Correction to: Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial.

The original version of this article unfortunately contained mistakes. The complete list of corrections is given below.

Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial.

PURPOSE: Implantation failure is a major limiting factor of successful in vitro fertilization (IVF). The objective of this study was to determine if endometrial mechanical stimulation (EMS) by endometrial biopsy in the luteal phase of the cycle prior to embryo transfer (ET) improves clinical outcomes in an unselected subfertile population. METHODS: Double-blind, randomized controlled trial of EMS versus sham biopsy and odds of clinical pregnancy after IVF and embryo transfer. Secondary outcomes included spontaneous miscarriage and live birth. RESULTS: One hundred women enrolled and were randomized from 2013 to 2017. Enrollment was terminated after futility analysis showed no difference in clinical pregnancy between EMS versus control, 47.2% vs 61.7% (OR 0.55, 95% CI 0.25-1.23, p = 0.15). There were no significant differences between women who underwent EMS and those who did not in terms of positive pregnancy test 54.7% vs 63.8% (OR 0.69, 95% CI 0.31-1.53, p = 0.36), miscarriage 7.5% vs 2.1% (OR 3.76 95% CI 0.41-34.85, p = 0.22), or live birth 43.4% vs 61.7% (OR 0.48 95% CI 0.21-1.06, p = 0.07). CONCLUSIONS: EMS in the luteal phase of the cycle preceding embryo transfer does not improve clinical outcomes in an unselected subfertile population and may result in a lower live birth rate. We caution the routine use of EMS in an unselected population.

Ultrasound-guided follicle aspiration at time of laparotomy in a patient with Mayer-Rokitansky-Küster-Hauser syndrome.

OBJECTIVE: To demonstrate a unique case of direct ultrasound-guided follicle aspiration at time of a laparotomy in a patient with Mayer-Rokitansky-Küster-Hauser Syndrome. DESIGN: Video presentation. SETTING: Academic fertility center PATIENT(S): A 32-year-old gravida 0 with Mayer-Rokitansky-Küster-Hauser Syndrome and bilateral ovarian masses presented as a fertility preservation consult from gynecologic oncology due to the possibility of bilateral oophorectomy. Due to the appearance and size of the left ovary oncology planned to perform an exploratory laparotomy and left oophorectomy, with possible right oophorectomy. The patient and her partner desired embryo cryopreservation with plans for future use in a gestational carrier. She had previously undergone vaginal dilator therapy, however her ovaries were inaccessible transvaginally due to their cephalad location and small caliber of the vaginal pouch. The plan was made to proceed with controlled ovarian stimulation and concurrent ultrasound-guided follicle aspiration of the right ovary at the time of laparotomy following left oophorectomy. INTERVENTION(S): Ultrasound-guided follicle aspiration in vivo at time of laparotomy. MAIN OUTCOME MEASURE(S): Successful controlled ovarian stimulation, oocyte retrieval and embryo cryopreservation. RESULT(S): The patient underwent a long agonist protocol and received a total of 2,525 units of gonadotropin with a peak estradiol of 3,264 pg/ml. She required a total of 9 days of stimulation. The normal right ovary responded as expected, and the left ovary remained unchanged. Following laparotomy and left oophorectomy, direct application of the transvaginal ultrasound probe was used to aspirate all visible follicles on the right side in vivo. Twenty-four oocytes were retrieved, 15 were mature and 5 blastocysts were cryopreserved. Final pathology of left ovary returned as serous cystadenoma. The right ovary was examined by gynecologic oncology prior to and following retrieval and was thought to be normal and remained in situ. CONCLUSION(S): Although the approach described here is not feasible in most cases, this video demonstrates a unique and successful fertility preservation technique by direct ultrasound-guided follicle aspiration in vivo at the time of laparotomy in a Mayer-Rokitansky-Küster-Hauser Syndrome patient and to our knowledge, is the first description of its kind. This retrieval would have otherwise been limited by lack of access transvaginally and limited visualization transabdominally. This combined approach should be considered in future patients with müllerian anomalies and similar complicating factors necessitating laparotomy.

Antral follicle count is increased in obese women placed on oral contraceptive pills.

