment), medically assisted reproduction (MAR, non-ART assistance with reproduction) and ART treatment were studied. Adjusted relative risk (aRR) was calculated using multivariable log binomial regression models. Results: We included 339,426 singleton live-born infants discharged from birth hospitalization. Compared to children born to fertile mothers, those born to UF, MAR and ART-treated mothers were more likely to have hospital-based care (aRR 1.06-1.21) in their first 4 years. Conclusions: Maternal subfertility with and without treatment was associated with small increases in child healthcare utilization.

Purpose We previously developed a subfertile comparison group with which to compare outcomes of assisted reproductive technology (ART) treatment. In this study, we evaluated whether insurance claims data in the Massachusetts All Payers Claims Database (APCD) defined a more appropriate comparison group. Methods We used Massachusetts vital records of women who delivered between 2013 and 2017 on whom APCD data were available. ART deliveries were those linked to a national ART database. Deliveries were subfertile if fertility treatment was marked on the birth certificate, had prior hospitalization with ICD code for infertility, or prior fertility treatment. An infertile group included women with an APCD outpatient or inpatient ICD 9/10 infertility code prior to delivery. Fertile deliveries were none of the above. Demographics, health risks, and obstetric outcomes were compared among groups. Multivariable generalized estimating equations were used to calculate adjusted relative risk (aRR) and 95% confidence intervals (CI). Results There were 70,726 fertile, 4,763 subfertile, 11,970 infertile, and 7,689 ART-treated deliveries. Only 3,297 deliveries were identified as both subfertile and infertile. Both subfertile and infertile were older, and had more education, chronic hypertension, and diabetes than the fertile group and less than the ART-treated group. Prematurity (aRR = 1.15–1.17) and birthweight (aRR = 1.10–1.21) were increased in all groups compared with the fertile group. Conclusion Although the APCD allowed identification of more women than the previously defined subfertile categorization and allowed us to remove previously unidentified infertile women from the fertile group, it is not clear that it offered a clinically significantly improved comparison group.

PURPOSE: Investigate the relationship between history of cancer and adverse pregnancy outcomes according to subfertility/fertility treatment. METHODS: Deliveries(2004–2013) from Massachusetts(MA) Registry of Vital Records and Statistics were linked to MA assisted reproductive technology data, hospital discharge records, and Cancer Registry. The relative risks(RR) and 95% confidence intervals of adverse outcomes(gestational diabetes(GDM), gestational hypertension(GHTN), cesarean section(CS), low birth weight(LBW), small for gestational age(SGA), preterm birth(PTB), neonatal mortality, and prolonged neonatal hospital stay) were modeled with log-link and Poisson distribution generalized estimating equations. Differences by history of subfertility/fertility treatment were investigated with likelihood ratio tests. RESULTS: Among 662,630 deliveries, 2,983 had a history of cancer. Women with cancer history were not at greater risk of GDM, GHTN, or CS. However, infants born to women with prior cancer had higher risk of LBW(RR:1.19 [1.07–1.32]), prolonged neonatal hospital stay(RR:1.16[1.01–1.34]), and PTB(RR:1.19[1.07–1.32]). We found clinically and statistically significant differences in the relationship between cancer history and SGA by subfertility/fertility treatment(p-value, test for heterogeneity=0.02); among deliveries with subfertility or fertility treatment, those with history of cancer experienced greater risk of SGA(RRsubfertile:1.36[1.02–1.83]). CONCLUSIONS: Women with a history of cancer had greater risk of some adverse pregnancy outcomes; this relationship varied by subfertility and fertility treatment.

PURPOSE: Among infants following ART-treated, subfertile, and fertile deliveries to determine (1) the presence and magnitude of sex differences in health outcomes and (2) whether the presence of sex differences varied among maternal fertility groups. METHODS: Retrospective cohort analysis of infants born in Massachusetts (MA) in 2004–2013 who were conceived by ART. The Society for Assisted Reproductive Technology Clinic Outcome Reporting System was linked to the Pregnancy to Early Life Longitudinal data system, which links birth certificates to hospital discharge records for MA mothers and infants. Included were singletons born via ART-treated, subfertile, and fertile deliveries. Multivariable logistic regression was used to model the association between infant sex and health outcomes, controlling for maternal demographic and health characteristics. RESULTS: A total of 16,034 ART-treated, 13,277 subfertile, and 620,375 fertile singleton live births were included. For all three groups, males had greater odds of being preterm (AOR range 1.15–1.2), having birth defects (AOR range 1.31–1.71), experiencing respiratory (AOR range 1.33–1.35) and neurologic (AOR range 1.24–1.3) conditions, and prolonged hospital stay (AOR range 1.19–1.25) compared to females. The interaction between maternal fertility group and infant sex for all infant outcomes was nonsignificant, denoting that the presence of sex differences among fertile, subfertile, and ART groups did not vary. CONCLUSION: Sex differences in birth outcomes of infants following ART-treated, subfertile, and fertile deliveries exist but the magnitude of these differences does not vary among these maternal fertility groups. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s10815-020-02004-0) contains supplementary material, which is available to authorized users.

To determine the maternal demographic, health, and fertility variables underlying prematurity.Retrospective: Society for Assisted Reproductive Technology Clinic Outcome Reporting System data linked to Massachusetts birth certificates and hospital stays.Not applicable.We included 166,963 privately insured, singleton, first births to women ≥18 years of age between 2004 and 2013. Deliveries were as follows: assisted reproductive technology (ART) when linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System, medically assisted reproduction (MAR) when fertility treatment was indicated on the birth certificate, unassisted subfertile (USF) when there were indications of subfertility but no treatment, and fertile if none of the above.None.Late preterm birth (LPTB; 34-36 weeks) and early preterm birth (EPTB;34 weeks) were compared with term deliveries (≥37 weeks). Covariates that statistically significantly influenced prematurity in binary analysis were modeled by using multinomial logistic regression. Backward elimination and mediation analysis were used to determine the influence of single parameters on outcomes of others.LPTB was increased in the USF (adjusted odds ratio [AOR] 1.32, 95% confidence interval [CI] 1.06-1.65) and ART (AOR 1.42, 95% CI 1.30-1.56) but not MAR (AOR 1.16, 95% CI 0.98-1.37). ETPB was increased in all (USF: AOR 1.67, 95% CI 1.21-2.31; MAR: AOR 1.67, 95% CI 1.31-2.12; ART: AOR 1.40, 95% CI 1.21-1.61). The strongest effectors of prematurity were placental problems (LPTB: AOR 4.02; EPTB: AOR 10.28), pregnancy hypertension (LPTB: AOR 2.14; EPTB: AOR 2.88), and chronic hypertension (LPTB: AOR 1.85; EPTB: AOR 2.79). Mediation analysis demonstrated a statistically significant indirect effect of placental problems for ART and subfertility.The greatest effectors of prematurity were placental problems and hypertensive disorders. ART and, to a lesser extent, subfertility were both associated with preterm birth directly and indirectly mediated by placenta problems.

