Use of Intracytoplasmic Sperm Injection and Birth Outcomes in Women Conceiving through In Vitro Fertilization.

BACKGROUND: Despite questionable evidence of benefits over conventional in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) use has markedly increased in recent decades among couples without male factor infertility. We assessed the frequency of ICSI use and its effect on birth outcomes. METHODS: A retrospective cohort study was conducted in 141 030 women conceiving through IVF using 2006-2010 data from the Society for Assisted Reproductive Technology (SART). RESULTS: Between 2006 and 2010, overall ICSI use in women conceiving through IVF increased from 68.9% to 73.1%. This increase was greater among women without male factor infertility (53.0-59.2%) than in women with male factor infertility (92.0-93.4%). Women conceiving through IVF with and without ICSI had similar rates of multiple pregnancy, preterm delivery, stillbirth, and neonatal death. However, ICSI pregnancies were associated with an increased risk of birth defects over conventional IVF (3.0% for ICSI vs. 2.5% for conventional IVF; adjusted odds ratio (OR) 1.2, 95% confidence interval (CI) 1.2, 1.3). These increases were observed in both women conceiving through ICSI with male factor infertility (3.2% vs. 2.5%; OR 1.4, 95% CI 1.3, 1.5) and without male factor infertility (2.7% vs. 2.5%; OR 1.1, 95% CI 1.1, 1.2). CONCLUSIONS: Higher rates of birth defects were observed among women conceiving through ICSI. Since approximately half of all ICSI procedures are performed in couples without male factor infertility, ICSI may be overused in practice.

Birth Weight by Gestational Age for 76,710 Twins Born in the United States as a Result of In Vitro Fertilization: 2006 to 2010.

Objective The objective of this study was to establish twin-specific birth weight percentiles by gestational age using U.S. twin births resulting from in vitro fertilization (IVF). Study Design A retrospective analysis of birth weight by completed weeks of gestation for 76,710 twin IVF births reported to the Society for Assisted Reproductive Technologies from 2006 to 2010. Mean and median birth weights and 3rd, 5th, 10th, 25th, 50th, 75th, 90th, and 97th percentiles were calculated by completed week of gestation and infant sex. Results IVF twin birth weight accelerates until term and then declines. The deceleration in twin birth weight occurs at 39 completed weeks of gestation for larger twins, those at or above the 50th percentile in weight. For smaller twins, the growth deceleration occurs earlier, at 38 weeks of gestation. IVF female and male twin birth weights for gestational age were similar to all IVF twins, showing similar decelerations near term. Conclusion Using U.S. IVF twin-specific growth charts, with known date of conception, twins demonstrate a deceleration in birth weight near term. Larger twins demonstrate a deceleration in birth weight by 39 completed weeks of gestation; smaller twins show a deceleration at 38 weeks. These data may assist in the clinical management of twins near term.

Singleton birthweight by gestational age following in vitro fertilization in the United States.

BACKGROUND: Assisted reproductive technology has been reported to account for a disproportionate higher number of low birthweight infants, even in singleton births. Low birthweight infants occur from preterm birth, decreased intrauterine growth, or both. It is unclear whether infants conceived by in vitro fertilization (IVF) have a reduced intrauterine growth rate or intrauterine growth restriction. Growth-restricted newborns have higher perinatal morbidity and are at increased risk for adult-onset illnesses. To date, there are no national standards for birthweight percentiles by gestational week, allowing for fetal growth assessment of singletons conceived by assisted reproductive technology in the United States. OBJECTIVE: The objective of the study was to establish US singleton IVF reference standards using birthweight percentiles by gestational age for singleton live births resulting from IVF in the United States. STUDY DESIGN: We studied birthweight by completed weeks of gestation for 93,443 singleton IVF births reported to the Society for Assisted Reproductive Technologies, 2006-2010. The third to 97th birthweight percentiles per completed week of gestation for weeks between 24 and 42 were calculated and were compared with recently published birthweight percentiles by gestational age for 3,812,730 US singleton births in 2011. RESULTS: Smoothed birthweight for gestational age charts and curves were created for all US IVF singletons and female-male singletons from 24 to 42 weeks. Over the span of 31-41 weeks of gestation, the 10th, 50th, and 90th birthweight percentile values of IVF singletons were comparable with recently published birthweight percentile values of US singletons. At 40 completed weeks of gestation, the 10th, 50th, and 90th birthweight percentiles of all IVF singletons were 3078, 3506, and 4053 g, as compared with corresponding 3005, 3499, and 4057 g of US singletons. The 10th, 50th, and 90th birthweight percentile values for female and male IVF singletons were also comparable with US female and male singletons. CONCLUSION: Birthweight percentiles per completed week of gestation of IVF and US singletons are approximately equal from 31 until 41 completed weeks, suggesting that intrauterine growth is not reduced in IVF singleton infants.