OBJECTIVE: To determine the effect of short-term combined oral contraceptive (OCP) use on antral follicle count (AFC) in obese and nonobese women with infertility. STUDY DESIGN: A retrospective review of women who had an AFC (sum of 2-10 mm bilateral ovarian follicles on basal follicular phase ultrasound) measured before and after short-term OCP use between the years 2005 and 2010. These were women who had a baseline AFC measurement during an unsuccessful controlled ovarian hyperstimulation/intrauterine insemination who were then placed on OCPs prior to an in vitro fertilization (IVF) cycle that included a subsequent AFC measurement at baseline. RESULTS: A total of 57 IVF cycles met criteria for inclusion in the study. AFC was not impacted by OCP use in the nonobese cohort (BMI < 30). Baseline AFC in obese women (BMI ≥ 30), however, increased after OCP use (18 ± 6 vs. 28 ± 9, p = 0.002). CONCLUSION: Use of suppressive medications like OCPs in obese women increases AFC during IVF, potentially by AFC cohort synchrony. This observation warrants consideration when using AFC to predict gonadotropin/ART response as well as future prospective research to further elucidate potential etiologies.

State-mandated insurance coverage is associated with the approach to hydrosalpinges before IVF.

The aim of this study was to determine whether practice in states with infertility insurance mandates is associated with physician-reported practice patterns regarding hydrosalpinx management in assisted reproduction clinics. A cross-sectional, internet-based survey of 442 members of Society for Reproductive Endocrinology and Infertility or Society of Reproductive Surgeons was performed. Physicians practising in states without infertility insurance mandates were more likely to report performing diagnostic surgery after an inconclusive hysterosalpingogram than physicians practising in states with mandates (RR 1.2, 95% CI 1.1-1.3, P < 0.01). Additionally, respondents in states without mandates were more likely to report that, due to lack of infertility insurance coverage, they did not perform salpingectomy (SPX) or proximal tubal occlusion (PTO) before assisted reproduction treatment (RR 1.4, 95% CI 1.1-1.8, P = 0.01). Finally, respondents in states without mandates were less likely to report that the presence of assisted reproduction treatment coverage determined the urgency with which they pursued SPX or PTO before treatment (RR 0.7, 95% CI 0.5-1.0, NS). These results persisted after controlling for physician years in practice, age and clinic volume. In conclusion, self-reported physician practice interventions for hydrosalpinges before assisted reproduction treatment may be associated with state-mandated infertility insurance. Fallopian tube dysfunction is a known cause of infertility and severe dysfunction is manifested by dilation and occlusion, known as hydrosalpinx. Outcomes with assisted reproductive techniques (ART) are lower when hydrosalpinges are present and while there are several theories for this, reproductive specialist recommend "neutralizing" the tube either by occlusion or removal in order to enhance pregnancy rates. In the United States, coverage for infertility services is not uniform with only 15 states having some legislation requiring infertility benefits. Some states where ART is covered liberally, physicians might have different practice patterns related to the neutralization of hydrosalpinges compared to those who are in non -mandated states. We utilized a survey of over 400 providers in the United States to examine their practice patterns as it relates to hydrosalpinges based on which state they practice in and whether or not that state has mandated coverage of not.

Sex-related growth differences are present but not enhanced in in vitro fertilization pregnancies.

OBJECTIVE: To determine whether IVF modifies the effect of fetal sex on growth. DESIGN: Retrospective cohort study. SETTING: Tertiary care center and related facilities. PATIENT(S): Singleton live births without fetal/maternal comorbidities from fertile women who conceived without the use of assisted reproductive technologies and infertile women who conceived with IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was birth weight (BW). Secondary outcomes were fetal crown-rump length (CRL) in the first trimester, biparietal diameter (BPD), and estimated fetal weight (EFW) in the second trimester. RESULT(S): There were no differences in baseline characteristics between women carrying male fetuses and those carrying female fetuses in either mode of conception. In unadjusted analyses, the male-female differentials in fetal BPD and BW were more pronounced in the IVF cohort than in the unassisted cohort. In multivariable regression analysis, male BPD exceeded female BPD by 0.12 cm, male EFW exceeded female EFW by 12 g, and male BW exceeded female BW by 172 g. IVF did not have a significant effect on BPD but was associated with a 52 g increase in EFW in the midgestation. IVF was associated with an 81-g reduction in BW. IVF did not modify the magnitude of size differences between the sexes in the midgestation or at birth. CONCLUSION(S): Comparable sex-dependent differential growth occurs in unassisted and IVF pregnancies.