STUDY QUESTION Are toddlers conceived by fertility treatment at higher risk of failing a screening tool for autism spectrum disorders (ASD) than toddlers not conceived by treatment? SUMMARY ANSWER Compared with children not conceived by infertility treatment, children conceived by any infertility treatment, ovulation induction with or without intrauterine insemination (OI/IUI), or assisted reproductive technologies (ART) appeared to have had higher odds of failing an ASD screening; however, results were inconclusive and need replication. WHAT IS KNOWN ALREADY Although most of the studies which have examined risk of ASD after ART show no association, the results are mixed. Thus, further studies are needed to clarify this association. STUDY DESIGN SIZE, DURATION The Upstate KIDS Study is a population-based, prospective cohort study of children born in New York State between 2008 and 2010. Children were screened for ASD using the Modified Checklist for Autism in Toddlers (M-CHAT) at ages 18 and 24 months. PARTICIPANTS/MATERIALS, SETTING, AND METHODS The New York State live-birth registry was used to identify newborns conceived with and without fertility treatment with a 1:3 ratio, frequency matched on region of birth. At 18 and 24 months, 3183 and 3063 mothers, respectively, completed the M-CHAT questionnaire. The current analysis included 2586 singletons and 1296 twins with M-CHAT information at 18 and/or 24 months. Multivariable logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (aOR) and 95% confidence intervals (CI) after adjustment for covariates such as maternal age, education and plurality. MAIN RESULTS AND THE ROLE OF CHANCE We found that 200 (5.2%) and 115 (3.0%) children failed the M-CHAT at 18 and 24 months, respectively. The associations between use of infertility treatment and failing the M-CHAT at 18 and/or 24 months were positive but inconclusive as they failed to exclude no association (18 months aOR 1.71, 95% CI: 0.81–3.61; 24 months aOR 1.78, 95% CI: 0.66–4.81; and both 18 and 24 months aOR 1.53, 95% CI: 0.78–2.99). The relationships between OI/IUI and ART with M-CHAT failure at 18 and/or 24 months were similar to those of using any fertility treatment. In vitro fertilization with intracytoplasmic sperm injection was not consistently positively or inversely associated with M-CHAT failure at each time point (18 months aOR 1.20, 95% CI: 0.51–2.83; 24 months aOR 0.93, 95% CI: 0.37–2.31; and both 18 and 24 months aOR 1.09, 95% CI: 0.50–2.60). LIMITATIONS REASONS FOR CAUTION The M-CHAT is a screening tool used for ASD risk assessment, and therefore, M-CHAT failure does not indicate ASD diagnosis. In addition, we did not have power to detect associations of small magnitude. Finally, non-response to follow-up may bias the results. WIDER IMPLICATIONS OF THE FINDINGS Despite lack of precision, the positive associations between ART and M-CHAT failure suggest that larger population-based studies with longer follow-up are needed. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, HHSN267200700019C). The sponsor played no role in the study design, data collection, data analysis or interpretation, writing of the manuscript or decision to submit the article for publication. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable.

To define specific risk factors for placenta previa in pregnancies conceived with assisted reproductive technology (ART).Retrospective cohort.Fertility centers and inpatient obstetric units in Massachusetts.Patients conceiving with ART and delivering at 20 weeks gestation or later between 2011 and 2017 in Massachusetts.Patient demographic and medical factors and specific components of their cycles. Data were obtained by linking vital records of the State of Massachusetts to reproductive clinic data obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, and then supplementing this information with laboratory and obstetric data from 2 large academic hospitals.Associations were tested between multiple cycle- and patient-related factors and placenta previa or low-lying placenta at delivery. After testing for confounders, multivariate models were adjusted for maternal age, history of prior cesarean delivery and birth plurality, and are reported as adjusted relative risks (aRR).We included 18,939 pregnancies, with 553 (2.9%) having placenta previa at delivery. Advanced maternal age (aRR, 1.25; 95% confidence interval [CI], 1.06-1.48), endometriosis, (aRR, 2.22; 95% CI, 1.71-2.86), and controlled ovarian hyperstimulation (aRR, 1.33; 95% CI, 1.12-1.59) were associated with placenta previa, whereas multiple births (aRR, 0.63; 95% CI, 0.48-0.81) and a history of polycystic ovary syndrome or ovulation disorders (aRR, 0.59; 95% CI, 0.46-0.75) had negative associations. The endometriosis association was strong in nulliparas and the controlled ovarian hyperstimulation association was strong in parous patients in a stratified analysis. No association was seen with prior history of cesarean delivery.Patients conceiving with ART do not have the typical previa risk factors of prior cesarean delivery and multiple gestations, whereas endometriosis and fresh embryo transfers contributed moderate risk. The embryo transfer process itself may affect previa development in this population.

