A risk factor profile for placenta accreta spectrum in pregnancies conceived with assisted reproductive technology.

Objective: To identify independent risk factors for placenta accreta spectrum among pregnancies conceived with assisted reproductive technology. Design: Retrospective cohort study. Setting: Tertiary hospital. Patients: Individuals who conceived with assisted reproductive technology and reached 20 weeks' gestation or later from 2011 to 2017. Interventions: Patient and cycle data was abstracted from hospital records and supplemented with state-level data. Poisson regression was used for multivariate analyses and reported as adjusted relative risks (aRR). Main Outcome Measures: Clinical or histologic placenta accreta spectrum. Results: Of 1,975 qualifying pregnancies, 44 (2.3%) met criteria for accreta spectrum at delivery. In the multivariate model, significant risk factors included low-lying placenta at delivery (aRR, 15.44; 95% CI 7.76-30.72), uterine factor infertility or prior uterine surgery (aRR, 4.68; 95% CI, 2.72-8.05), initial low-lying placentation that resolved (aRR, 3.83; 95% CI, 1.90-7.73), and use of frozen embryos (aRR, 3.02; 95% CI, 1.66-5.48). When the fresh vs frozen variable was replaced with controlled ovarian hyperstimulation, the final model did not change (aRR, 2.40 for unstimulated cycles, 95% CI, 1.32-4.38). With frozen transfers, the accreta rate was 16% when the endometrial thickness was < 6mm vs 3.8% with thicker endometrium (P=.02). Conclusions: Among pregnancies conceived with assisted reproductive technology, accreta spectrum is associated with low placental implantation (even when resolved), uterine factor infertility and prior uterine surgery, and the use of frozen embryo transfer or unstimulated cycles.

Electronic Monitoring of Mom's Schedule (eMOMSTM): A Qualitative Study of Experiences in a Lifestyle Change Program with Lactation Support.

PURPOSE: To elicit feedback from participants who completed the eMOMSTM study, a feasibility randomized controlled trial (NCT04021602), on their perceptions of program strengths and weaknesses. STUDY DESIGN: Qualitative - Semi-structured, telephone interview guide using open-ended questions. SETTING: Rural Great Plains state, United States. PARTICIPANTS: Of 26 individuals who completed the eMOMSTM study, 24 consented to an interview. METHOD: Interviews were completed between October 2020 and May 2021. Audio-recordings were transcribed verbatim and organized in Microsoft 365. Data were analyzed using an exploratory, inductive thematic analysis. RESULTS: Participants' mean age was 27.5 (± 5.4) years and mean pre-pregnancy BMI was 29.5 kg/m2 (± 2.7). The majority (71%) were non-Hispanic White and 54% had a high school education/some college. Based on specific areas of inquiry, the following themes emerged: convenience of online program access using Facebook, importance of health coach's support and online interaction, positivity toward improving one's health, increased consciousness of health behaviors, diverse lactation educational needs, importance of educational materials on depression, and grief over the loss of birth expectations during COVID-19. CONCLUSION: Findings suggest participants' perceived value of a lifestyle change program coupled with lactation education and support delivered using social media. Findings inform future studies to further adapt lifestyle change programs.

Examining attention-deficit/hyperactivity disorder and related behavioral disorders by fertility treatment exposure in a prospective cohort.

PURPOSE: To evaluate whether underlying infertility and mode of conception are associated with childhood behavioral disorders. METHODS: Oversampling on fertility treatment exposure using vital records, the Upstate KIDS Study followed 2057 children (of 1754 mothers) from birth to 11 years. Type of fertility treatment and time to pregnancy (TTP) were self-reported. Mothers completed annual questionnaires reporting symptomology, diagnoses, and medications at 7-11 years of age. The information identified children with probable attention-deficit/hyperactivity disorder, anxiety or depression, and conduct or oppositional defiant disorders. We estimated adjusted relative risks (aRR) for disorders by underlying infertility (TTP > 12 months) or treatment exposure groups compared to children born to parents with TTP ≤ 12 months. RESULTS: Children conceived with fertility treatment (34%) did not have an increased risk of attention-deficit/hyperactivity disorder (aRR): 1.21; 95% CI: 0.88, 1.65), or conduct or oppositional defiant disorders (aRR: 1.31; 0.91, 1.86), but did have an increased risk of anxiety or depression (aRR: 1.63; 1.18, 2.24), which remained elevated even after adjusting for parental mood disorders (aRR: 1.40; 0.99, 1.96). Underlying infertility without the use of treatment was also associated with a risk of anxiety or depression (aRR: 1.82; 95% CI: 0.96, 3.43). CONCLUSIONS: Underlying infertility or its treatment was not associated with risk of attention-deficit/hyperactivity disorder. Observations of increased anxiety or depression require replication.

