Tubal flushing with oil- or water-based contrast medium: can we identify markers that indicate treatment benefit?

STUDY QUESTION: Can we identify patient characteristics that distinguish which ovulatory infertile women undergoing hysterosalpingography (HSG) benefit more or less from flushing with oil-based contrast medium compared to water-based contrast medium? SUMMARY ANSWER: In ovulatory infertile women, HSG with oil-based contrast medium resulted in higher 6-month ongoing pregnancy and live birth rates as compared to HSG with water-based contrast medium and this treatment effect was independent of characteristics of the couple. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, flushing with oil-based contrast medium resulted in more ongoing pregnancies than flushing with water-based contrast medium. STUDY DESIGN SIZE DURATION: We used data from our randomized clinical trial (RCT) in which 1,119 ovulatory infertile women undergoing HSG during fertility work-up were randomized for use of oil-based (N = 557) or water-based (N = 562) contrast medium. PARTICIPANTS/MATERIALS SETTING METHODS: We built logistic regression models to predict ongoing pregnancy and live birth (secondary outcome) as a function of the specific contrast, the specific marker, and marker-by-contrast-interaction. Markers considered were female age, maternal ethnicity, female smoking, body mass index (BMI), duration of infertility, infertility being primary or secondary, sperm quality, and previous appendectomy. MAIN RESULTS AND THE ROLE OF CHANCE: The 6-month ongoing pregnancy rates in the overall population were 39.7% after use of oil-based contrast versus 29.1% after use of water-based contrast medium [relative risk (RR), 1.37; 95% confidence interval (CI), 1.16-1.61; P < 0.001]. Among the studied baseline characteristics, BMI (P = 0.002) and semen volume (P = 0.02) were statistically significant prognosticators. The treatment effect of oil-based contrast was stronger in women with a BMI ≤30 kg/m2 [RR, 1.54; 95% CI, 1.23-1.92; P = 0.002], and in women whose partner had a semen volume >3 ml [RR, 1.77; 95% CI, 1.28-2.46; P = 0.02]. Also, in women who smoked, the treatment effect of flushing with oil was stronger, but this interaction did not reach statistical significance (P = 0.066). We found no positive effect of oil-based contrast in obese women. We found similar but weaker associations for live birth, which was probably due to lower number of events resulting in less power. LIMITATIONS REASONS FOR CAUTION: The RCT was restricted to infertile ovulatory women younger than 39 years of age without endocrinological disorders and at low risk for tubal pathology. Our results should not be generalized to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: All infertile, ovulatory women younger than 39 years with a low risk for tubal pathology will benefit from an HSG with oil-based contrast; therefore, this should be offered to them after fertility work-up. STUDY FUNDING/COMPETING INTERESTS: The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The study displayed in this paper was funded by an unconditional research grant from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). K.D. reports consultancy for Guerbet, during the conduct of the study, and also reports research grants from Guerbet. C.B.L. reports grants from Guerbet, during the conduct of the study, and grants from Ferring, grants from Merck, and personal fees from Ferring, outside the submitted work. P.H. reports grants from Guerbet, during the conduct of the study, and grants from Ferring and Merck, outside the submitted work. V.M. reports receiving travel and speakers fee as well as research grants from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, and Guerbet, and research grants from Guerbet and Merck. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: NTR 3270 www.trialregister.nl. TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

Oil-based or water-based contrast for hysterosalpingography in infertile women: a cost-effectiveness analysis of a randomized controlled trial.

OBJECTIVE: To determine the cost effectiveness of the use of oil-based versus water-based contrast in infertile women undergoing hysterosalpingography (HSG). DESIGN: Economic evaluation alongside a multicenter randomized trial. SETTING: Hospitals. PATIENT(S): Infertile women with an ovulatory cycle, 18-39 years of age, low risk of tubal pathology. INTERVENTION(S): Use of oil-based versus water-based contrast during HSG. MAIN OUTCOME MEASURE(S): Costs per additional ongoing pregnancy and per live birth within 6 months of randomization, incremental cost-effective ratios (ICERs). RESULT(S): A total of 1,119 women were randomized to HSG (oil-based contrast, n = 557; water-based contrast, n = 562). After HSG, most women had no additional treatment; a minority had IUI or IVF. In the oil group, 39.7% women had an ongoing pregnancy within 6 months of randomization versus 29.1% women in the water group. There was a 10.7% increase in the live birth rate in the oil group. For ongoing pregnancy, the mean costs per couple were US$2,014 in the oil group and US$1,144 in the water group, with a corresponding ICER of US$8,198 per additional ongoing pregnancy. For live birth, the mean costs per couple were US$11,532 in the oil group and US$8,310 in the water group, with a corresponding ICER of US$30,112 per additional live birth. CONCLUSION(S): Hysterosalpingography with oil-based contrast results in higher 6-month ongoing pregnancy and live birth rate. If society is willing to pay US$8,198 for an additional ongoing pregnancy, HSG with oil-based contrast is a cost-effective strategy compared with HSG with water-based contrast for infertile, ovulatory women at low risk for tubal pathology. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Register, NTR 6577 (www.trialregister.nl).

Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial.

BACKGROUND: In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. METHODS: In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. FINDINGS: Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05-1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97-1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. INTERPRETATION: In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. FUNDING: The Netherlands Organization for Health Research and Development.

Oil-Based or Water-Based Contrast for Hysterosalpingography in Infertile Women.

BACKGROUND: Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect. METHODS: We performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle. RESULTS: A total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval [CI], 1.16 to 1.61; P<0.001), and 214 of 552 women in the oil group (38.8%) and 155 of 552 women in the water group (28.1%) had live births (rate ratio, 1.38; 95% CI, 1.17 to 1.64; P<0.001). Rates of adverse events were low and similar in the two groups. CONCLUSIONS: Rates of ongoing pregnancy and live births were higher among women who underwent hysterosalpingography with oil contrast than among women who underwent this procedure with water contrast. (Netherlands Trial Register number, NTR3270 .).

Cost-effectiveness of single versus double embryo transfer in IVF in relation to female age.

OBJECTIVE: To evaluate the cost-effectiveness of single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available, as compared to double embryo transfer in relation to female age. STUDY DESIGN: We used a decision tree model to evaluate the costs from a healthcare provider perspective and the pregnancy rates of two embryo transfer policies: one fresh single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available (strategy I), and double embryo transfer (strategy II). The analysis was performed on an intention-to-treat basis. Sensitivity analyses were carried out to evaluate the robustness of our model and to identify which model parameters had the strongest impact on the results. RESULTS: SET followed by an additional frozen-thawed single embryo transfer if available was dominant, less costly and more effective, over DET in women under 32 years. In women aged 32 or older DET was more effective than SET followed by an additional frozen-thawed single embryo transfer if available but also more costly. CONCLUSION: SET followed by an additional frozen-thawed single embryo transfer should be the preferred strategy in women under 32 undergoing IVF. The choice for SET followed by an additional frozen-thawed single embryo transfer or DET in women aged 32 or older depends on individual patient preferences and on how much society is willing to pay for an extra child. There is a strong need for a randomized clinical trial comparing the cost and effects of SET followed by an additional frozen-thawed single embryo transfer and DET in the latter category of women.

A revised prediction model for natural conception.

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples (20%). All predictors of the Hunault model were selected into the revised model plus an additional seven (woman's body mass index, cycle length, basal FSH levels, tubal status,history of previous pregnancies in the current relationship (ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 (95% CI 0.69 to 0.73) compared with 0.59 (95% CI 0.57 to 0.61).

The effectiveness of intrauterine insemination: A matched cohort study.

OBJECTIVE: To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception. STUDY DESIGN: A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment. RESULTS: After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59-2.2)(p=0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p=0.86). CONCLUSIONS: In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples.

Reporting multiple cycles in trials on medically assisted reproduction.

Trials assessing effectiveness in medically assisted reproduction (MAR) should aim to study the desired effect over multiple cycles, as this reflects clinical practice and captures the relevant perspective for the couple. The aim of this study was to assess the extent to which multiple cycles are reported in MAR trials. A sample of randomized controlled trials (RCT) was collected on MAR, published in four time periods, in 11 pre-specified peer-reviewed journals; 253 trials were included: 196 on IVF, 37 on intrauterine insemination and 20 on ovulation induction. Forty-eight (19%) reported on multiple cycles, which was significantly more common in trials on intrauterine insemination and ovulation induction compared with trials on IVF (P < 0.01). Both trials on IVF were multi-centre trials, and those using live birth as primary outcome, reported significantly more often on multiple cycles (OR 3.7 CI 1.1 to 12.5) and (OR 8.7 CI 1.8 to 40.3), respectively. Trials designed to compare protocol variations reported multiple cycles less often (OR 0.07 CI 0.01 to 0.74). Most RCT on MAR, especially those on IVF, do not report cumulative pregnancy rates. As not all women become pregnant in their first cycle, the clinical significance of these trials is limited.