Endometriosis and uterine fibroids are common gynecologic conditions associated with a greater risk for infertility. Previous research has suggested that these conditions are associated with adverse pregnancy outcomes, potentially because of increased utilization of fertility treatments.Our objective was to investigate whether women with a history of endometriosis or fibroids had a greater risk for adverse pregnancy outcomes and whether this risk varied by infertility history and fertility treatment utilization.Deliveries (2013-2017) recorded in Massachusetts' vital records were linked to assisted reproductive technology data, hospital stays, and all-payer claims database. We identified endometriosis and fibroids diagnoses via the all-payer claims database before index delivery. Adjusted relative risks for pregnancy complications were modeled using generalized estimating equations with a log link and Poisson distribution. The influence of subfertility or infertility and assisted reproductive technology was also investigated.Among 91,825 deliveries, 1560 women had endometriosis and 4212 had fibroids. Approximately 30% of women with endometriosis and 26% of women with fibroids experienced subfertility or infertility without utilizing assisted reproductive technology, and 34% of women with endometriosis and 21% of women with fibroids utilized assisted reproductive technology for the index delivery. Women with a history of endometriosis or fibroids were at a greater risk for pregnancy-induced hypertension, preeclampsia, or eclampsia (endometriosis relative risk, 1.17; fibroids relative risk, 1.08), placental abnormalities (endometriosis relative risk, 1.65; fibroids relative risk, 1.38), and cesarean delivery (endometriosis relative risk, 1.22; fibroids relative risk, 1.17) than women with no history of those conditions. Neonates born to women with a history of endometriosis or fibroids were also at a greater risk for preterm birth (endometriosis relative risk, 1.24; fibroids relative risk, 1.17). Associations between fibroids and low birthweight varied by fertility status or assisted reproductive technology (P homogeneity=.01) and were stronger among noninfertile women.Endometriosis or fibroids increased the risk for adverse pregnancy outcomes, possibly warranting differential screening or treatment.

To evaluate whether children conceived using assisted reproductive technology (ART) or ovulation induction (OI) have greater cardiometabolic risk than children conceived without treatment.Clinical assessments in 2018-2019 in the Upstate KIDS cohort.Clinical sites in New York.Three hundred thirty-three singletons and 226 twins from 448 families.Mothers reported their use of fertility treatment and its specific type at baseline and approximately 4 months after delivery. High validity of the self-reported use of ART was previously confirmed. The children were followed up from infancy through 8-10 years of age. A subgroup was invited to participate in clinic visits.The measurements of blood pressure (BP), arterial stiffness using pulse wave velocity, anthropometric measures, and body fat using bioelectrical impedance analysis were performed (n = 559). The levels of plasma lipids, C-reactive protein, and hemoglobin A1c were measured using blood samples obtained from 263 children.The average age of the children was 9.4 years at the time of the clinic visits Approximately 39% were conceived using fertility treatment (18% using ART and 21% using OI). Singletons conceived using fertility treatment (any type or using ART or OI specifically) did not statistically differ in systolic or diastolic BP, heart rate, or pulse wave velocity. Singletons conceived using OI were smaller than singletons conceived without treatment, but the average body mass index of the latter was higher (z-score: 0.41 [SD, 1.24]) than the national norms. Twins conceived using either treatment had lower BP than twins conceived without treatment. However, twins conceived using OI had significantly higher arterial stiffness (0.59; 95% CI, 0.03-1.15 m/s), which was attenuated after accounting for maternal BP (0.29; 95% CI, -0.03 to 0.46 m/s). Twins did not significantly differ in size or fat measures across the groups. The mode of conception was not associated with the levels of lipids, C-reactive protein, or glycosylated hemoglobin.Clinical measures at the age of 9 years did not indicate greater cardiometabolic risk in children conceived using ART or OI compared with that in children conceived without treatment.ClinicalTrials.gov #NCT03106493.

Objective To compare neonatal health outcomes after fresh versus frozen ET (FET). Design Retrospective analysis of a population-based database of linked clinically assisted reproductive technology (ART) data with state vital records. Multivariable logistic regression was used to model the association between deliveries from fresh versus FET and adverse health outcomes, controlling for maternal characteristics. Setting Not applicable. Patient(s) Live-born singleton infants born to Massachusetts women who conceived by fresh or FET after ART using autologous oocytes between July 1, 2004, and December 31, 2013. Intervention(s) None. Main Outcome Measure(s) Preterm birth, low birth weight, neonatal mortality, birth defects, organ system conditions. Result(s) Compared with infants conceived from fresh embryos, those born to mothers who underwent FET were less likely to be small for gestational age (adjusted odds ratio [AOR] = 0.56; 95% confidence interval [CI], 0.44–0.70) and low birth weight (AOR = 0.72; 95% CI, 0.59–0.88) but more likely to be large for gestational age (AOR = 1.47; 95% CI, 1.26–1.70) and to experience greater odds of infectious disease (AOR = 1.46; 95% CI, 1.03–2.06), respiratory (AOR = 1.23; 95% CI, 1.07–1.41), and neurologic (AOR = 1.32; 95% CI, 1.04–1.68) conditions. There were no statistically significant differences in preterm birth, neonatal mortality, birth defects, cardiovascular, hematologic, and gastrointestinal/feeding conditions, and for infants ≥ 35 weeks, no statistically significant differences in prolonged hospital stay (>3 days for vaginal delivery, >5 days for cesarean). Conclusion(s) Compared with infants conceived from fresh ET, those born by FET have higher birth weight but increased odds of infectious disease, hematologic, respiratory, and neurologic abnormalities. These risks should be considered when making decisions on fresh versus FET.

PURPOSE: To investigate assisted reproductive technology (ART) outcomes among adolescent and young-adult female cancer survivors. METHODS: The Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to the Massachusetts Cancer Registry for 90,928 ART cycles in Massachusetts to women ≥ 18 years old from 2004 to 2013. To estimate relative risks (RR) and 95% confidence intervals (CI), we used generalized estimating equations with a log link that accounted for multiple cycles per woman and a priori adjusted for maternal age and cycle year. The main outcomes of interest were ART treatment patterns; number of autologous oocytes retrieved, fertilized, and transferred; and rates of implantation, clinical intrauterine gestation (CIG), live birth, and pregnancy loss. RESULTS: We saw no difference in number of oocytes retrieved (aRR: 0.95 (0.89–1.02)) or proportion of autologous oocytes fertilized (aRR: 0.99 (0.95–1.03)) between autologous cycles with and without a history of cancer; however, cancer survivors required a higher total FSH administered (aRR: 1.12 (1.06–1.19)). Among autologous cycle starts, cycles in women with a history of cancer were less likely to result in CIG compared to no history of cancer (aRR: 0.73 (0.65–0.83)); this relationship was absent from donor cycles (aRR: 1.01 (0.85–1.20)). Once achieving CIG, donor cycles for women with a history of cancer were two times more likely to result in pregnancy loss (aRR: 1.99 (1.26–3.16)). CONCLUSIONS: Our analysis suggests that cancer may influence ovarian stimulation response, requiring more FSH and resulting in lower CIG among cycle starts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02376-x.