Assisted Reproductive Technology or Infertility: What underlies adverse outcomes? Lessons from the Massachusetts Outcome Study of Assisted Reproductive Technology.

Numerous studies have demonstrated that assisted reproductive technology (ART: defined here as including only in vitro fertilization and related technologies) is associated with increased adverse pregnancy, neonatal, and childhood developmental outcomes, even in singletons. The comparison group for many had often been a fertile population that conceived without assistance. The Massachusetts Outcome Study of Assisted Reproductive Technology (MOSART) was initiated to define a subfertile population with which to compare ART outcomes. Over more than 10 years, we have used the MOSART database to study pregnancy abnormalities and delivery complications but also to evaluate ongoing health of women, infants, and children. This article will review studies from MOSART in the context of how they compare with those of other investigations. We will present MOSART studies that identified the influence of ART and subfertility/infertility on adverse pregnancy (pregnancy hypertensive disorder, gestational diabetes, placental abnormality) and delivery (preterm birth, low birthweight) outcomes as well as on maternal and child hospitalizations. We will provide evidence that although subfertility/infertility increases the risk of adverse outcomes, there is additional risk associated with the use of ART. Studies exploring the contribution of placental abnormalities as one factor adding to this increased ART-associated risk will be described.

A unique placenta previa risk factor profile for pregnancies conceived with assisted reproductive technology.

OBJECTIVE: To define specific risk factors for placenta previa in pregnancies conceived with assisted reproductive technology (ART). DESIGN: Retrospective cohort. SETTING: Fertility centers and inpatient obstetric units in Massachusetts. PATIENT(S): Patients conceiving with ART and delivering at 20 weeks gestation or later between 2011 and 2017 in Massachusetts. INTERVENTION(S): 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. MAIN OUTCOME MEASURE: 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). RESULT(S): 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. CONCLUSION(S): 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.

Polycystic ovary syndrome and risk of adverse pregnancy outcomes: a registry linkage study from Massachusetts.

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 (<30, ≥30, <25 and ≥25 kg/m2) and between non-infertile deliveries and deliveries that used ART or had a history of subfertility (defined by birth certificates, SART CORS records, APCD or hospital records). 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 <30 kg/m2. 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.

Conception by fertility treatment and cardiometabolic risk in middle childhood.

OBJECTIVE: To evaluate whether children conceived using assisted reproductive technology (ART) or ovulation induction (OI) have greater cardiometabolic risk than children conceived without treatment. DESIGN: Clinical assessments in 2018-2019 in the Upstate KIDS cohort. SETTING: Clinical sites in New York. PATIENT(S): Three hundred thirty-three singletons and 226 twins from 448 families. INTERVENTION(S): 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. MAIN OUTCOME MEASURE(S): 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. RESULT(S): 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. CONCLUSION(S): 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. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov #NCT03106493.

The impact of single-step and sequential embryo culture systems on obstetric and perinatal outcomes in singleton pregnancies: the Massachusetts Outcomes Study of Assisted Reproductive Technology.

OBJECTIVE: To compare the obstetric and perinatal outcomes of deliveries conceived with embryos from single-step vs. sequential culture media systems. DESIGN: 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. SETTING: Not applicable. PATIENTS: 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. INTERVENTIONS: None. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: Single-step culture is associated with increased odds of LGA, indicating that embryo culture media systems may affect perinatal outcomes.

Assisted reproductive technology treatment increases obstetric and neonatal risks over that of the underlying infertility diagnosis.

OBJECTIVE: To determine whether assisted reproductive technology (ART) treatment adds obstetric and neonatal risks over and above that of underlying infertility-related diagnoses. DESIGN: Retrospective study of linked ART, birth certificate, hospital discharge data, and outpatient insurance claims data in Massachusetts (2013-2017). SETTING: Database. PATIENT(S): 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. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): 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). RESULT(S): 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. CONCLUSION(S): 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.