Sperm banking for fertility preservation: a 20-year experience.

OBJECTIVE: Sperm banking is an effective method to preserve fertility, but is not universally offered to males facing gonadotoxic treatment in the United States. We compared the disposition and semen parameters of cryopreserved sperm from individuals referred for sperm banking secondary to a cancer diagnosis to those of sperm from men banking for infertility reasons. STUDY DESIGN: We performed a retrospective cohort study that reviewed 1118 records from males who presented to bank sperm at Washington University between 1991 and 2010. We collected and analyzed demographics, semen parameters, and disposition of banked sperm. RESULTS: Four hundred and twenty-three men with cancer and 348 banking for infertility reasons attempted sperm cryopreservation in our unit during the specified time period. The most prevalent cancers in our cohort were testicular (32%), lymphoma (25%), and leukemia (11%). Patients with leukemia had the lowest pre-thaw counts and motility. Most cancer patients (57%) who banked elected to use, transfer to another facility, or keep their specimens in storage. The remaining samples were discarded electively (34%) or following death (8%). Overall semen parameters were similar between the cancer and infertility groups, but demographics, ability to bank a sample, azoospermia rates, length of storage, current banking status, and use of banked sperm differed significantly between the two groups. CONCLUSIONS: The majority of cancer patients who banked survived their cancer and chose to continue storage of banked samples. Cancer patients were more likely than infertility patients to use or continue storage of banked samples. Our study provides evidence that sperm banking is a utilized modality of fertility preservation in patients with a myriad of cancer diagnoses and should be offered to all men facing gonadotoxic therapies. Further work is needed to determine where disparities in access to sperm banking exist to improve the potential for future fertility in these males.

A retrospective cross-sectional study: fresh cycle endometrial thickness is a sensitive predictor of inadequate endometrial thickness in frozen embryo transfer cycles.

BACKGROUND: The purpose of this study is to assess predictors of inadequate endometrial cavity thickness (ECT), defined as < 8 mm, in frozen embryo transfer (FET) cycles. METHODS: This is a retrospective cross-sectional study at an academic fertility center including 274 women who underwent their first endometrial preparation with estradiol for autologous FET in our center from 2001-2009. Multivariable logistic regression was performed to determine predictors of inadequate endometrial development in FET cycles. RESULTS: Neither age nor duration of estrogen supplementation were associated with FET endometrial thickness. Lower body mass index, nulliparity, previous operative hysteroscopy and thinner fresh cycle endometrial lining were associated with inadequate endometrial thickness in FET cycles. A maximum thickness of 11.5 mm in a fresh cycle was 80% sensitive and 70% specific for inadequate frozen cycle thickness. CONCLUSIONS: Previous fresh cycle endometrial cavity thickness is associated with subsequent FET cycle endometrial cavity thickness. Women with a fresh cycle thickness of 11.5 mm or less may require additional intervention to achieve adequate endometrial thickness in preparation for a frozen cycle.

How members of the Society for Reproductive Endocrinology and Infertility and Society of Reproductive Surgeons evaluate, define, and manage hydrosalpinges.