Objective. Assisted reproductive technology (ART)-treated women exhibit increased risk of premature delivery compared to fertile women. We evaluated whether ART treatment modalities increase prematurity and whether placental abnormalities and pregnancy-induced hypertensive (PIH) disorders mediate these risks. Method(s): This retrospective study of ART-treated and fertile deliveries (2004–2017) used an ART-cycle database linked to Massachusetts birth certificates and hospital discharges. Outcomes of late preterm birth (LPTB: 34–36 weeks gestation) and early preterm birth (EPTB: &lt, 34 weeks gestation) were compared with term deliveries (≥37 weeks gestation) in ART-treated (linked to the ART database) and fertile (no indicators of infertility or ART) deliveries. ART treatments with autologous oocyte, donor oocyte, fresh or frozen embryo transfer (FET), intracytoplasmic sperm injection (ICSI) and no-ICSI were separately compared to the fertile group. Adjusted odds ratios (AOR) were calculated with multivariable logistic regression: placental abnormalities or PIH were quantified in the pathway as mediators. Results: There were 218,320 deliveries: 204,438 fertile and 13,882 ART-treated. All treatment types increased prematurity (AOR 1.31–1.58, LPTB, AOR 1.34–1.48, EPTB). Placental abnormalities mediated in approximately 22% and 38% of the association with LPTB and EPTB, respectively. PIH mediated 25% and 33% of the association with LPTB and EPTB in FET and donor oocyte cycles, more than other treatments (&lt, 10% LPTB and &lt, 13% EPTB). Conclusions: ART-treatment and all ART modalities increased LPTB and EPTB when compared with fertile deliveries. Placental abnormalities modestly mediated associations approximately equally, while PIH was a stronger mediator in FET and donor oocyte cycles. Reasons for differences require exploration.

To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment.Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.New York State (excluding New York City).This analysis included 855 newborns and 152 children at approximately 9 years of age.None.DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction.ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.

Background Overweight and obesity are major risk factors for gestational diabetes among U.S. women. Evidence suggests that longer duration of breastfeeding among women with a history of gestational diabetes is associated with lower incidence of developing type 2 diabetes after pregnancy. Women may potentially benefit from a lifestyle change program that includes breastfeeding education and support. Purpose To describe the design and justification of a combined breastfeeding, national Diabetes Prevention Program (DPP)-based feasibility randomized controlled trial, the electronic Monitoring Of Mom's Schedule (eMOMSTM) study. eMOMSTM compares the feasibility and efficacy of three interventions on six-month postpartum weight loss among women with a BMI ≥25. Methods The intervention is delivered via Facebook and includes three groups: DPP and breastfeeding (eMOMS1); DPP only (eMOMS2); and Usual Care (eMOMS3). Recruitment is ongoing at two clinical sites (rural and urban). A total of 72 women, 24 per group, will be randomly assigned to one of the three groups. It is anticipated that women in eMOMS1 will have greater weight loss and increased length of breastfeeding at three and six months postpartum compared to women in eMOMS2 and eMOMS3. Additional data will be collected on metabolic markers, anthropometrics, physical activity, nutrition, breastfeeding, and depression. Program cost will be compared to that of traditionally scheduled group meetings. Expected study completion date: October 2021. Conclusions This study has the potential to define a high impact, cost effective intervention that can improve public health by reducing negative health outcomes associated with gestational diabetes among an at-risk population., Highlights • Delivery of a combined breastfeeding and lifestyle change program via social media. • Comparison of 3 programs on 6-month postpartum weight loss among high-BMI women. • Comparison of 3 programs on length of breastfeeding among high-BMI women. • Programs: lifestyle change and breastfeeding, lifestyle change only, and usual care. • Cost analysis of online program delivery versus in-person meetings.

Objective: To measure delivery length of stay (LOS) and cost as proxies for infant morbidity in assisted reproductive technology (ART) and subfertile deliveries. Study Design: Massachusetts singleton births, ≥23 weeks gestational age (GA) between 2004 and 2010 were linked with ART data, vital records, and hospital discharges. LOS and costs (2010 US Dollars) of infants born to fertile (no ART or indicators of infertility), subfertile (indicators of infertility but no ART), and ART-treated (linked to ART data) deliveries were compared. Least square means and standard errors (SE) were calculated. Results: Of 345,756 singletons, (fertile n=332,481, subfertile n=4,987 and ART-treated n=8,288), overall LOS was 3.79±0.01, 4.32±0.05, and 4.90±0.04 days and costs were $2,980±6, $3,217±58, and $4,483 ±62, respectively. GA and birthweight predicted much of the intergroup difference. Conclusions: Maternal fertility group was not an independent predictor of infant LOS and costs. Prematurity and birthweight were driving factors in resource utilization.

OBJECTIVE To analyze changes in intracytoplasmic sperm injection (ICSI) utilization, indications, and outcomes across U.S. regions. METHODS We conducted a retrospective cohort study. Data sets for 2000-2014 were obtained from the Centers for Disease Control and Prevention. Clinics with 100 or greater fresh, nondonor cycles were grouped by 10 nationally recognized Department of Health and Human Services (DHHS) regions and were compared for use of ICSI, frequency of male factor infertility, preimplantation genetic therapies, pregnancy, and live birth rates per cycle among fresh in vitro fertilization cycles in women younger than 35 years of age. RESULTS Nationwide ICSI utilization increased 52% (46.3±6.1% to 70.0±7.1%) from 2000 to 2014, whereas pregnancy and live birth rates per cycle modestly increased by 8.5% (39.2±3.8% to 42.5±2.5%) and 7.6% (34.4±3.6% to 37±2.6%), respectively, showing a positive correlation (r=0.78, P

