Aniket Kulkarni

Fertility Treatments and Multiple Births in the United States

BACKGROUND The advent of fertility treatments has led to an increase in the rate of multiple births in the United States. However, the trends in and magnitude of the contribution of fertility treatments to the increase are uncertain. METHODS We derived the rates of multiple births after natural conception from data on distributions of all births from 1962 through 1966 (before fertility treatments were available). Publicly available data on births from 1971 through 2011 were used to determine national multiple birth rates, and data on in vitro fertilization (IVF) from 1997 through 2011 were used to estimate the annual proportion of multiple births that were attributable to IVF and to non-IVF fertility treatments, after adjustment for maternal age. Trends in multiple births were examined starting from 1998, the year when clinical practice guidelines for IVF were developed with an aim toward reducing the incidence of multiple births. RESULTS We estimated that by 2011, a total of 36% of twin births and 77% of triplet and higher-order births resulted from conception assisted by fertility treatments. The observed incidence of twin births increased by a factor of 1.9 from 1971 to 2009. The incidence of triplet and higher-order births increased by a factor of 6.7 from 1971 to 1998 and decreased by 29% from 1998 to 2011. This decrease coincided with a 70% reduction in the transfer of three or more embryos during IVF (P<0.001) and a 33% decrease in the proportion of triplet and higher-order births attributable to IVF (P<0.001). CONCLUSIONS Over the past four decades, the increased use of fertility treatments in the United States has been associated with a substantial rise in the rate of multiple births. The rate of triplet and higher-order births has declined over the past decade in the context of a reduction in the transfer of three or more embryos during IVF. (Funded by the Centers for Disease Control and Prevention.).

Trends and Outcomes for Donor Oocyte Cycles in the United States, 2000-2010

IMPORTANCE The prevalence of oocyte donation for in vitro fertilization (IVF) has increased in the United States, but little information is available regarding maternal or infant outcomes to improve counseling and clinical decision making. OBJECTIVES To quantify trends in donor oocyte cycles in the United States and to determine predictors of a good perinatal outcome among IVF cycles using fresh (noncryopreserved) embryos derived from donor oocytes. DESIGN, SETTING, AND PARTICIPANTS Analysis of data from the Centers for Disease Control and Preventions National ART Surveillance System, to which fertility centers are mandated to report and which includes data on more than 95% of all IVF cycles performed in the United States. Data from 2000 to 2010 described trends. Data from 2010 determined predictors. MAIN OUTCOMES AND MEASURES Good perinatal outcome, defined as a singleton live-born infant delivered at 37 weeks or later and weighing 2500 g or more. RESULTS From 2000 to 2010, data from 443 clinics (93% of all US fertility centers) were included. The annual number of donor oocyte cycles significantly increased, from 10,801 to 18,306. Among all donor oocyte cycles, an increasing trend was observed from 2000 to 2010 in the proportion of cycles using frozen (vs fresh) embryos (26.7% [95% CI, 25.8%-27.5%] to 40.3% [95% CI, 39.6%-41.1%]) and elective single-embryo transfers (vs transfer of multiple embryos) (0.8% [95% CI, 0.7%-1.0%] to 14.5% [95% CI, 14.0%-15.1%]). Good perinatal outcomes increased from 18.5% (95% CI, 17.7%-19.3%) to 24.4% (95% CI, 23.8%-25.1%) (P < .001 for all listed trends). Mean donor and recipient ages remained stable at 28 (SD, 2.8) years and 41 (SD, 5.3) years, respectively. In 2010, 396 clinics contributed data. For donor oocyte cycles using fresh embryos (n = 9865), 27.5% (95% CI, 26.6%-28.4%) resulted in good perinatal outcome. Transfer of an embryo at day 5 (adjusted odds ratio [OR], 1.17 [95% CI, 1.04-1.32]) and elective single-embryo transfers (adjusted OR, 2.32 [95% CI, 1.92-2.80]) were positively associated with good perinatal outcome; tubal (adjusted OR, 0.72 [95% CI, 0.60-0.86]) or uterine (adjusted OR, 0.74 [95% CI, 0.58-0.94]) factor infertility and non-Hispanic black recipient race/ethnicity (adjusted OR, 0.48 [95% CI, 0.35-0.67]) were associated with decreased odds of good outcome. Recipient age was not associated with likelihood of good perinatal outcome. CONCLUSIONS AND RELEVANCE In the United States from 2000 to 2010, there was an increase in number of donor oocyte cycles, accompanied by an increase in good outcomes. Further studies are needed to understand the mechanisms underlying the factors associated with less successful outcomes.