Dropout rates in couples undergoing in vitro fertilization and intrauterine insemination.

OBJECTIVE: To compare dropout rates in couples undergoing conventional in vitro fertilization with single embryo transfer (IVF-SET), in vitro fertilization in a modified natural cycle (IVF-MNC) or intrauterine insemination with ovarian stimulation (IUI-OS). STUDY DESIGN: Secondary analysis of a multicentre randomized controlled trial between January 2009 and February 2012. 602 couples with unexplained or mild male subfertility, allocated to IVF-SET (N=201), IVF-MNC (N=194) and IUI-OS (N=207). MAIN OUTCOME MEASURES: Dropouts, defined as couples who discontinued their allocated three cycles of IVF-SET, six cycles of IVF-MNC or IUI-OS, without having achieved a pregnancy. We classified dropouts as "following medical advice" or "patient initiated". RESULT(S): Thirty couples (15%) allocated to IVF-SET dropped out and 45 couples (23%) allocated to IVF-MNC, compared to 26 couples (13%) allocated to IUI-OS; relative risk (RR) 1.2 (95%CI; 0.73-1.9) for IVF-SET and 1.9 (95%CI; 1.2-2.9) for IVF-MNC, both compared to IUI-OS. Nine couples (4.5%) allocated to IVF-SET, 14 (7.2%) allocated to IVF-MNC and 14 (6.8%) allocated to IUI-OS dropped out following medical advice; RR of 0.51 (95%CI; 0.21-1.2) for IVF-SET and 0.84 (95%CI; 0.39-1.80) for IVF-MNC, both versus IUI-OS. Twenty-one couples (10%) allocated to IVF-SET were patient initiated dropouts, as were 31 (16%) allocated to IVF-MNC and 12 (5.8%) allocated to IUI-COS; RR 1.8 (95%CI; 0.91-3.6) for IVF-SET and 2.8 (95%CI; 1.5-5.2) for IVF-MNC both versus IUI-OS. CONCLUSION(S): IVF-SET and IUI-OS result in comparable drop-out rates, while drop-out rates after IVF-MNC are almost twice as high, mainly driven by patient preferences.

Embryo Transfer with Controlled Injection Speed to Increase Pregnancy Rates: A Randomized Controlled Trial.

BACKGROUND/AIMS: Catheter injection speed affects depth and placement of the embryo into the uterine cavity and is shown to be highly variable in, and between, subjects in a manually performed embryo transfer. In an effort to standardize the injection speed during embryo transfer, we developed an automated transfer pump: the pump-regulated embryo transfer (PRET) device. In this randomized controlled trial, we aimed to investigate if standardization of the injection speed and pressure with this PRET results in a better controlled positioning of the transferred embryo(s). METHODS: Five hundred ninety-nine in-vitro fertilization/intracytoplasmic sperm injection/frozen-thawed embryo transfer cycles were randomly assigned to the PRET or manual transfer. Positioning of the embryo(s) into the uterine cavity was measured with ultrasound. RESULTS: The PRET device generates a significantly smaller variance of the positioning of the embryo(s) into the uterine cavity. This resulted in an ongoing pregnancy rate of 21% in the PRET versus 17% in the manual (p = 0.22) transfer group; frozen-thawed embryo transfers resulted in 17.5 versus 10.9% (p = 0.097), respectively. CONCLUSION: The PRET results in better controlled positioning of the embryo(s), and it also gives the opportunity to standardize embryo transfer. Whether the PRET may positively influence pregnancy rates, needs to be investigated in a multicenter trial.

Reducing Inter-Laboratory Differences between Semen Analyses Using Z Score and Regression Transformations.

BACKGROUND: Standardization of the semen analysis may improve reproducibility. We assessed variability between laboratories in semen analyses and evaluated whether a transformation using Z scores and regression statistics was able to reduce this variability. MATERIALS AND METHODS: We performed a retrospective cohort study. We calculated between-laboratory coefficients of variation (CVB) for sperm concentration and for morphology. Subsequently, we standardized the semen analysis results by calculating laboratory specific Z scores, and by using regression. We used analysis of variance for four semen parameters to assess systematic differences between laboratories before and after the transformations, both in the circulation samples and in the samples obtained in the prospective cohort study in the Netherlands between January 2002 and February 2004. RESULTS: The mean CVBwas 7% for sperm concentration (range 3 to 13%) and 32% for sperm morphology (range 18 to 51%). The differences between the laboratories were statistically significant for all semen parameters (all P<0.001). Standardization using Z scores did not reduce the differences in semen analysis results between the laboratories (all P<0.001). CONCLUSION: There exists large between-laboratory variability for sperm morphology and small, but statistically significant, between-laboratory variation for sperm concentration. Standardization using Z scores does not eliminate between-laboratory variability.