Background Contemporary embryo biopsy in the United States involves the removal of several cells from a blastocyst that would become the placenta for preimplantation genetic testing. Embryos are then cryopreserved while patients await biopsy results, with transfers occurring in a subsequent cycle as a single frozen-thawed embryo transfer, if euploid. Objective We sought to determine if removal of these cells for preimplantation genetic testing was associated with adverse obstetrical or neonatal outcomes after frozen-thawed single embryo transfer. Study Design We linked assisted reproductive technology surveillance data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System to birth certificates and maternal and neonatal hospitalization discharge diagnoses in Massachusetts from 2014 to 2017, considering only singleton births after frozen-thawed single embryo transfers. We compared outcomes of cycles having embryo biopsy (n=585) to those having no biopsy (n=2191) using chi-square for categorical and binary variables and logistic regression for adjusted odds ratios and 95% confidence intervals, adjusting for mother’s age, race, education, parity, body mass index, birth year, insurance, and all infertility diagnoses. Results Considering no biopsy as the reference, there was no difference between groups with respect to preeclampsia (adjusted odds ratio, 0.82; 95% confidence interval, 0.42–1.61; P=.5685); pregnancy-induced hypertension (adjusted odds ratio, 0.85; 95% confidence interval, 0.46–1.59; P=.6146); placental disorders, including placental abruption, placenta previa, placenta accreta, placenta increta, and placenta percreta (adjusted odds ratio, 1.16; 95% confidence interval, 0.60–2.24; P=.6675); preterm birth (adjusted odds ratio, 1.22; 95% confidence interval 0.73–2.03; P=.4418); low birthweight (adjusted odds ratio, 1.12; 95% confidence interval, 0.58–2.15; P=.7355); cesarean delivery (adjusted odds ratio, 1.04; 95% confidence interval, 0.79–1.38; P=.7762); or gestational diabetes mellitus (adjusted odds ratio, 0.83; 95% confidence interval, 0.50–1.38; P=.4734). In addition, there was no difference between the groups for prolonged hospital stay for mothers (adjusted odds ratio, 1.23; 95% confidence interval, 0.83–1.80; P=.3014) or for infants (95% confidence interval, 1.29; 95% confidence interval, 0.72–2.29; P=.3923). Conclusion Embryo biopsy for preimplantation genetic testing does not increase the odds for diagnoses related to placentation (preeclampsia, pregnancy-related hypertension, placental disorders, preterm delivery, or low birthweight), maternal conditions (gestational diabetes mellitus), or maternal or infant length of stay after delivery.

Background Assisted reproductive technology (ART) has been associated with birth defects, but the contributions of multiple births and underlying subfertility remain unclear. We evaluated the effects of subfertility and mediation by multiple births on associations between ART and nonchromosomal birth defects. Methods We identified a retrospective cohort of Massachusetts live births and stillbirths from 2004 to 2010 among ART-exposed, ART-unexposed subfertile, and fertile mothers using linked information from fertility clinics, vital records, hospital discharges, and birth defects surveillance. Log-binomial regression was used to estimate prevalence ratios and 95% confidence intervals (CIs). Mediation analyses were performed to deconstruct the ART-birth defects association into the direct effect of ART, the indirect effect of multiple births, and the effect of ART-multiples interaction. Results Of 17,829 ART-exposed births, 355 had a birth defect, compared with 162 of 9431 births to subfertile mothers and 6183 of 445,080 births to fertile mothers. The adjusted prevalence ratio was 1.5 (95% CI, 1.3–1.6) for ART and 1.3 (95% CI, 1.1–1.5) in subfertile compared with fertile deliveries. We observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects. Conclusion Although the risk of birth defects with ART is small, a substantial portion of the relative effect is mediated through multiple births, with subfertility contributing an important role. Future research is needed to determine the impact of newer techniques, such as single embryo transfer, on these risks. Birth Defects Research, 2017. © 2017 Wiley Periodicals, Inc.

Background Anecdotal evidence suggests that US practice patterns for ART differ by geographical region. The purpose of this study was to determine whether use of ICSI differs by region and to evaluate whether these rates are correlated with differences in live birth rates. Methods Public data for 2012 were obtained from the Centers for Disease Control and Prevention. Clinics with ≥100 fresh, non-donor cycles were grouped by 10 nationally recognized Department of Health & Human Services regions and 11 metropolitan Megaregions and were compared for use of ICSI, frequency of male factor infertility, and live birth rate in women

INTRODUCTION: We examined the prevalence of autism spectrum disorders (ASD) in Massachusetts (MA) comparing children born via assisted reproductive technology (ART) and children born to women with indicators of subfertility but no ART [Subfertile], to children born to women with neither ART nor indicators of subfertility [Fertile]. We assessed the direct, indirect, and total effects of ART and subfertility on ASD among singletons. METHODS: This study included 10,147 ART, 8,072 Subfertile and 441,898 Fertile MA resident births from the MA Outcome Study of ART (MOSART) database linked with Early Intervention program participation data. ART included fresh in vitro fertilization (IVF), fresh intracytoplasmic sperm injection (ICSI), and frozen embryo transfer. We estimated the prevalence of ASD by fertility group. We used logistic regression to assess the natural direct (NDE), natural indirect (NIE) through preterm birth, and total effects of each fertility group on ASD. RESULTS: The NDE indicated that, compared to the Fertile group, the odds of ASD were not statistically higher in the ART (OR(NDE): 1.07; 95% CI: 0.88-1.30), Subfertile (OR(NDE): 1.11; 95% CI: 0.89-1.38), IVF (OR(NDE): 0.91; 95% CI: 0.68-1.22), or ICSI (OR(NDE): 1.13; 95% CI: 0.84-1.51) groups, even if the rate of preterm birth was the same across all groups. The total effect (product of NDE and NIE) was not significant for ART (OR(Total Effect): 1.08; 95% CI: 0.89-1.30), Subfertile (OR(Total Effect): 1.11; 95% CI: 0.89-1.38), IVF (OR(Total Effect): 0.92; 95% CI: 0.69-1.23), or ICSI (OR(Total Effect): 1.13; 95% CI: 0.84-1.52). CONCLUSION: Compared to children born to Fertile women, children born to ART, ICSI, or IVF, or Subfertile are not at increased risk of receiving an ASD diagnosis.

