Daksha Gopal

Perinatal outcomes associated with assisted reproductive technology: the Massachusetts Outcomes Study of Assisted Reproductive Technologies (MOSART)

OBJECTIVE To compare on a population basis the birth outcomes of women treated with assisted reproductive technologies (ART), women with indicators of subfertility but without ART, and fertile women. DESIGN Longitudinal cohort study. SETTING Not applicable. PARTICIPANT(S) A total of 334,628 births and fetal deaths to Massachusetts mothers giving birth in a Massachusetts hospital from July 1, 2004, to December 31, 2008, subdivided into three subgroups for comparison: ART 11,271, subfertile 6,609, and fertile 316,748. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Four outcomes-preterm birth, low birth weight, small for gestational age, and perinatal death-were modeled separately for singletons and twins with the use of logistic regression for the primary comparison between ART births and those to the newly created population-based subgroup of births to women with indicators of subfertility but no ART. RESULT(S) For singletons, the risks for both preterm birth and low birth weight were higher for the ART group (adjusted odds ratios [AORs] 1.23 and 1.26, respectively) compared with the subfertile group, and risks in both the ART and the subfertile groups were higher than those among the fertile births group. For twins, the risk of perinatal death was significantly lower among ART births than fertile (AOR 0.55) or subfertile (AOR 0.15) births. CONCLUSION(S) The use of a population-based comparison group of subfertile births without ART demonstrated significantly higher rates of preterm birth and low birth weight in ART singleton births, but these differences are smaller than differences between ART and fertile births. Further refinement of the measurement of subfertile births and examination of the independent risks of subfertile births is warranted.

Adverse pregnancy and birth outcomes associated with underlying diagnosis with and without assisted reproductive technology treatment

OBJECTIVE To compare the risks for adverse pregnancy and birth outcomes by diagnoses with and without assisted reproductive technology (ART) treatment to non-ART pregnancies in fertile women. DESIGN Historical cohort of Massachusetts vital records linked to ART clinic data from Society for Assisted Reproductive Technology Clinic Outcome Reporting System. SETTING Not applicable. PATIENT(S) Diagnoses included male factor (ART only), endometriosis, ovulation disorders, tubal (ART only), and reproductive inflammatory disorders (non-ART only). Pregnancies resulting in singleton and twin live births from 2004 to 2008 were linked to hospital discharges in women who had ART treatment (n = 3,689), women with no ART treatment in the current pregnancy (n = 4,098), and non-ART pregnancies in fertile women (n = 297,987). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Risks of gestational diabetes, prenatal hospitalizations, prematurity, low birth weight, and small for gestational age were modeled using multivariate logistic regression with fertile deliveries as the reference group adjusted for maternal age, race/ethnicity, education, chronic hypertension, diabetes mellitus, and plurality (adjusted odds ratios [AORs] and 95% confidence intervals [CIs]). RESULT(S) Risk of prenatal hospital admissions was increased for endometriosis (ART: 1.97, 1.38-2.80; non-ART: 3.34, 2.59-4.31), ovulation disorders (ART: 2.31, 1.81-2.96; non-ART: 2.56, 2.05-3.21), tubal factor (ART: 1.51, 1.14-2.01), and reproductive inflammation (non-ART: 2.79, 2.47-3.15). Gestational diabetes was increased for women with ovulation disorders (ART: 2.17, 1.72-2.73; non-ART: 1.94, 1.52-2.48). Preterm delivery (AORs, 1.24-1.93) and low birth weight (AORs, 1.27-1.60) were increased in all groups except in endometriosis with ART. CONCLUSION(S) The findings indicate substantial excess perinatal morbidities associated with underlying infertility-related diagnoses in both ART-treated and non-ART-treated women.