OBJECTIVE: To describe the management of hydrosalpinges among Society for Reproduction Endocrinology and Infertility (SREI)/Society of Reproductive Surgeons (SRS) members. DESIGN: Cross-sectional survey of SREI/SRS members. SETTING: Academic and private practice-based reproductive medicine physicians. PARTICIPANT(S): A total of 442 SREI and/or SRS members. INTERVENTION(S): Internet-based survey. MAIN OUTCOME MEASURE(S): To understand how respondents evaluate, define, and manage hydrosalpinges. RESULT(S): Of 1,070 SREI and SRS members surveyed, 442 responded to all items, for a 41% response rate. Respondents represented both academic and private practice settings, and differences existed in the evaluation and management of hydrosalpinges. More than one-half (57%) perform their own hysterosalpingograms (HSGs), and 54.5% involve radiologists in their interpretation of tubal disease. Most respondents thought that a clinically significant hydrosalpinx on HSG is one that is distally occluded (80.4%) or visible on ultrasound (60%). Approximately one in four respondents remove a unilateral hydrosalpinx before controlled ovarian hyperstimulation (COH)/intrauterine insemination (IUI) and clomiphene citrate (CC)/IUI (29.3% and 22.8%, respectively), and physicians in private practice were more likely to intervene (COH: risk ratio [RR] 1.81, 95% confidence interval [CI] 1.31-2.51; CC: RR 1.98, 95% CI 1.33-2.95). Although laparoscopic salpingectomy was the preferred method of surgical management, nearly one-half responded that hysteroscopic tubal occlusion should have a role as a primary method of intervention. CONCLUSION(S): SREI/SRS members define a "clinically significant hydrosalpinx" consistently, and actual practice among members reflects American Society for Reproductive Medicine/SRS recommendations, with variation attributed to individual patient needs. Additionally, one in four members intervene before other infertility treatments when there is a unilateral hydrosalpinx present.

Smaller fetal size in singletons after infertility therapies: the influence of technology and the underlying infertility.

OBJECTIVE: To determine whether fetal size differences exist between matched fertile and infertile women and among women with infertility achieving pregnancy through various treatment modalities. DESIGN: Retrospective cohort study with propensity score analysis. SETTING: Tertiary care center and affiliated community hospitals. PATIENT(S): 1,246 fertile and 461 infertile healthy women with singleton livebirths over a 10-year period. INTERVENTION(S): Infertile women conceiving without medical assistance, with ovulation induction, or with in vitro fertilization. MAIN OUTCOME MEASURE(S): Birthweight; secondary outcomes included crown-rump length, second-trimester estimated fetal weight, and incidence of low birth weight and preterm delivery. RESULT(S): Compared with matched fertile women, infertile women had smaller neonates at birth (3,375 ± 21 vs. 3,231 ± 21 g) and more low-birth-weight infants (relative risk = 1.68, 95% confidence interval, 1.06, 2.67). Neonates conceived via ovulation induction were the smallest among the infertility subgroups compared with the neonates of fertile women (3,092 ± 46 vs. 3,397 ± 44 g). First-trimester fetal size was smaller in infertile versus fertile women (crown-rump length 7.9 ± 0.1 vs. 8.5 ± 0.1 mm). Within the infertility subgroups, no differences in fetal or neonatal size were found. CONCLUSION(S): The inherent pathologic processes associated with infertility may have a larger impact on fetal growth than infertility therapies.

Elevated serum α-linolenic acid levels are associated with decreased chance of pregnancy after in vitro fertilization.

OBJECTIVE: To analyze relationships between serum free fatty acid (FFA) concentrations and pregnancy. DESIGN: Prospective cohort. SETTING: University hospital. PATIENT(S): Ninety-one women undergoing IVF. INTERVENTION(S): Serum was analyzed for total and specific serum FFAs, including myristic, palmitic, stearic, oleic, linoleic, and α-linolenic acids. MAIN OUTCOME MEASURE(S): Univariate analyses were used to identify specific FFAs and other factors associated with pregnancy after IVF. Logistic regression was performed modeling relationships between identified factors and chance of pregnancy. RESULT(S): In unadjusted analyses, women with elevated serum α-linolenic acid (ALA) levels (highest quartile) demonstrated a decreased chance of pregnancy compared with women with the lowest levels (odds ratio 0.24, 95% confidence interval 0.052-0.792). No associations between other FFAs and pregnancy were identified. In a multivariable regression model, associations between elevated serum ALA levels and decreased chance of pregnancy remained after adjusting for patient age, body mass index, and history of endometriosis or previous live birth (adjusted odds ratio 0.139, 95% confidence interval 0.028-0.686). CONCLUSION(S): Elevated serum ALA levels are associated with decreased chance of pregnancy in women undergoing IVF. Further work is needed to determine whether ALA is involved in early reproductive processes and whether the relationship between ALA and pregnancy is associated with excess ALA intake, impaired ALA metabolism, or both.

Associations between free fatty acids, cumulus oocyte complex morphology and ovarian function during in vitro fertilization.