Elective oophorectomy in the United States: Trends and in-hospital complications, 1998-2006

OBJECTIVES: To examine trends in rates of elective bilateral salpingo-oophorectomy in the United States and to assess the association of perioperative complications with elective bilateral salpingo-oophorectomy. METHODS: This cross-sectional study uses 1998–2006 data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, a nationally representative sample of inpatient hospitalizations. Analyses were limited to women aged 15 years or older at average risk for ovarian cancer who underwent hysterectomy for a benign gynecologic condition. Tests for trends in elective bilateral salpingo-oophorectomy rates were performed using weighted least squares regression for two time periods, 1998 to 2001 and 2002 to 2006. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for risks of complications associated with elective bilateral salpingo-oophorectomy were estimated using logistic regression. RESULTS: During the period from 1998 to 2006, 39% of the 2,250,041 women who underwent hysterectomy for benign gynecologic indications had elective bilateral salpingo-oophorectomy (rate, 8.3 per 10,000). The elective bilateral salpingo-oophorectomy rate increased from 7.8 per 10,000 in 1998 to 9.0 per 10,000 in 2001 (P trend <.05) and decreased from 9.0 per 10,000 in 2002 to 7.4 per 10,000 in 2006 (P trend <.05). The largest decline from 2002 to 2006 (20.3%) occurred among those aged 45 to 49 years. Compared with hysterectomy only, elective bilateral salpingo-oophorectomy was associated with an increased risk of complications when performed vaginally (OR 1.12; 95% CI 1.08–1.17) and a decreased risk of complications when performed abdominally (OR 0.91; 95% CI 0.89–0.94) or laparoscopically (OR 0.89; 95% CI 0.83–0.94). CONCLUSION: Elective bilateral salpingo-oophorectomy rates declined since 2002. However, the risks compared with the benefits of the procedure have not been clearly established. Prospective studies examining elective bilateral salpingo-oophorectomy with and without estrogen therapy are needed to guide practice patterns. LEVEL OF EVIDENCE: III

Embryo transfer practices and multiple births resulting from assisted reproductive technology: an opportunity for prevention

OBJECTIVE To evaluate assisted reproductive technology (ART) ET practices in the United States and assess the impact of these practices on multiple births, which pose health risks for both mothers and infants. DESIGN Retrospective cohort analysis using the National ART Surveillance System data. SETTING US fertility centers reporting to the National ART Surveillance System. PATIENT(S) Noncanceled ART cycles conducted in the United States in 2012. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Multiple birth (birth of two or more infants, at least one of whom was live-born). RESULT(S) Of 134,381 ART transfer cycles performed in 2012, 51,262 resulted in live births, of which 13,563 (26.5%) were multiple births: 13,123 twin and 440 triplet and higher order births. Almost half (46.1%) of these multiple births resulted from the following four cycle types: two fresh blastocyst transfers among favorable or average prognosis patients less than 35 years (1,931 and 1,341 multiple births, respectively), two fresh blastocyst transfers among donor-oocyte recipients (1,532 multiple births), and two frozen/thawed ETs among patients less than 35 years (1,452 multiple births). More than half of triplet or higher order births resulted from the transfer of two embryos (52.5% of births among fresh autologous transfers, 67.2% of births among donor-oocyte recipient transfers, and 42.9% among frozen/thawed autologous transfers). CONCLUSION(S) A substantial reduction of ART-related multiple (both twin and triplet or higher order) births in the United States could be achieved by single blastocyst transfers among favorable and average prognosis patients less than 35 years of age and donor-oocyte recipients.