Identifying women with indicators of subfertility in a statewide population database: operationalizing the missing link in assisted reproductive technology research

OBJECTIVE To identify a group of deliveries to mothers with indicators of subfertility (SUBFERTILITY). DESIGN Longitudinal cohort study. SETTING Hospital. PATIENT(S) A total of 334,152 deliveries to Massachusetts mothers in a Massachusetts hospital between July 1, 2004, and December 31, 2008. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Subfertility was defined by an indication on a current or past birth certificate or hospital utilization data of infertility or assisted reproductive technology (ART) cycle before index delivery and no indication of ART use with index delivery. RESULT(S) Initially, 12,367 deliveries met the inclusion criteria for SUBFERTILITY (8,019 from birth certificates, 2,777 from hospital data, 1,571 from prior ART treatment). Removing deliveries from more than one data source resulted in 10,764 unique deliveries. Removing deliveries resulting from ART treatments left 6,238 deliveries in the SUBFERTILITY category. Demographic analysis indicated that deliveries in SUBFERTILITY were more similar to those in the ART population than to those in the fertile population. CONCLUSION(S) We have demonstrated the feasibility of using existing population-based linked public health data sets to identify SUBFERTILITY deliveries, and we have used ART data to distinguish ART and SUBFERTILITY births. The SUBFERTILITY category can serve as a comparison group of subfertile patients for studies of ART delivery and longitudinal health outcomes.

Severe Maternal Morbidity and the Use of Assisted Reproductive Technology in Massachusetts.

OBJECTIVE: To assess whether risk of severe maternal morbidity at delivery differed for women who conceived using assisted reproductive technology (ART), those with indicators of subfertility but no ART (“subfertile”), and those who had neither ART nor subfertility (“fertile”). METHODS: This retrospective cohort study was part of the larger Massachusetts Outcomes Study of Assisted Reproductive Technology. To construct the Massachusetts Outcomes Study of Assisted Reproductive Technology database and identify ART deliveries, we linked ART treatment records to birth certificates and maternal and infant hospitalization records occurring in Massachusetts between 2004 and 2010. An algorithm of International Classification of Diseases, 9th Revision, Clinical Modification diagnosis and procedure codes identified severe maternal morbidity. We used logistic generalized estimating equations to estimate odds of severe maternal morbidity associated with fertility status, adjusting for maternal demographic and health factors and gestational age, stratifying on plurality and method of delivery. RESULTS: The prevalence of severe maternal morbidity among this population (n=458,918) was 1.16%. The overall, crude prevalences of severe maternal morbidity among fertile, subfertile, and ART deliveries were 1.09%, 1.44%, and 3.14%, respectively. The most common indicator of severe maternal morbidity was blood transfusion. In multivariable analyses, among singletons, ART was associated with increased odds of severe maternal morbidity compared with both fertile (vaginal: adjusted odds ratio [OR] 2.27, 95% confidence interval [CI] 1.78–2.88; cesarean: adjusted OR 1.67, 95% CI 1.40–1.98, respectively) and subfertile (vaginal: adjusted OR 1.97, 95% CI 1.30–3.00; cesarean: adjusted OR 1.75, 95% CI 1.30–2.35, respectively) deliveries. Among twins, only cesarean ART deliveries had significantly greater severe maternal morbidity compared with cesarean fertile deliveries (adjusted OR 1.48, 95% CI 1.14–1.93). CONCLUSION: Women who conceive through ART may have elevated risk of severe maternal morbidity at delivery, largely indicated by blood transfusion, even when compared with a subfertile population. Further research should elucidate mechanisms underlying this risk.

Adverse pregnancy, birth, and infant outcomes in twins: effects of maternal fertility status and infant gender combinations; the Massachusetts Outcomes Study of Assisted Reproductive Technology