Maternal age and preterm births in singleton and twin pregnancies conceived by in vitro fertilisation in the United States.

BACKGROUND: Among natural conceptions, advanced maternal age (≥ 35 years) is associated with an increased risk of preterm birth. However, few studies have specifically examined this association in births resulting from in vitro fertilisation (IVF). METHODS: A retrospective cohort study was conducted in 97288 singleton and 40961 twin pregnancies resulting from fresh non-donor IVF cycles using 2006-10 data from the Society for Assisted Reproductive Technology Clinic Online Reporting System. RESULTS: Rates of very early preterm (<28), early preterm (<32), and preterm birth (<37 completed weeks) decreased with increasing maternal age in both singleton and twin births (PTrend <0.01). With women aged 30-34 years as the reference, those aged <30 years were at an increased risk of all types of preterm births. The adjusted odd ratio (95% confidence interval [CI]) for very early preterm birth, early preterm birth, and preterm birth in women aged 25-29 years were 1.3 [95% CI 1.1, 1.5], 1.2 [95% CI 1.1, 1.4], and 1.1 [95% CI 1.02, 1.2] in singletons. This increased risk of preterm births among younger women was even more significant in twin births. However, women aged ≥ 35 years were not at an increased risk of any type of preterm births in both singleton and twin births. CONCLUSIONS: In contrast to natural conception, advanced maternal age is not associated with an increased risk of preterm births in pregnancies conceived by IVF. Women who seek IVF treatments before 30 years old are at higher risk of all stages of preterm births.

Impact of monozygotic twinning on multiple births resulting from in vitro fertilization in the United States, 2006-2010.

OBJECTIVE: To determine the contribution of monozygotic twining to in vitro fertilization multiple births. STUDY DESIGN: We performed a retrospective analysis of the incidence of monozygotic twining in multiple births resulting from fresh embryo transfers using 2006-2010 data from the Society for Reproductive Technology Clinic Outcome Reporting System. RESULTS: The number of embryos transferred were fewer than the number of births in 0.5% (223/40950) of twin, 29% (659/2289) of triplet, and 64% (43/67) of quadruplet births resulting from transfer of fresh embryos from 2006 to 2010. In 2010, 37% of triplets and 100% of quadruplet births occurred when fewer than 3 and fewer than 4 embryos respectively were transferred. CONCLUSION: Monozygotic twinning plays a key role in the development of triplet and quadruplet pregnancies achieved through in vitro fertilization.

Racial and ethnic disparities in preterm births in infants conceived by in vitro fertilization in the United States.