OBJECTIVE: To determine if follicular free fatty acid (FFA) levels are associated with cumulus oocyte complex (COC) morphology. DESIGN: Prospective cohort study. SETTING: University in vitro fertilization (IVF) practice. PATIENT(S): A total of 102 women undergoing IVF. INTERVENTION(S): Measurement of FFAs in serum and ovarian follicular fluid. MAIN OUTCOME MEASURE(S): Total and specific follicular and serum FFA levels, correlations between follicular and serum FFAs, and associations between follicular FFA levels and markers of oocyte quality, including COC morphology. RESULT(S): Predominant follicular fluid and serum FFAs were oleic, palmitic, linoleic, and stearic acids. Correlations between follicular and serum FFA concentrations were weak (r=0.252, 0.288, 0.236, 0.309, respectively for specific FFAs; r=0.212 for total FFAs). A receiver operating characteristic curve determined total follicular FFAs≥0.232 µmol/mL distinguished women with a lower versus higher percentage of COCs with favorable morphology. Women with elevated follicular FFAs (n=31) were more likely to have COCs with poor morphology than others (n=71; OR 3.3, 95% CI1.2-9.2). This relationship held after adjusting for potential confounders, including age, body mass index, endometriosis, and amount of gonadotropin administered (ß=1.2; OR 3.4, 95% CI 1.1-10.4). CONCLUSION(S): Elevated follicular FFA levels are associated with poor COC morphology. Further work is needed to determine what factors influence follicular FFA levels and if these factors impact fertility.

Polycystic ovary syndrome and maternal obesity affect oocyte size in in vitro fertilization/intracytoplasmic sperm injection cycles.

To determine the impact of maternal metabolic state on oocyte development in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), we retrospectively analyzed a cohort of women with PCOS undergoing IVF/ICSI from 2008-2009 in a university-based fertility center. We determined that women with PCOS and obesity have smaller oocytes than control subjects, and that when further subdivided by body mass index, both PCOS and obesity independently influence oocyte size.

In vitro fertilization after bariatric surgery.

Few data exist regarding IVF in women who have undergone bariatric surgery. Our experience with five patients suggests that IVF is a safe and effective fertility treatment for these women, although special considerations should be made when treating patients who have undergone bariatric surgery. Considering the type of bypass procedure the patient underwent is particularly important should a patient develop concerning symptoms during her IVF cycle.

Embryo transfer practices in the United States: a survey of clinics registered with the Society for Assisted Reproductive Technology.

OBJECTIVE: To gain a better understanding of factors influencing clinicians' embryo transfer practices. DESIGN: Cross-sectional survey. SETTING: Web-based survey conducted in December 2008 of individuals practicing IVF in centers registered with the Society for Assisted Reproductive Technology (SART). PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of clinicians reporting following embryo transfer guidelines recommended by the American Society for Reproductive Medicine (ASRM), prevalence among these clinicians to deviate from ASRM guidelines in commonly encountered clinical scenarios, and practice patterns related to single embryo transfer. RESULT(S): Six percent of respondents reported following their own, independent guidelines for the number of embryos to transfer after IVF. Of the 94% of respondents who reported routinely following ASRM embryo transfer guidelines, 52% would deviate from these guidelines for patient request, 51% for cycles involving the transfer of frozen embryos, and 70% for patients with previously failed IVF cycles. All respondents reported routinely discussing the risks of multiple gestations associated with standard embryo transfer practices, whereas only 34% reported routinely discussing single embryo transfer with all patients. CONCLUSION(S): Although the majority of clinicians responding to our survey reported following ASRM embryo transfer guidelines, at least half would deviate from these guidelines in a number of different situations.

A prospective, randomized, double-blinded study of assisted hatching in women younger than 38 years undergoing in vitro fertilization.