BACKGROUND: Anti-Mullerian hormone is produced by small antral follicles and reflects ovarian reserve. Obesity is associated with lower serum anti-Mullerian hormone but it is unclear whether lower levels of anti-Mullerian hormone in women with obesity reflects lower ovarian reserve. OBJECTIVE: To determine whether lower Anti-Mullerian hormone in women with obesity undergoing in vitro fertilization is associated with oocyte yield and live-birth rate. STUDY DESIGN: Retrospective cohort from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database of 13316 women with obesity and 16579 women with normal BMI undergoing their first autologous IVF with fresh transfers between 2012 and 2014. Normal BMI was defined as BMI 18.5–24.9 kg/m(2), obesity was defined as BMI ≥30 kg/m(2) and subjects with obesity were stratified as Class 1 obesity (BMI 30.0–34.9 kg/m(2)), Class 2 obesity (BMI 35.0–39.9 kg/m(2)) and Class 3 obesity (BMI ≥40 kg/m(2)) based on the World Health Organization BMI guidelines. Anti-Mullerian hormone levels were stratified as normal (>1.1 ng/ml), low (0.16–1.1 ng/ml) and undetectable (≤ 0.16 ng/ml). Multivariable modeling was used to assess oocyte yield using linear regression with a logarithmic transformation and odds of live birth using logistic regression. RESULTS: Women with obesity were older (36.0 ± 4.8 vs. 35.5 ± 4.8, P

PURPOSE: Pre-pregnancy and post-delivery hospitalizations were compared as markers for health among women who conceived using assisted reproductive technology (ART), non-ART medically assisted reproduction (MAR), no treatment (unassisted subfertile), and who were fertile. METHODS: We analyzed hospital discharge data linked to Massachusetts birth certificates from 2004 to 2013 within 5 years prior to pregnancy and 8–365 days post-delivery. ART deliveries were linked from a national ART database; MAR deliveries had fertility treatment but not ART; unassisted subfertile women had subfertility but no ART or MAR; and fertile women had none of these. Prevalence of diagnoses during hospitalization was quantified. Multivariable logistic regression models with fertile deliveries as reference were adjusted for maternal age, race, education, year, and plurality (post-delivery only) with results reported as adjusted odds ratios (AORs) and 95% confidence intervals (CI). RESULTS: Of 170,605 privately insured, primiparous deliveries, 10,458 were ART, 3005 MAR, 1365 unassisted subfertile, and 155,777 fertile. Pre-pregnancy hospitalization occurred in 6.8% and post-delivery in 2.8% of fertile women. Subfertile groups had more pre-pregnancy hospitalizations (AOR, 95% CI: 1.84, 1.72–1.96 ART; 1.41, 1.24–1.60 MAR; 3.02, 2.62–3.47 unassisted subfertile) with endometriosis, reproductive organ disease, ectopic pregnancy/miscarriage, and disorders of menstruation, ovulation, and genital tract being common. Post-delivery hospitalizations were significantly more frequent in the ART (AOR 1.19, 95% CI 1.05–1.34) and unassisted subfertile (1.59, 1.23–2.07) groups with more digestive tract disorders, thyroid problems, and other grouped chronic disease conditions. CONCLUSIONS: Greater likelihood of hospitalization in the ART, MAR, and unassisted subfertile groups is largely explained by admissions for conditions associated with subfertility.

The objective of this study was to evaluate the effect of changing fertility status on perinatal outcomes of singleton siblings, conceived with and without assisted reproductive technology (ART).A longitudinal cohort study of Massachusetts resident women having two consecutive singleton births during 2004-2010 was performed. Women were classified as ART (A), subfertile (S), or fertile (F) and categorized by their fertility status in each birth as A-A, A-S, S-A, S-S, F-A, F-S, and F-F. Within categories, adjusted mean birthweights, gestations, and birthweight Z scores were estimated with linear generalized estimating equations. Risks of low birthweight (LBW,2500 g), preterm birth (PTB,37 weeks), and placental complications were modeled using logistic regression by fertility status as adjusted odds ratios (AORs) and 95 % confidence intervals (CIs).Birthweights in second pregnancies averaged 74-155 g higher, except for births to F-A women, who averaged -16 g lower. Most women had a reduction in length of gestation in their second pregnancies, with F-A women having the largest decline (-0.5 weeks). In first birth models, the risks for LBW and placental complications were increased for subfertile (AOR 1.39 [1.07-1.81] and 1.97 [1.33-2.93], respectively) and ART women (AOR 1.58 [1.29-1.93] and 3.40 [2.64-4.37], respectively). Second birth models showed increased risks for ART births of LBW (AOR 3.13 [2.19-4.48]) and placental complications (AOR 2.45 [1.56-3.86]) and greater risks of PTB for both ART (AOR 2.37 [1.74-3.23]) and subfertile women (AOR 1.47 [1.02-2.13]).Declining fertility status, with and without assisted reproductive technology treatment, is associated with increasing risks for adverse outcomes, greatest for women whose fertility status declined the most.

The purpose of the present study is to estimate the proportion of women with cancer who return to use the embryos that they have banked and to compare this proportion to that of women without cancer who bank embryos. This is a cohort study of three groups of women from New York, Texas, and Illinois who used embryo banking in their first assisted reproductive technology (ART) treatment cycle: two groups with cancer (222 women without an infertility diagnosis and 48 women with an infertility diagnosis) and a control group without cancer (68 women with the infertility diagnosis of male factor only). Women were included only if their first ART cycle reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) occurred between 2004 and 2009. Cancer cases were identified from each State Cancer Registry from 5 years prior to initiation of ART treatment to 6 months post-initiation; mean follow-up after the first ART cycle was 2.0 years. Women with cancer without an infertility diagnosis returned for a subsequent ART cycle at a lower rate (10.8 %) than those with an infertility diagnosis (31.3 %, p = 0.0010) or the control group (85.3 %, p

Objective To compare incidence, risk factors, and etiology of women's deaths in fertile, subfertile, and undergoing assisted reproductive technology (ART) in the years after delivery. Design Retrospective cohort. Setting University hospital. Patient(s) Women who had delivered in Massachusetts. Intervention(s) This study used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System linked to vital records, hospital stays, and the Massachusetts death file. Mortality of patients delivered from 2004-2013 was evaluated through 2015. The exposure groups, determined on the basis of the last delivery, were ART-treated (linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System), subfertile (no ART but with indicators of subfertility including birth certificate checkbox for fertility treatment, prior hospitalization for infertility [International Classification of Disease codes 9 628 or V23], and/or prior delivery with checkbox or ART), or fertile (neither ART nor subfertile). Numbers (per 100,000 women-years) and causes of death were obtained from the Massachusetts death file. Main Outcome Measure(s) Mortality of women after delivery in each of the three fertility groups and the most common etiology of death in each. Result(s) We included 483,547 women: 16,429 ART, 11,696 subfertile, and 455,422 fertile among whom there were 1,280 deaths with 21.1, 25.5, and 44.7 deaths, respectively, per 100,000 women-years. External causes (violence, accidents, and poisonings) were the most common reasons for death in the fertile group. Deaths occurred on average 46 months after delivery. When external causes of death were removed, there were 19.1, 17.0, and 25.6 deaths per 100,000 women-years and leading causes of death in all groups were cancer and circulatory problems. Conclusion(s) The study presents reassuring data that death rates within 5 years of delivery in ART-treated and subfertile women do not differ from those in fertile women.