OBJECTIVE: The objective of the study was to examine racial and ethnic differences in preterm births in infants conceived by in vitro fertilization (IVF). STUDY DESIGN: A retrospective cohort study was conducted of 97,288 singleton and 40,961 twin pregnancies resulting from fresh, nondonor IVF cycles using 2006-2010 data from the Society for Assisted Reproductive Technology Clinic Online Reporting System. RESULTS: Rates of very early preterm (<28 weeks), early preterm (<32 weeks), and preterm birth (<37 completed weeks) varied across racial and ethnic groups in both singleton and twin pregnancies. In singletons, with white women as the referent, after adjustment of confounding variables, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of very early preterm birth, early preterm birth, and preterm birth in black women were 4.8 (95% CI, 4.1-5.7), 3.9 (95% CI, 3.4-4.4), and 2.1 (95% CI, 1.9-2.3). Hispanic women had a significantly lower rate of preterm births as compared with black women and similar or slightly higher rates as compared with white women. Native American women were not at an increased risk of any types of preterm births; Asian women were at a reduced risk of preterm twin births (adjusted OR, 0.8; 95% CI, 0.7-0.9). CONCLUSION: There exist notable racial and ethnic disparities in preterm births in infants conceived by IVF, suggesting that mechanisms other than socioeconomic disparities contribute to this difference.

Effect of maternal height and weight on risk for preterm singleton and twin births resulting from IVF in the United States, 2008-2010.

OBJECTIVE: To analyze the effects of preconception maternal height and weight on the risk of preterm singleton and twin births resulting from in vitro fertilization (IVF). STUDY DESIGN: We performed a retrospective cohort analysis of the incidence of very early preterm birth (VEPTB), early preterm birth (EPTB), and preterm birth (PTB), before 28, 32, and 37 completed weeks, respectively, in 60,232 singleton and 24,111 twin live births using 2008-2010 live birth outcome data from the Society for Reproductive Technology Clinic Outcome Reporting System. RESULT: Maternal obesity is associated with significantly increased risk of VEPTB, EPTB, and PTB in pregnancies conceived by IVF. For morbidly obese women (body mass index ≥35) with singletons, rates of VEPTB, EPTB, and PTB were 1.7%, 3.6%, and 16.4%, with adjusted risk ratios (aRRs) and 95% confidence levels (CIs) of 2.6 (1.8-3.6), 2.2 (1.8-2.6), and 1.5 (1.4-1.7) using corresponding rates for normal body mass index (95% CI, 18.6-24.9) as referent. For morbidly obese women with twins, rate of VEPTB and EPTB were 6.5% and 12.5%, with aRRs and 95% CIs of 2.4 (1.8-3.0) and 1.5 (1.3-1.8). For singletons, the rate of PTB for short stature women (<150 cm) was 14.2%, as compared with 11.8% in those women with height ranging between 160-167 cm (referent), with aRRs and 95% CIs of 1.2 (1.0-1.4). CONCLUSION: Preconception maternal obesity and short stature are associated with significantly increased risk of VEPTB and early preterm singleton and twin births in pregnancies resulting from IVF.

A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization.

OBJECTIVE: To compare the effects of oral contraceptive (OC) pill pretreatment in recombinant FSH/GnRH-antagonist versus recombinant FSH/GnRH-agonist stimulation in in vitro fertilization (IVF) patients, and to evaluate optimization of retrieval day. DESIGN: Prospective, randomized, multicenter study. SETTING: Private practice and university centers. PATIENT(S): Eighty patients undergoing IVF who met the appropriate inclusion criteria. INTERVENTION(S): Four study centers recruited 80 patients. The OC regimen began on cycle days 2 to 4 and was discontinued on a Sunday after 14 to 28 days. The recombinant FSH regimen was begun on the following Friday. The GnRH-agonist group was treated with a long protocol; the GnRH-antagonist was initiated when the lead follicle reached 12 to 14 mm. When two follicles had reached 16 to 18 mm, hCG was administered. MAIN OUTCOME MEASURE(S): The primary outcome measures were the number of cumulus-oocyte complexes, day of the week for oocyte retrieval, and total dose and days of stimulation of recombinant FSH. Secondary efficacy variables included pregnancy and implantation rate; serum E(2) levels on stimulation day 1; serum E(2), P, and LH levels on the day of hCG administration; follicle size on day 6 and day of hCG administration; the total days of GnRH-analogue treatment; total days on OC; total days from end of OC to oocyte retrieval; and the cycle cancellation rate. RESULT(S): Patient outcomes were similar for the days of stimulation, total dose of gonadotropin used, two-pronuclei embryos, pregnancy (44.4% GnRH-antagonist vs. 45.0% GnRH-agonist, P=.86) and implantation rates (22.2% GnRH-antagonist vs. 26.4% GnRH-agonist, P=.71). Oral contraceptive cycle scheduling resulted in 78% and 90% of retrievals performed Monday through Friday for GnRH-antagonist and GnRH-agonist. A one day delay in OC discontinuation and recombinant FSH start would result in over 90% of oocyte retrievals occurring Monday through Friday in both groups. CONCLUSION(S): The OC pretreatment in recombinant FSH/GnRH-antagonist protocols provides a patient-friendly regimen and can be optimized for weekday retrievals. No difference was seen in number of 2PN embryos, cryopreserved embryos, embryos transferred, implantation and pregnancy rates between the two stimulation protocols.

Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles.

OBJECTIVE: To determine factors responsible for high-order multiple pregnancy (HOMP) and high-order multiple births when multiple cycles of controlled ovarian hyperstimulation-IUI (COH-IUI) are performed. DESIGN: Retrospective analysis. SETTING: Private infertility clinic. PATIENT(S): Women (n = 2,272) who underwent 4,067 consecutive COH-IUI cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): High-order multiple pregnancy rate, pregnancy rate (PR), and birth rate (PR) per cycle. RESULT(S): High-order multiple pregnancy was related to number of follicles of diameter > or = 10 mm, age, and treatment cycle. For age <32 years, HOMP was 6% for three to six follicles and 20% for seven or more follicles. For ages 32 to 37 years, HOMP was 5% for three to six follicles and 12% for seven or more follicles. In the first COH-IUI cycle, HOMP was 8% for three to six follicles and 15% for seven or more follicles. In the second cycle, HOMP did not occur unless there were more than six follicles. No HOMP occurred after the second cycle. Pregnancy rate did not increase significantly when there were more than four follicles. Continuing COH-IUI past the third cycle resulted in additional pregnancies in patients with one to eight follicles. CONCLUSION(S): High-order multiple pregnancy can be predicted by age and number of follicles of diameter > or = 10 mm. Controlled ovarian hyperstimulation is not necessary to achieve satisfactory overall pregnancy rates if ovulation induction is continued past the third cycle in low responders.

Polycystic ovarian syndrome and the metabolic syndrome.

Polycystic ovarian syndrome (PCOS), first described in 1937, was defined by specific ovarian histopathology and a constellation of signs and symptoms. Through the years, the etiology remained elusive, with heated debates focusing in turn on the ovary and then the pituitary as the causative agents. In the last several decades, it has become clear that insulin resistance makes up a very important component of this syndrome. With this knowledge, new therapies have emerged along with the realization that PCOS and the metabolic syndrome are closely related through their shared insulin resistance. In this review, the diagnosis, pathophysiology, and therapy of PCOS are discussed and upon this background, those areas held in common by PCOS and the metabolic syndrome are explored.

Embryonic loss in iatrogenic multiples.

Spontaneous reduction of multiple gestational sacs occurs less often in pregnancies conceived as a result of ovulation induction and assisted reproductive technology compared with spontaneously conceived multiple pregnancies. Whereas most spontaneous multiple pregnancies are twin gestations, a higher proportion of multiple pregnancies that result from ovulation induction and assisted reproductive technology are triplet and higher-order gestations. Recent evidence, described in this article, indicates that although twin and higher-order multiple gestations found on initial ultrasound subsequently may undergo spontaneous reduction to singletons or twins, there may be important consequences for the outcome of the surviving fetus or fetuses.

