Jennifer F. Kawwass

Update: Interim Guidance for Health Care Providers Caring for Women of Reproductive Age with Possible Zika Virus Exposure — United States, 2016

CDC has updated its interim guidance for U.S. health care providers caring for women of reproductive age with possible Zika virus exposure to include recommendations on counseling women and men with possible Zika virus exposure who are interested in conceiving. This guidance is based on limited available data on persistence of Zika virus RNA in blood and semen. Women who have Zika virus disease should wait at least 8 weeks after symptom onset to attempt conception, and men with Zika virus disease should wait at least 6 months after symptom onset to attempt conception. Women and men with possible exposure to Zika virus but without clinical illness consistent with Zika virus disease should wait at least 8 weeks after exposure to attempt conception. Possible exposure to Zika virus is defined as travel to or residence in an area of active Zika virus transmission ( http://www.cdc.gov/zika/geo/active-countries.html), or sex (vaginal intercourse, anal intercourse, or fellatio) without a condom with a man who traveled to or resided in an area of active transmission. Women and men who reside in areas of active Zika virus transmission should talk with their health care provider about attempting conception. This guidance also provides updated recommendations on testing of pregnant women with possible Zika virus exposure. These recommendations will be updated when additional data become available.

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.

Novel H1N1 Virus Infection and Pregnancy

Abstract Human infection with the novel H1N1 influenza virus, initially popularly termed “swine flu,” was first reported in April 2009 and has since prompted the World Health Organization (WHO) to raise its pandemic alert to the highest level. During pregnancy both mother and baby are at increased risk when infected with either pandemic or seasonal influenza. Because of concerns about the severity of the disease during pregnancy, the Centers for Disease Control and Prevention (CDC) has implemented enhanced surveillance for infection with this novel virus in pregnant women and has placed them in a group that merits priority vaccine administration. The benefit of treatment with the antiviral medication oseltamivir outweighs its theoretical risk, as pregnant women are at increased risk of severe complications from H1N1 virus infection. In addition to confirmed H1N1 cases, the associated symptoms, particularly fever, merit immediate attention. Moreover, precautions must be taken by both patients and health care professionals when confirmed or suspected H1N1-infected pregnant women present to labor and delivery, or the doctors office. After delivery, pregnant women infected with H1N1 may breastfeed but must follow specific guidelines. Although the current strain of H1N1 virus has fairly mild sequelae, the virus may have mutated over the summer months and we must anticipate a possible second wave of more severe illness moving into fall 2009 and winter 2010.

Tubal Factor Infertility and Perinatal Risk After Assisted Reproductive Technology

OBJECTIVE: To assess trends of tubal factor infertility and to evaluate risk of miscarriage and delivery of preterm or low birth weight (LBW) neonates among women with tubal factor infertility using assisted reproductive technology (ART). METHODS: We assessed trends of tubal factor infertility among all fresh and frozen, donor, and nondonor ART cycles performed annually in the United States between 2000 and 2010 (N=1,418,774) using the National ART Surveillance System. The data set was then limited to fresh, nondonor in vitro fertilization cycles resulting in pregnancy to compare perinatal outcomes for cycles associated with tubal compared with male factor infertility. We performed bivariate and multivariable analyses controlling for maternal characteristics and calculated adjusted risk ratios (RRs) and 95% confidence intervals (CI). RESULTS: The percentage of ART cycles associated with tubal factor infertility diagnoses decreased from 2000 to 2010 (26.02–14.81%). Compared with male factor infertility, tubal factor portended an increased risk of miscarriage (14.0% compared with 12.7%, adjusted RR 1.08, 95% CI 1.04–1.12); risk was increased for both early and late miscarriage. Singleton neonates born to women with tubal factor infertility had an increased risk of preterm birth (15.8% compared with 11.6%, adjusted RR 1.27, 95% CI 1.20–1.34) and LBW (10.9% compared with 8.5%, adjusted RR 1.28, 95% CI 1.20–1.36). Significant increases in risk persisted for early and late preterm delivery and very low and moderately LBW delivery. A significantly elevated risk was also detected for twin, but not triplet, pregnancies. CONCLUSION: Tubal factor infertility, which is decreasing in prevalence in the United States, is associated with an increased risk of miscarriage, preterm birth, and LBW delivery as compared with couples with male factor infertility using ART. LEVEL OF EVIDENCE: II