OBJECTIVE: To determine whether assisted hatching is beneficial to IVF patients younger than 38 years whose embryos have a thickened zona pellucida (ZP). DESIGN: Prospective, randomized, double-blinded, crossover study. SETTING: University-based infertility center. PATIENT(S): One hundred twenty-one women less than 38 years of age, undergoing IVF at Washington University between April 2004 and February 2007, with ZP thickness > or =13 microm for any embryos. INTERVENTION(S): Measurement of ZP thickness in embryos undergoing IVF; randomization of women with embryos with ZP thickness > or =13 microm to no procedure or assisted hatching performed by acidic Tyrode's solution. MAIN OUTCOME MEASURE(S): Clinical intrauterine pregnancy rate, implantation rate, spontaneous pregnancy loss, and live birth rate. RESULT(S): Baseline characteristics and ZP thickness were not significantly different between the two study arms (hatched and unhatched). No significant differences were observed between hatched and unhatched patients in the rates of clinical pregnancy (47% vs. 50% respectively) or live birth (46% vs. 45% respectively). Further, no significant differences were noted between hatched and unhatched groups in rates of spontaneous abortions, monozygotic twinning, dizygotic twinning, chromosomal abnormalities, or ectopic gestations. In addition, mean ZP thickness did not have a significant effect on pregnancy. CONCLUSION(S): In patients younger than 38 years with embryos with ZP thickness of > or =13 microm, assisted hatching does not improve the rates of implantation, clinical pregnancy, or live birth, and thus does not appear to offer any benefit to patients in this age group undergoing IVF.

Qualitative point-of-care and over-the-counter urine hCG devices differentially detect the hCG variants of early pregnancy.

BACKGROUND: Qualitative point-of-care (POC) tests for human chorionic gonadotropin (hCG) vary in their ability to detect purified hCG variants and there is data to suggest that over-the-counter (OTC) devices might also display similar variability. This could potentially influence the detection of urine hCG in early pregnancy. METHODS: Six OTC devices were tested for their ability to detect 5 hCG variants. Ten early pregnancy urine specimens were selected for their diverse expression of hCG variants. The samples were tested with 6 brands of POC and 6 OTC devices. RESULTS: OTC devices consistently recognized intact hCG, hCGn, and hCGbeta. hCGbetan was consistently recognized by 4 out of 6 brands. One brand inconsistently recognized hCGbetacf. OTC and POC devices varied greatly in their ability to detect hCG in early pregnancy urine, despite the fact that urine samples were adjusted to the same intact hCG concentration. Interestingly, we found that the OTC devices had better analytical sensitivity than the POC devices. Clinitest and First Response demonstrated the lowest hCG detection limits for POC and OTC devices, respectively. CONCLUSIONS: Both OTC and POC devices are capable of detecting hCG concentrations in early pregnancy urine, and OTC devices demonstrated better analytical sensitivity relative to POC devices.

Morbid obesity is associated with lower clinical pregnancy rates after in vitro fertilization in women with polycystic ovary syndrome.

OBJECTIVE: To determine whether morbid obesity is associated with decreased pregnancy and live birth rates after IVF in women with polycystic ovary syndrome (PCOS). DESIGN: Retrospective cohort study. SETTING: University-based fertility center. PATIENT(S): Seventy-two women with PCOS who completed their first IVF cycle between 2001 and 2006. INTERVENTION(S): Outcomes of IVF were compared between women with a body mass index (BMI) of <40 kg/m(2) vs. those with a BMI of > or =40 kg/m(2). MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, live birth rate. RESULT(S): Morbidly obese women with PCOS (n = 19) had significantly lower clinical pregnancy rates after IVF than patients with PCOS who were not morbidly obese (n = 53) (32% vs. 72%, relative risk 0.44, 95% confidence interval 0.22-0.87). Their live birth rates were lower too, although this difference was not statistically significant (32% vs. 60%, relative risk 0.52, 95% confidence interval 0.26-1.05). CONCLUSION(S): Morbid obesity is associated with lower pregnancy rates in women with PCOS after IVF, raising the question of whether weight loss may improve IVF success rates for morbidly obese PCOS patients.

Encouraging patient-driven single-embryo transfer.

Single-embryo transfer (SET) removes the risk of multiples in in vitro fertilization (IVF), but women with unfavorable IVF prognosis have been dissuaded from SET despite their desire to avoid multiples. In our clinic, 54% of the women who requested SET delivered healthy singletons, even though only two of them had met the American Society for Reproductive Medicine's SET guidelines. This demonstrates the value of encouraging patient-driven SET.