Highly purified human-derived follicle-stimulating hormone (Bravelle) has equivalent efficacy to follitropin-beta (Follistim) in infertile women undergoing in vitro fertilization.

BACKGROUND: These data compare the efficacy and safety of highly purified human-derived follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta (Follistim) in women undergoing in vitro fertilization. METHODS: This report describes the pooled data from two, nearly identical, randomized, controlled, parallel-group, multicenter studies conducted in a total of 19 academic and private IVF-ET centers in the United States. Infertile premenopausal women underwent pituitary down-regulation using leuprolide acetate followed by a maximum of 12 days of subcutaneous Bravelle (n = 120) or Follistim (n = 118), followed by administration of human chorionic gonadotropin, oocyte retrieval and embryo transfer. The primary efficacy measure was the mean number of oocytes retrieved; secondary efficacy measures included the total dose and duration of gonadotropin treatment; peak serum estradion levels; embryo transfer and implantation rates; chemical, clinical and continuing pregnancies; and live birth rates. All adverse events were recorded and injection site pain was recorded daily using a patient, self-assessment diary. RESULTS: Similar efficacy responses were observed for all outcome parameters in the two treatment groups. Although patients receiving Bravelle consistently reported a greater number of chemical, clinical and continuing pregnancies, as well as an increased rate of live birth, the data did not attain statistical significance (P > 0.05). The overall incidence of adverse events was similar in both groups, but compared to Follistim, injections of Bravelle were reported by patients to be significantly less painful (P < 0.001). CONCLUSIONS: Bravelle and Follistim had comparable efficacy in controlled ovarian hyperstimulation in women undergoing IVF-ET. There were no differences in the nature or number of adverse events between the treatment groups although Bravelle injections were reported to be significantly less painful.

Comparison of the efficacy and safety of a highly purified human follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta for in vitro fertilization: a prospective, randomized study.

OBJECTIVE: To compare the efficacy and safety of Bravelle s.c., Bravelle i.m., and Follistim s.c. in patients undergoing controlled ovarian hyperstimulation for IVF-ET. DESIGN: Open-label, randomized, parallel group, multicenter study. SETTING: Eleven academic and private fertility clinics with experience in IVF-ET. PATIENT(S): Infertile premenopausal women with regular ovulatory menstrual cycles undergoing IVF-ET. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of Bravelle s.c. (n = 60), Bravelle i.m. (n = 59), or Follistim s.c. (n = 58); hCG administration, oocyte retrieval, and ET. MAIN OUTCOME MEASURE(S): Mean number of oocytes retrieved; patients with ET, chemical, clinical and continuing pregnancies; mean peak serum E2 levels; adverse events and injection site pain scores. RESULT(S): There were no significant differences among treatment groups in mean number of oocytes retrieved, peak serum E2 levels, patients with ET, continuing pregnancies, or live births. There were no significant differences among the treatment groups in the number, nature, or intensity of adverse events. Patients treated with Bravelle s.c. or Bravelle i.m. experienced significantly less injection site pain than patients treated with Follistim s.c. CONCLUSION(S): Bravelle s.c. and Bravelle i.m. are comparable in efficacy and safety to Follistim s.c. in patients undergoing controlled ovarian hyperstimulation for IVF-ET.

Clomiphene citrate intrauterine insemination (IUI) before gonadotropin IUI affects the pregnancy rate and the rate of high-order multiple pregnancies.