Background It is unknown whether the risk of adverse outcomes in twin pregnancies among subfertile women, conceived with and without in vitro fertilization, differs from those conceived spontaneously. Objective We sought to evaluate the effects of fertility status on adverse perinatal outcomes in twin pregnancies on a population basis. Study Design All twin live births of ≥22 weeks’ gestation and ≥350 g birthweight to Massachusetts resident women in 2004 through 2010 were linked to hospital discharge records, vital records, and in vitro fertilization cycles. Women were categorized by their fertility status as in vitro fertilization, subfertile, or fertile, and by twin pair genders (all, like, unlike). Women whose births linked to in vitro fertilization cycles were classified as in vitro fertilization; those with indicators of subfertility but without in vitro fertilization treatment were classified as subfertile; all others were classified as fertile. Risks of 6 adverse pregnancy outcomes (gestational diabetes, pregnancy hypertension, uterine bleeding, placental complications [placenta abruptio, placenta previa, and vasa previa], prenatal hospitalizations, and primary cesarean) and 9 adverse infant outcomes (very low birthweight, low birthweight, small‐for‐gestation birthweight, large‐for‐gestation birthweight, very preterm [<32 weeks], preterm, birth defects, neonatal death, and infant death) were modeled by fertility status with the fertile group as reference, using multivariate log binomial regression and reported as adjusted relative risk ratios and 95% confidence intervals. Results The study population included 10,352 women with twin pregnancies (6090 fertile, 724 subfertile, and 3538 in vitro fertilization). Among all twins, the risks for all 6 adverse pregnancy outcomes were significantly increased for the subfertile and in vitro fertilization groups, with highest risks for uterine bleeding (adjusted relative risk ratios, 1.92 and 2.58, respectively) and placental complications (adjusted relative risk ratios, 2.07 and 1.83, respectively). Among all twins, the risks for those born to subfertile women were significantly increased for very preterm birth and neonatal and infant death (adjusted relative risk ratios, 1.36, 1.89, and 1.87, respectively). Risks were significantly increased among in vitro fertilization twins for very preterm birth, preterm birth, and birth defects (adjusted relative risk ratios, 1.28, 1.07, and 1.26, respectively). Conclusion Risks of all maternal and most infant adverse outcomes were increased for subfertile and in vitro fertilization twins. Among all twins, the highest risks were for uterine bleeding and placental complications for the subfertile and in vitro fertilization groups, and neonatal and infant death in the subfertile group. These findings provide further evidence supporting single embryo transfer and more cautious use of ovulation induction.

Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology

Background Births to subfertile women, with and without infertility treatment, have been reported to have lower birthweights and shorter gestations, even when limited to singletons. It is unknown whether these decrements are due to parental characteristics or aspects of infertility treatment. Objective The objective of the study was to evaluate the effect of maternal fertility status on the risk of pregnancy, birth, and infant complications. Study Design All singleton live births of ≥22 weeks’ gestation and ≥350 g birthweight to Massachusetts resident women in 2004–2010 were linked to hospital discharge and vital records. Women were categorized by their fertility status as in vitro fertilization, subfertile, or fertile. Women whose births linked to in vitro fertilization cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System were classified as in vitro fertilization. Women with indicators of subfertility but not treated with in vitro fertilization were classified as subfertile. Women without indicators of subfertility or in vitro fertilization treatment were classified as fertile. Risks of 15 adverse outcomes (gestational diabetes, pregnancy hypertension, antenatal bleeding, placental complications [placenta abruptio and placenta previa], prenatal hospitalizations, primary cesarean delivery, very low birthweight [<1500 g], low birthweight [<2500 g], small‐for‐gestation birthweight [z‐score ≤–1.28], large‐for‐gestation birthweight [z‐score ≥1.28], very preterm [<32 weeks], preterm [<37 weeks], birth defects, neonatal death [0–27 days], and infant death [0–364 days of life]) were modeled by fertility status with the fertile group as reference and the subfertile group as reference, using multivariate log binomial regression and reported as adjusted risk ratios and 95% confidence intervals. Results The study population included 459,623 women (441,420 fertile, 8054 subfertile, and 10,149 in vitro fertilization). Women in the subfertile and in vitro fertilization groups were older than their fertile counterparts. Risks for 6 of 6 pregnancy outcomes and 6 of 9 infant outcomes were increased for the subfertile group, and 5 of 6 pregnancy outcomes and 7 of 9 infant outcomes were increased for the in vitro fertilization group. For 4 of the 6 pregnancy outcomes (uterine bleeding, placental complications, prenatal hospitalizations, and primary cesarean) and 2 of the infant outcomes (low birthweight and preterm) the risk was greater in the in vitro fertilization group, with nonoverlapping confidence intervals to the subfertile group, indicating a substantially higher risk among in vitro fertilization–treated women. The highest risks for the in vitro fertilization women were uterine bleeding (adjusted risk ratio, 3.80; 95% confidence interval, 3.31–4.36) and placental complications (adjusted risk ratio, 2.81; 95% confidence interval, 2.57–3.08), and for in vitro fertilization infants, very preterm birth (adjusted risk ratio, 2.13; 95% confidence interval, 1.80–2.52), and very low birthweight (adjusted risk ratio, 2.15; 95% confidence interval, 1.80–2.56). With subfertile women as reference, risks for the in vitro fertilization group were significantly increased for uterine bleeding, placental complications, prenatal hospitalizations, primary cesarean delivery, low and very low birthweight, and preterm and very preterm birth. Conclusion These analyses indicate that, compared with fertile women, subfertile and in vitro fertilization–treated women tend to be older, have more preexisting chronic conditions, and are at higher risk for adverse pregnancy outcomes, particularly uterine bleeding and placental complications. The greater risk in in vitro fertilization–treated women may reflect more severe infertility, more extensive underlying pathology, or other unfavorable factors not measured in this study.