Direct effects of leptin and adiponectin on peripheral reproductive tissues: a critical review

Obesity is a risk factor for infertility and adverse reproductive outcomes. Adipose tissue is an important endocrine gland that secretes a host of endocrine factors, called adipokines, which modulate diverse physiologic processes including appetite, metabolism, cardiovascular function, immunity and reproduction. Altered adipokine expression in obese individuals has been implicated in the pathogenesis of a host of health disorders including diabetes and cardiovascular disease. It remains unclear whether adipokines play a significant role in the pathogenesis of adverse reproductive outcomes in obese individuals and, if so, whether the adipokines are acting directly or indirectly on the peripheral reproductive tissues. Many groups have demonstrated that receptors for the adipokines leptin and adiponectin are expressed in peripheral reproductive tissues and that these adipokines are likely, therefore, to exert direct effects on these tissues. Many groups have tested for direct effects of leptin and adiponectin on reproductive tissues including the testis, ovary, uterus, placenta and egg/embryo. The hypothesis that decreased fertility potential or adverse reproductive outcomes may result, at least in part, from defects in adipokine signaling within reproductive tissues has also been tested. Here, we present a critical analysis of published studies with respect to two adipokines, leptin and adiponectin, for which significant data have been generated. Our evaluation reveals significant inconsistencies and methodological limitations regarding the direct effects of these adipokines on peripheral reproductive tissues. We also observe a pervasive failure to account for in vivo data that challenge observations made in vitro. Overall, while leptin and adiponectin may directly modulate peripheral reproductive tissues, existing data suggest that these effects are minor and non-essential to human or mouse reproductive function. Current evidence suggests that direct effects of leptin or adiponectin on peripheral reproductive tissues are unlikely to factor significantly in the adverse reproductive outcomes observed in obese individuals.

Trends and Correlates of Monozygotic Twinning After Single Embryo Transfer

OBJECTIVE: To evaluate trends of monozygotic twinning after single embryo transfer and its association with patient and treatment factors. METHODS: Our retrospective cohort study included 28,596 pregnancies after fresh, nondonor single embryo transfer during 2003–2012 reported to the National ART Surveillance System. We examined trends of monozygotic twin pregnancies (number of fetal heart tones on first-trimester ultrasonography more than one or number of neonates born more than one) and assessed patient and treatment factors for monozygotic twin compared with singleton pregnancies. Modified Poisson regression models were used to estimate adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for association between monozygotic twinning and selected factors stratified by day 2–3 and day 5–6 transfer. RESULTS: During 2003–2012, the incidence of monozygotic twinning after single embryo transfer was lower for day 2–3 transfers than for day 5–6 transfers (1.71%, 95% CI 1.45–1.98, n=162 compared with 2.50%, 95% CI 2.28–2.73, n=472); the incidence did not change significantly over the study period. Among day 2–3 transfers, assisted hatching increased the risk for monozygotic twinning compared with singletons (adjusted RR 2.16, 95% CI 1.53–3.06); use of intracytoplasmic sperm injection decreased the risk (adjusted RR 0.60, 95% CI 0.42–0.85). Having one or more prior pregnancies increased the risk for monozygotic twinning among day 5–6 transfers (adjusted RR 1.26, 95% CI 1.03–1.53). CONCLUSION: Monozygotic twinning after single embryo transfers was more common among day 5–6 embryo transfers than day 2–3 transfers. Use of assisted hatching was associated with increased risk for monozygotic twinning for day 2–3 transfers. 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).

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.