OBJECTIVE: To determine if previous treatment with clomiphene citrate intrauterine insemination (CC-IUI) affects pregnancy and high-order multiple pregnancy (HOMP) rates in subsequent hMG-IUI or FSH-IUI cycles. DESIGN: Retrospective cohort study. SETTING: Private infertility clinic. PATIENT(S): Five hundred fifty-one patients (age <38 years) without tubal factor infertility, treated with 918 cycles of hMG/FSH-IUI after one or more unsuccessful cycles of CC-IUI; 908 patients treated with 1459 cycles of hMG/FSH-IUI without prior CC-IUI. INTERVENTION(S): CC-IUI, hMG-IUI, FSH-IUI. MAIN OUTCOME MEASURE(S): Pregnancy rate per cycle, HOMP (three or more gestational sacs). RESULT(S): Pregnancy rates during the first three hMG-IUI or FSH-IUI cycles averaged 21.8 +/- 1.1% without previous CC-IUI, 19.6 +/- 1.3% after one to four cycles of CC-IUI, and 3.6 +/- 2.6% after >or= five previous CC-IUI cycles. The HOMP rates were 8.8% without previous CC-IUI, 7.5% after one, 5.7% after two and <2.6% (0 out of 38) after >or= three previous CC-IUI cycles. CONCLUSION(S): Pregnancy rates in hMG/FSH-IUI cycles are significantly reduced after four unsuccessful CC-IUI cycles. High-order multiple pregnancies due to hMG/HMG-IUI are reduced following previous unsuccessful CC-IUI cycles.

Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on the outcome of multiple cycles of clomiphene citrate-intrauterine insemination.

OBJECTIVE: To determine how diagnosis, age, sperm quality, and number of preovulatory follicles affect pregnancy rates when multiple cycles of clomiphene citrate (CC)-IUI are performed. DESIGN: Fifteen-year prospective observational study. SETTING: Private infertility clinic. PATIENT(S): Three thousand, three hundred eighty-one cycles of husband or donor IUI. INTERVENTION(S): Ovulation induction with CC and IUI. MAIN OUTCOME MEASURE(S): Per-cycle pregnancy rate (PR), cumulative pregnancy rate (CPR). RESULT(S): Pregnancy rates remained constant through four cycles, then fell significantly for diagnoses other than ovulatory dysfunction. Mean PRs for cycles 1-4 were significantly lower for patients with the following characteristics: age >/=43 years, poor semen quality, single preovulatory follicles, and diagnoses other than ovulatory dysfunction. Additional cycles of CC-IUI compensated for low PRs because of age, semen quality, or number of follicles. After four cycles, CPRs were 46% for ovulatory dysfunction; 38% for cervical factor, male factor, and unexplained infertility; 34% for endometriosis; and 26% for tubal factor. After six cycles, CPRs were 65% for ovulation dysfunction, 35% for endometriosis, and unchanged for other diagnoses. CONCLUSION(S): Clomiphene citrate-intrauterine insemination should be performed for a minimum of four cycles. Additional cycles of CC-IUI can compensate for low pregnancy rates due to age, semen quality, or follicle number in patients with ovulation dysfunction.

Effect of maternal height and weight on risk of preterm birth in singleton and twin births resulting from in vitro fertilization: a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System.

OBJECTIVE: To examine the effect of height, weight, and body mass index (BMI) on the risk of preterm birth of singleton and twin pregnancies conceived by vitro fertilization (IVF). DESIGN: Retrospective cohort study using 2006-2008 data from the Society for Reproductive Technology Clinic Outcome Reporting System (SART CORS). SETTING: SART-associated assisted reproductive technology programs. PATIENT(S): 56,556 singleton and 23,804 twin live births resulting from fresh nondonor IVF cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of very early preterm (VEPTB; <28 weeks), very preterm (VPTB; <32 weeks), and preterm birth (<37 weeks) births. RESULT(S): In both singleton and twin births, increased maternal height was associated with a decreased risk of preterm birth. Maternal overweight and obesity were associated with significantly increased risk of VEPTB and VPTB in twin pregnancies. For very obese women (BMI > 35 kg/m(2)) twins were associated with a threefold increased risk of VEPTB (6.1% vs. 2.0%) and a twofold increased risk of VPTB (11.5% vs. 5.9%) compared with women of normal weight (BMI 18.4-24.9 kg/m(2)). CONCLUSION(S): Obesity and short stature significantly increase the risk of VEPTB and VPTB in twins conceived by IVF.