Protecting life in a time of war.

Despite centuries of lessons from history, war endures. Across Earth, during nearly every year from the beginning of the twentieth century to present day, over 30 wars have been fought resulting in 187 million casualties, excluding the most recent conflict, which is the impetus for this essay (Timeline of 20th and 21st century wars). We are, sadly, a war-mongering people. The word "war" word infiltrates our vernacular, e.g., the war on poverty, on drugs, on cancer, on COVID, and, apropos, on terror. How did rational approaches to disagreement and conflict evade the world's progress? Reproductive physicians and scientists are dedicated to safeguard lives and build families. Violence is antithetical to our mission as professionals, and moral integrity as humans. We are deeply concerned for, and stand in unity with, our Ukrainian colleagues-the embryologists, scientists, OBGYN and REI physicians, infertility patients, and all people under siege. Reproductive health services for Ukrainians (as with many other war-torn regions) have collapsed. Deeply disturbing reports have emerged that cite civilian hospitals (including maternity centers) being targeted. Liquid nitrogen supplies are scarce. Pregnant mothers and gestational carriers are at emergent risk of delivering in extremely harsh conditions, cold underground bunkers and refugee queues.

Pregnancy outcomes among women with endometriosis and fibroids: registry linkage study in Massachusetts.

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: Endometriosis or fibroids increased the risk for adverse pregnancy outcomes, possibly warranting differential screening or treatment.

History of cancer and fertility treatment outcomes: a registry linkage study in Massachusetts.

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.

Hospitalizations up to 8 years following delivery in assisted reproductive technology-treated and subfertile women.

OBJECTIVE: To investigate hospitalizations up to 8 years after live birth among women who used assisted reproductive technology (ART) or who were subfertile compared with women who conceived naturally. DESIGN: Retrospective cohort. SETTING: Deliveries among privately insured women aged ≥18 years between 2004 and 2017 from Massachusetts state vital records were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System and hospital observational/inpatient stays. PATIENT(S): We compared patients with ART, medically assisted reproduction (MAR), and unassisted subfertile (USF) delivery with those with fertile delivery. INTERVENTION(S): NA. MAIN OUTCOME MEASURE(S): Postdelivery hospitalization information was derived from the International Classification of Diseases codes for discharges and combined by type. The relative risks and 95% confidence intervals (CIs) of hospitalization for up to the first 8 years postdelivery were modeled. RESULT(S): Among 492,515 deliveries, 5.6% used ART, 1.6% used MAR, and 1.8% were USF. Compared with fertile deliveries, deliveries that used ART or MAR or were USF were more likely to have hospital utilization (inpatient or observational stay) for any reason for up to 8 years of follow-up (USF, adjusted relative risk [aRR], 1.18 [95% CI, 1.12-1.25]; MAR, aRR, 1.20 [1.13-1.27]; and ART, aRR, 1.29 [1.25-1.34]). Assisted reproductive technology deliveries had an increased risk of hospitalization for conditions of the cardiovascular system (aRR, 1.31 [95% CI, 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 MAR and subfertility had similar patterns of hospitalization as ART deliveries. CONCLUSION(S): Women who conceived through fertility treatment or experienced subfertility were at increased risk of subsequent hospitalization resulting from a variety of chronic and acute conditions.

Influence of Placental Abnormalities and Pregnancy-Induced Hypertension in Prematurity Associated with Various Assisted Reproductive Technology Techniques.

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: <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 (<10% LPTB and <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.

Embryo biopsy and maternal and neonatal outcomes following cryopreserved-thawed single embryo transfer.

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.

Conception by fertility treatment and offspring deoxyribonucleic acid methylation.

OBJECTIVE: 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. DESIGN: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment. SETTING: New York State (excluding New York City). PATIENT(S): This analysis included 855 newborns and 152 children at approximately 9 years of age. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted. RESULT(S): 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. CONCLUSION(S): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.

Association of maternal fertility status and receipt of fertility treatment with healthcare utilization in infants up to age four.

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.

Optimizing the control group for evaluating ART outcomes: can outpatient claims data yield a better control group?

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.

Early-life cancer, infertility, and risk of adverse pregnancy outcomes: a registry linkage study in Massachusetts.

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 a history of cancer experienced a 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.