Cryopreserved oocyte versus fresh oocyte assisted reproductive technology cycles, United States, 2013

OBJECTIVE To compare characteristics, explore predictors, and compare assisted reproductive technology (ART) cycle, transfer, and pregnancy outcomes of autologous and donor cryopreserved oocyte cycles with fresh oocyte cycles. DESIGN Retrospective cohort study from the National ART Surveillance System. SETTING Fertility treatment centers. PATIENT(S) Fresh embryo cycles initiated in 2013 utilizing embryos created with fresh and cryopreserved, autologous and donor oocytes. INTERVENTION(S) Cryopreservation of oocytes versus fresh. MAIN OUTCOMES MEASURE(S) Cancellation, implantation, pregnancy, miscarriage, and live birth rates per cycle, transfer, and/or pregnancy. RESULT(S) There was no evidence of differences in cancellation, implantation, pregnancy, miscarriage, or live birth rates between autologous fresh and cryopreserved oocyte cycles. Donor cryopreserved oocyte cycles had a decreased risk of cancellation before transfer (adjusted risk ratio [aRR] 0.74, 95% confidence interval [CI] 0.57-0.96) as well as decreased likelihood of pregnancy (aRR 0.88, 95% CI 0.81-0.95) and live birth (aRR 0.87, 95% CI 0.80-0.95); however, there was no evidence of differences in implantation, pregnancy, or live birth rates when cycles were restricted to those proceeding to transfer. Donor cryopreserved oocyte cycles proceeding to pregnancy had a decreased risk of miscarriage (aRR 0.75, 95% CI 0.58-0.97) and higher live birth rate (aRR 1.05, 95% CI 1.01-1.09) with the transfer of one embryo, but higher miscarriage rate (aRR 1.28, 95% CI 1.07-1.54) and lower live birth rate (aRR 0.95, 95% CI 0.92-0.99) with the transfer of two or more. CONCLUSION(S) There was no evidence of differences in ART outcomes between autologous fresh and cryopreserved oocyte cycles. There was evidence of differences in per-cycle and per-pregnancy outcomes between donor cryopreserved and fresh oocyte cycles, but not in per-transfer outcomes.

Endometriosis and Assisted Reproductive Technology: United States Trends and Outcomes 2000–2011

OBJECTIVE To assess endometriosis-associated infertility trends among assisted reproductive technology (ART) cycles, and to compare cancellation and hyperstimulation risks and pregnancy and live birth rates among women using ART for endometriosis-associated vs. male factor infertility. DESIGN Descriptive and multivariable analyses of Centers for Disease Control and Prevention (CDC) National ART Surveillance System data. SETTING Fertility centers. PATIENT(S) All reported fresh autologous ART cycles in the United States between 2000 and 2011 (n = 1,589,079). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Oocyte yield, hyperstimulation, cancellation, implantation, pregnancy, live birth. RESULT(S) The absolute number of ART cycles with an endometriosis diagnosis fell in recent years, from 16,751 (2000) to 15,311 (2011); the percentage fell over time, from 17.0% (2000) to 9.6% (2011) of all cycles. Compared with male factor (n = 375,557), endometriosis-associated cycles (n = 112,475) yielded fewer oocytes (50.5% vs. 42.5% of cycles with only 0-10 oocytes retrieved), lower risk of hyperstimulation (1.1% vs. 1.3%, adjusted risk ratio [aRR] 0.82, 95% confidence interval [CI] 0.74-0.91), and an increased risk of cancellation (12.9% vs. 10.1%, aRR 1.30, 95% CI 1.25-1.35). Endometriosis was associated with a statistically decreased but likely clinically insignificant difference in the following outcomes: chance of pregnancy per transfer (43.7% vs. 44.8%, aRR 0.96, 95% CI 0.95-0.98) among couples who did not also have tubal factor infertility and live birth per transfer (37.2% vs. 37.6%, aRR 0.96, 95% CI 0.94-0.98). CONCLUSION(S) The percentage of endometriosis-associated ART cycles has decreased over time. As compared with male factor infertility, endometriosis is associated with increased cancellation and decreased hyperstimulation risks. Despite decreased oocyte yield and higher medication dose, the difference in pregnancy and live birth rates may be of limited clinical significance, suggesting comparable pregnancy outcomes per transfer.