OBJECTIVE: To assess the impact of using donor sperm in assisted reproductive technology (ART) cycles on perinatal outcomes. DESIGN: Historical cohort study. SETTING: US national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2012 to 2013. PATIENT(S): Patients undergoing the first fresh autologous ART cycle using either donor or partner sperm. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Miscarriage, preterm birth, low birthweight rates. RESULTS: A total of 134,710 fresh autologous ART cycles were evaluated from the SART CORS database. Following exclusion criteria and after restricting to the first cycle, 2,123 donor sperm and 42,799 partner sperm ART cycles were included in the final analyses. After adjusting for all confounding variables (including maternal age, race, body mass index, smoking status, gravidity, history of preterm birth, highest follicle stimulating hormone count, blastocyst transfer percentage, total embryo transferred, and etiology of infertility), no statistically significant differences in miscarriage rates, preterm births, very preterm births, low birthweight, and very low birthweight were observed. Birthweight was significantly lower in the partner sperm group than in the donor sperm group (3,292 ± 601 and 3,233 ± 592 g in donor and partner sperm groups, respectively, adjusted P value 0.003); however, this small absolute difference (adjusted effect estimate 42 g, 95% CI 14.7–70.9) does not carry clinical significance. CONCLUSIONS: The use of donor sperm in fresh autologous ART cycles was not associated with increased miscarriage, preterm births, or low birthweights, as compared to cycles using partner sperm. This information can be used in patient counseling to reassure patients using donor sperm in ART cycles.

OBJECTIVES: To assess the risk of adverse health outcomes for infants after assisted reproductive technology (ART)–treated and subfertile as compared with fertile deliveries. METHODS: Live-born singleton infants ≥23 weeks’ gestational age (GA) born in Massachusetts between July 1, 2004, and December 31, 2010, were analyzed by linking a clinical ART database with state vital records. χ2 tests were used to compare the outcomes of fertile (those without ART treatment or other indicators of infertility), subfertile (indicators of infertility, no ART), and ART-treated (linked to ART deliveries) mothers, stratified by GA. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by using multivariate logistic regression within each GA stratum, controlling for maternal sociodemographic and health characteristics. RESULTS: Compared with infants of fertile mothers (n = 336 705), infants born to subfertile (n = 5043) or ART-treated (n = 8375) mothers were more likely to be preterm (aOR 1.39 [95% CI 1.26–1.54] and aOR 1.72 [95% CI 1.60–1.85], respectively) and have respiratory and gastrointestinal and/or nutritional conditions (aOR range: 1.12–1.18). When stratified by GA, infants of subfertile or ART-treated mothers were at greater risk for congenital malformations and infectious diseases as well as cardiovascular and respiratory conditions (aOR range: 1.30–2.61; 95% CI range: 1.02–4.59). Compared with infants born to subfertile mothers, infants born to ART-treated mothers were at lower risk for being small for GA and having congenital malformations and cardiovascular conditions and at higher risk for infectious disease conditions. CONCLUSIONS: Compared with infants born to fertile mothers, infants of subfertile and ART-treated mothers are at greater risk for adverse health outcomes at birth beyond prematurity. The occurrence and magnitude of these risks vary by GA and organ systems.

PURPOSE: To determine whether differences in birth outcomes among assisted reproductive technology (ART)-treated, subfertile, and fertile women exist in primiparous women with, singleton, vaginal deliveries. METHODS: Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) data were linked to Massachusetts vital records and hospital discharges for deliveries between July 2004 and December 2010. Primiparous women with in-state vaginal deliveries, adequate prenatal care, and singleton birth at ≥ 20 weeks (n = 117,779) were classified as ART-treated (linked to ART data from SART CORS, n = 3138); subfertile (not ART-treated but with indicators of subfertility, n = 1507); or fertile (neither ART-treated nor subfertile, n = 113,134). Outcomes of prematurity ( 3 days) were compared using multivariable logistic regression. RESULTS: Compared to fertile, higher odds were found for prematurity among ART-treated (adjusted odds ratio [AOR] 1.40, 95% confidence interval [CI] 1.25–1.50) and subfertile (AOR 1.25, 95% CI 1.03–1.50) women, low birthweight among ART-treated (AOR 1.41, 95% CI 1.23–1.62) and subfertile (AOR 1.40, 95% CI 1.15–1.71) women, perinatal death among subfertile (AOR 2.64, 95% CI 1.72–4.05), and prolonged LOS among ART-treated (AOR 1.33, 95% CI 1.19–1.48) women. Differences remained despite stratification by young age and absence of pregnancy/delivery complications. CONCLUSIONS: Greater odds of prematurity and low birthweight in ART-treated and subfertile, and perinatal death in subfertile deliveries are evident among singleton vaginal deliveries. The data suggest that even low-risk pregnancies to ART-treated and subfertile women be managed for adverse outcomes.

Angiotensin II (AngII) is a pivotal peptide implicated in the regulation of blood pressure. In addition to its systemic vascular and renal effects, AngII acts centrally to modulate the activities of neuroendocrine and sympathetic neuronal networks, influencing in turn sympatho-humoral outflows to the circulation. Moreover, a large body of evidence supports AngII signalling dysregulation as a key mechanism contributing to exacerbated sympathoexcitation during hypertension. Due to its hydrophilic actions, circulating AngII does not cross the blood-brain barrier (BBB), signalling to the brain via the circumventricular organs which lack a tight BBB. In this review, we present and discuss recent studies from our laboratory showing that elevated circulating levels of AngII during hypertension result in disruption of the BBB integrity, allowing access of circulating AngII to critical sympathoexcitatory brain centres such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. We propose the novel hypothesis that AngII-driven BBB breakdown constitutes a complementary mechanism by which circulating AngII, working in tandem with the central renin-angiotensin system, further exacerbates sympatho-humoral activation during hypertension. These results are discussed within the context of a growing body of evidence in the literature supporting AngII as a pro-inflammatory signal, and brain microglia as key cell targets mediating central AngII actions during hypertension.