Number of Embryos Transferred After In Vitro Fertilization and Good Perinatal Outcome

OBJECTIVE: To assess the association between number of embryos transferred and a measure of assisted reproductive technology success that emphasizes good perinatal outcome. METHODS: We analyzed assisted reproductive technology cycles initiated in 2011 that progressed to fresh embryo transfer among women using autologous oocytes and reported to the U.S. National Assisted Reproductive Technology Surveillance System (n=82,508). Percentages of good perinatal outcome (live birth of a term [at or after 37 weeks of gestation], normal birth weight [2,500 g or greater] singleton) were stratified by prognosis (favorable, average, less favorable), age, embryo stage (day 3, day 5), and number of embryos transferred. Differences in the percentages by number of embryos transferred were evaluated using Fisher’s exact test with Bonferroni correction. RESULTS: Among patients younger than 35 years with a favorable prognosis, chances of a good perinatal outcome were higher with transferring a single (compared with double) day 5 (43% compared with 27%) or day 3 embryo (36% compared with 30%). Likewise, a higher chance of a good perinatal outcome was observed with transferring a single day 5 embryo in patients 35–37 years old with a favorable prognosis (39% compared with 28%) or patients younger than 35 years old with an average prognosis (35% compared with 26%). A higher chance of good perinatal outcome was associated with transferring two (compared with one) day 3 embryos among patients aged 40 years or younger with an average prognosis or patients younger than 35 years old with a less favorable prognosis. CONCLUSION: The association between number of embryos transferred and the birth of a term, normal birth weight singleton is described. Among patients younger than 35 years of age undergoing in vitro fertilization with a favorable prognosis, the highest chance of good perinatal outcome is associated with a single embryo transfer. LEVEL OF EVIDENCE: II

Safety of assisted reproductive technology in the United States, 2000-2011.

Use of assisted reproductive technology (ART) continues to increase in the United States and globally. In an effort to improve patient safety, stimulation protocols have become less aggressive, oocyte retrieval has transitioned from laparoscopic to transvaginal, and pregnancy rates have improved.1 However, limited data exist regarding the incidence of maternal complications.2 We explored incidence and trends in reported patient and donor complications in fresh ART cycles using the US Centers for Disease Control and Prevention National ART Surveillance System (NASS).

Obesity, Assisted Reproductive Technology, and Early Preterm Birth—Florida, 2004–2006

Florida resident birth certificates for 2004-2006 were linked to the Centers for Disease Control and Preventions National ART Surveillance System and were used to investigate 1) whether the association of assisted reproductive technology (ART) with preterm birth varies by prepregnancy body mass index and 2) whether the association varies by plurality. Preterm birth was defined as early preterm birth (gestation <34 weeks) and late preterm birth (gestation 34-36 weeks). Descriptive statistics and multinomial logistic regression were used to explore maternal and infant differences by ART status and plurality. Of 581,403 women included in the study, 24.0% were overweight, 18.6% were obese, 7.3% had late preterm birth, 2.6% had early preterm birth, and 0.67% conceived through ART. Among singleton births, ART was associated with increased early preterm birth risk among underweight (odds ratio (OR) = 2.94, 95% confidence interval (CI): 1.27, 6.81), overweight (OR = 1.75, 95% CI: 1.12, 2.72), and obese (OR = 2.37, 95% CI: 1.51, 3.71) women. Among twins, ART was significantly associated with increased risk among overweight (OR = 1.61, 95% CI: 1.12, 2.32) and obese (OR = 1.85, 95% CI: 1.18, 2.90) women. Differences in the associations between ART and early preterm birth by body mass index and plurality warrant further investigation.