Does the postcoital test predict pregnancy in WHO II anovulatory women? A prospective cohort study.

OBJECTIVE: To assess the capacity of the postcoital test (PCT) to predict pregnancy in WHO II anovulatory women who are ovulatory on clomiphene citrate (CC). In these women, an abnormal PCT result could be associated with lower pregnancy chances, but this has never been proven or refuted. STUDY DESIGN: Prospective cohort study was performed between December 2009 and September 2012 for all women who started ovulation induction with CC in one university clinic and two teaching hospitals in the Netherlands. A PCT was performed in one of the first three ovulatory cycles. Ovulation induction with CC was continued for at least six cycles. The PCT was judged to be positive if at least one progressive motile spermatozo was seen in one of five high power fields at 400× magnification. The primary outcome was time to ongoing pregnancy, within six ovulatory cycles. RESULTS: In 152 women the PCT was performed. 135 women had a reliable, well-timed PCT. The ongoing pregnancy rate was 44/107 (41%) for a positive and 10/28 (36%) for a negative PCT. The hazard rate for ongoing pregnancy was 1.3 (95% CI 0.64-2.5) for a positive versus a negative PCT. Thirty five of 77 (46%) women with clear mucus had an ongoing pregnancy versus 12 of 45 (27%) women in whom the mucus was not clear (HR 2.0; 95% CI 1.02-3.84, p=0.04). CONCLUSION: The present study suggests that the outcome of the postcoital test in women with WHO-II anovulation that undergo ovulation induction with CC does not have a large effect on ongoing pregnancy chances over time.

Does polycystic ovary syndrome affect cognition? A functional magnetic resonance imaging study exploring working memory.

OBJECTIVE: To study effects of overexposure to androgens and subsequent antiandrogenic treatment on brain activity during working memory processes in women with polycystic ovary syndrome (PCOS). DESIGN: In this longitudinal study, working memory function was evaluated with the use of functional magnetic resonance imaging (MRI) in women with PCOS before and after antiandrogenic treatment. SETTING: Department of reproductive medicine, university medical center. PATIENT(S): Fourteen women with PCOS and with hyperandrogenism and 20 healthy control women without any features of PCOS or other hormonal disorders. INTERVENTION(S): Antiandrogenic hormone treatment. MAIN OUTCOME MEASURE(S): Functional MRI response during a working memory task. RESULT(S): At baseline women with PCOS showed more activation than the control group within the right superior parietal lobe and the inferior parietal lobe during task (all memory conditions). Task performance (speed and accuracy) did not differ between the groups. After antiandrogenic treatment the difference in overall brain activity between the groups disappeared and accuracy in the high memory load condition of the working memory task increased in women with PCOS. CONCLUSION(S): Women with PCOS may need additional neural resources during a working memory task compared with women without PCOS, suggesting less efficient executive functioning. This inefficiency may have effects on daily life functioning of women with PCOS. Antiandrogenic treatment appears to have a beneficial effect on this area of cognitive functioning. CLINICAL TRIAL REGISTRATION NUMBER: NTR2493.

Presence of human papillomavirus in semen in relation to semen quality.