A persistent finding is that assisted reproductive technology (ART) is associated with compromised birth outcomes, including higher risks for prematurity, low birthweight, and congenital malformations, even among singletons. Over the past decade, our research group, the Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART), has evaluated pregnancy and birth outcomes among three groups of women, those women treated with ART, those with indicators of subfertility but without ART treatment, and fertile women. We have also explored the influence of infertility-related diagnoses on outcomes for women and infants. Over the course of our research, we have changed our perspective from an original focus on ART treatment parameters as the primary cause of excess morbidity to one centered instead on the underlying infertility-related diagnoses. This paper summarizes the research findings from our group that support this change in focus for infertility-based research from a primary emphasis on ART treatment to greater attention to the contribution of preexisting pathology underlying the infertility and suggests directions for future analyses.

STUDY QUESTION How do the assisted reproductive technology (ART) outcomes of women presenting for ART after cancer diagnosis compare to women without cancer? SUMMARY ANSWER The likelihood of a live birth after ART among women with prior cancer using autologous oocytes is reduced and varies by cancer diagnosis but is similar to women without cancer when donor oocytes are used. WHAT IS KNOWN ALREADY Premenopausal patients faced with a cancer diagnosis frequently present for fertility preservation. STUDY DESIGN, SIZE, DURATION Population-based cohort study of women treated with ART in NY, TX and IL, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with their first ART treatment between 2004 and 2009 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database and linked to their respective State Cancer Registries based on name, date of birth and social security number. Years were rounded, i.e. year 1 = 6-18 months before treatment. This study used reports of cancer from 5 years, 6 months prior to treatment until 6 months after first ART treatment. Women who only presented for embryo banking were omitted from the analysis. The likelihood of pregnancy and of live birth with ART using autologous oocytes was modeled using logistic regression, with women without prior cancer as the reference group, adjusted for woman's age, parity, cumulative FSH dosage, infertility diagnosis, number of diagnoses, number of ART cycles, State of residency and year of ART treatment. Results of the modeling are reported as adjusted odds ratios (AORs) and (95% confidence intervals). MAIN RESULTS AND THE ROLE OF CHANCE The study population included 53 426 women; 441 women were diagnosed with cancer within 5 years prior to ART cycle start. Mean (±SD) age at cancer diagnosis was 33.4 ± 5.7 years; age at start of ART treatment was 34.9 ± 5.8 for women with cancer compared with 35.3 ± 5.3 years for women without cancer (P = 0.03). Live birth rates among women using autologous oocytes differed substantially by cancer status (47.7% without cancer versus 24.7% with cancer, P < 0.0001), and cancer diagnosis (ranging from 53.5% for melanoma to 14.3% for breast cancer, P < 0.0001. The live birth rates among women using donor oocytes did not vary significantly by cancer status (60.4% for women with any cancer versus 64.5% for women without cancer), or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer). Women with breast cancer make up about one-third of all cancers in this cohort. Among women with breast cancer, 2.8% of the 106 women who underwent ART within 6 months of being diagnosed with cancer used donor oocytes compared with 34.8% of the 46 women who received ART treatment a longer time after being diagnosed with cancer (P < 0.0001). We conjecture that the former group were either unaware that they had cancer or decided to undergo ART therapy prior to cancer treatment. However, their live birth rate was only 11.7% compared with 28.8%, the overall live birth rate for all women with cancer using autologous oocytes (P < 0.0001). The live birth rate for women diagnosed with breast cancer more than 6 months before ART (23.3%) did not differ significantly from the overall live birth rate for cancer (P = 0.49). If this difference is substantiated by a larger study, it would indicate a negative effect of severe recent illness itself on ART success, rather than the poor outcome being only related to the destructive effects of chemotherapies on ovarian follicles. Alternatively, because of the short time difference between cancer diagnosis and ART treatment, these pre-existing cancers may have been detected due to the increased medical surveillance during ART therapy. In women who only used autologous oocytes, women with prior cancers were significantly less likely to become pregnant and to have a live birth than those without cancer (adjusted odds ratio (AOR): 0.34, [95% confidence interval (CI): 0.27, 0.42] and 0.36 [0.28, 0.46], respectively). This was also evident with specific cancer diagnoses: breast cancer (0.20 [0.13, 0.32] and 0.19 [0.11, 0.30], respectively), cervical cancer (0.36 [0.15, 0.87] and 0.33 [0.13, 0.84], respectively) and all female genital cancers (0.49 [0.27, 0.87] and 0.47 [0.25, 0.86], respectively). Of note, among women with cancer who became pregnant, their likelihood of having a live birth did not differ significantly from women without cancer (85.8 versus 86.7% for women using autologous oocytes, and 85.3 versus 86.9% for women using donor oocytes). LIMITATIONS, REASONS FOR CAUTION Women may not have been residents of the individual States for the entire 5-year pre-ART period, and therefore some cancers may not have been identified through this linkage. As a result, the actual observed number of cancers may be an underestimate. In addition, the overall prevalence is low due to the age distributions. Also, because we restricted the pre-ART period to 5 years prior, we would not have identified women who were survivors of early childhood cancers (younger than age 13 years at cancer diagnosis), or who had ART more than 5 years after being diagnosed with cancer. Additional analyses are currently underway evaluating live birth outcomes after embryo banking among women with cancer prior to ART, cycles which were excluded from the analyses in this paper. Future studies are planned which will include more States, as well as linkages to vital records to obtain information on spontaneous conceptions and births, to further clarify some of the issues raised in this analysis. WIDER IMPLICATIONS OF THE FINDINGS Since the live birth rates using donor oocytes were not reduced in women with a prior cancer, but were reduced with autologous cycles, this suggests that factors acting in the pre- or peri-conceptional periods may be responsible for the decline. STUDY FUNDING/COMPETING INTERESTS The study was funded by grant R01 CA151973 from the National Cancer Institute, National Institutes of Health, USA. B.L. is a research consultant for the Society for Assisted Reproductive Technology. All other authors report no conflict of interest.