GnRH agonist and GnRH antagonist protocols: comparison of outcomes among good-prognosis patients using national surveillance data

Implantation and live birth rates resulting from IVF cycles using gonadotropin-releasing hormone (GnRH) agonist and (GnRH) antagonist IVF protocols were compared among good-prognosis patients using the Centers for Disease Control and Preventions National Assisted Reproductive Technology Surveillance System 2009-2010 data (n = 203,302 fresh, autologous cycles). Bivariable and multivariable analyses were conducted between cycles to compare outcomes. Cycles were restricted as follows: age younger than 35 years, maximum FSH less than 10 mIU/mL, first assisted reproduction technology cycle and FSH dose less than 3601 IU. A subgroup analysis including only elective single embryo transfer was also carried out. Among good-prognosis patients, the GnRH-agonist protocol was associated with a lower risk of cancellation before retrieval (4.3 versus 5.2%; P < 0.05) or transfer (5.5 versus 6.8%; P < 0.05), and a higher live birth rate per transfer (adjusted odds ratio [OR] 1.13, confidence interval [CI] 1.03 to 1.25) than the GnRH-antagonist group. Among the elective single embryo transfer group, the GnRH-agonist protocol was associated with a higher implantation rate (adjusted odds ratio [OR] 1.36, CI 1.08 to 1.73) and a higher live birth rate (adjusted OR 1.33, CI 1.07 to 1.66) compared with the GnRH-antagonist protocol. The GnRH-antagonist group had lower rates of ovarian hyperstimulation syndrome. Among good-prognosis patients, agonist protocols decreased cancellation risk and increased odds of implantation and live birth. Antagonist protocols may confer decreased risk of hyperstimulation.

Influence of Reproductive Factors on Mortality after Epithelial Ovarian Cancer Diagnosis

Introduction: Although many studies have examined the influence of reproductive factors on ovarian cancer risk, few have investigated their effect on ovarian cancer survival. We examined the prognostic influence of reproductive factors on survival after ovarian cancer diagnosis. Methods: We conducted a longitudinal analysis of 410women, ages 20 to 54 years, who participated in the 1980 to 1982 Cancer and Steroid Hormone study as incident ovarian cancer cases. We obtained their vital status by linking Cancer and Steroid Hormone records with Surveillance, Epidemiology, and End Results data. We used the Kaplan-Meier approach to estimate survival probabilities and Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: During a median follow-up of 9.2 years, 212women died. Of the reproductive factors examined, only age at menarche and number of lifetime ovulatory cycles (LOC) relative to age significantly predicted ovarian cancer survival. Risk for death was higher among women with highest number of LOC compared with those having fewest LOC (HR, 1.67; 95% CI, 1.20-2.33). Women with fewest LOC had the highest 15-year survival (56.7%; 95% CI, 47.8-64.6%), and women with the highest LOC had the poorest (33.3%; 95% CI, 25.3-41.5%). Women whose age at menarche was <12 years had a higher risk of death compared with women whose menses began at ≥14 years (HR, 1.51; 95% CI, 1.02-2.24). Conclusions: We found that high LOC and early age at menarche were associated with decreased survival after ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2035–41)

Sex education and adolescent sexual behavior: do community characteristics matter?

BACKGROUND Studies point to variation in the effects of formal sex education on sexual behavior and contraceptive use by individual and community characteristics. STUDY DESIGN Using the 2002 National Survey of Family Growth, we explored associations between receipt of sex education and intercourse by age 15, intercourse by the time of the interview and use of effective contraception at first sex among 15-19-year-olds, stratified by quartiles of three community characteristics and adjusted for demographics. RESULTS Across all quartiles of community characteristics, sex education reduced the odds of having sex by age 15. Sex education resulted in reduced odds of having sex by the date of the interview and increased odds of using contraception in the middle quartiles of community characteristics. CONCLUSION Variation in the effects of sex education should be explored. Research might focus on programmatic differences by community type and programmatic needs in various types of communities.