Assisted Reproductive Technology and Early Intervention Program Enrollment.

OBJECTIVES: We examined the prevalence of Early Intervention (EI) enrollment in Massachusetts comparing singleton children conceived via assisted reproductive technology (ART), children born to mothers with indicators of subfertility but no ART (Subfertile), and children born to mothers who had no indicators of subfertility and conceived naturally (Fertile). We assessed the natural direct effect (NDE), the natural indirect effect (NIE) through preterm birth, and the total effect of ART and subfertility on EI enrollment. METHODS: We examined maternal and infant characteristics among singleton ART (n = 6447), Subfertile (n = 5515), and Fertile (n = 306 343) groups and characteristics associated with EI enrollment includingpreterm birth using χ2 statistics (α = 0.05). We estimated the NDE and NIE of the ART–EI enrollment relationship by fitting a model for enrollment, conditional on ART, preterm and the ART-preterm delivery interaction, and covariates. Similar analyses were conducted by using Subfertile as the exposure. RESULTS: The NDE indicated that the odds of EI enrollment were 27% higher among the ART group (odds ratioNDE = 1.27; 95% confidence interval (CI): 1.19 ̶ 1.36) and 20% higher among the Subfertilegroup (odds ratioNDE = 1.20; 95% CI: 1.12 ̶ 1.29) compared with the Fertile group, even if the rate of preterm birth is held constant. CONCLUSIONS: Singleton children conceived through ART and children of subfertile mothers both have elevated risks of EI enrollment. These findings have implications for clinical providers as they counsel women about child health outcomes associated with ART or subfertility.

Health of Infants After ART-Treated, Subfertile, and Fertile Deliveries

With this population-based study, we assessed health outcomes of infants born to fertile, subfertile, and ART-treated mothers in Massachusetts. 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.

Length of stay and cost of birth hospitalization: effects of subfertility and ART

ObjectiveThe objective of this study is to measure delivery length of stay (LOS) and cost as proxies for infant morbidity in assisted reproductive technology (ART) and subfertile deliveries.Study DesignMassachusetts 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 SE were calculated.ResultsOf 345,756 singletons (fertile n = 332,481, subfertile n = 4987, and ART-treated n = 8288), overall LOS was 3.79 ± 0.01, 4.32 ± 0.15, and 4.90 ± 0.04 days, and costs were

Adverse pregnancy outcomes after in vitro fertilization: effect of number of embryos transferred and plurality at conception

2980 ± 6,