STUDY QUESTION: Is the presence of human papillomavirus (HPV) in semen associated with impairment of semen quality? SUMMARY ANSWER: In a large cohort of males seeking fertility evaluation, no associations were observed between seminal HPV presence and semen parameters. WHAT IS KNOWN ALREADY: HPV is commonly detected in semen samples. Whether the presence of HPV is related to impairment of semen quality, remains unclear. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included a cohort of 430 males. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male partners in couples seeking fertility evaluation provided one semen sample per person. Semen samples were tested for HPV-DNA using GP5+/6+-PCR. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. The presence of antisperm antibodies was assessed by a mixed agglutination reaction (MAR)-test. MAIN RESULTS AND THE ROLE OF CHANCE: Overall HPV was detected in 14.9% (64/430) of semen samples, including 2.1% (9/430) that contained both high-risk (hr) HPV and low-risk (lr) HPV types, 8.8% (38/430) with exclusively hrHPV types and 4.0% (17/430) with exclusively lrHPV types. The presence of HPV in semen was not associated with the age of the participants, seminal pH, semen volume, total sperm count, sperm concentration, progressive motility or the presence of antisperm antibodies. LIMITATIONS, REASONS FOR CAUTION: This study did not observe an association between HPV presence in semen and impairment of semen quality. However, we cannot exclude an effect of seminal HPV on early embryo development and clinical reproductive outcomes. WIDER IMPLICATIONS OF THE FINDINGS: As HPV is frequently present in semen, screening of donor semen for HPV should be considered to prevent iatrogenic cervical HPV infections in the recipient. However our findings do not support standardized HPV testing of semen in the diagnostic work-up of subfertile couples. STUDY FUNDING/COMPETING INTERESTS: This study was sponsored by an unrestricted grant of Stichting Researchfonds Pathology Amsterdam, the Netherlands. P.J.F.S. has been on the speakers bureau of Roche, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell B.V. J.B. has been on the speakers bureau of Qiagen and has been a consultant for Roche, DDL Diagnostic Laboratory, GlaxoSmithKline and Merck. D.A.M.H. has been member of the scientific advisory boards of Amgen and Pfizer, and has been on the speakers bureau of Hologic/Gen-Probe. C.J.L.M.M. has been on the speakers bureau of GlaxoSmithKline, Qiagen, Merck, Roche, Menarini and Seegene, has served occasionally on the scientific advisory board of GlaxoSmithKline, Qiagen, Merck, Roche and Genticel, and has occasionally been a consultant for Qiagen. Formerly, C.J.L.M.M. was a minority shareholder of Delphi Biosciences, which bankrupted in 2014. C.J.L.M.M. is a minority shareholder of Diassay B.V. P.J.F.S., D.A.M.H. and C.J.L.M.M. have minority stake in Self-Screen B.V., a spin-off company of VU University Medical Center. R.L., M.G.D., P.G.A.H., D.T.M.P., and I.H. do not have any conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome.

OBJECTIVE: Little is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls. DESIGN: Prospective case-control study. METHODS: Maternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E1), estradiol (E2), estriol (E3)) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. RESULTS: At 20 weeks of gestation: T (P=0.019) and ADION (P=0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E1, E2, and E3 were not different. Maternal concentration at birth: T (P=0.004) and ADION (P=0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E1, E2 and E3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E2, E3, and AMH between the PCOS mothers and the controls respectively. E1 was lower in girls from PCOS mothers (P=0.007). CONCLUSIONS: Despite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods.

Mid-pregnancy, perinatal, and neonatal reproductive endocrinology: a prospective cohort study in twins and singleton control subjects.

OBJECTIVE: To answer the questions: Are perinatal reproductive hormone profiles different in case of a twin compared with a singleton pregnancy? Are reproductive endocrine profiles of twin girls influenced by their male co-twin and vice versa? DESIGN: Prospective cohort study from January 2004 to October 2009. SETTING: Not applicable. PATIENT(S): A total of 204 mothers of twins and 248 singleton control subjects, aged >18 years, pregnant with a twin or singleton and no endocrine disease or malignancy. INTERVENTION(S): Blood samples were collected at mid-gestation from the mother and at delivery from the mothers and the umbilical cords. Estrogens, androgens, sex hormone-binding globulin, progesterone, and gonadotropins were measured. MAIN OUTCOME MEASURE(S): Hormonal profiles were compared between singletons and twins, different types of twins, and opposite-sex and same-sex twins. RESULT(S): Estrogen and progesterone concentrations were higher in mothers of twins compared with singletons, but twin babies had lower estrogen and progesterone concentrations at birth. Opposite-sex twin girls did not have higher androgens in cord blood compared with same-sex twin girls. Boys of an opposite-sex twin had lower luteinizing hormone concentrations compared with dizygotic twin boys with a brother as a co-twin. CONCLUSION(S): Children from a twin are not overexposed to sex steroids at the time of birth, despite higher concentrations in their mothers, and girls from opposite sex twins do not show androgenic influences from their male co-twin. The female co-twin may influence the hypothalamic-pituitary-testicular axis of her brother via central inhibition.

Presence of human papillomavirus in semen of healthy men is firmly associated with HPV infections of the penile epithelium.

OBJECTIVE: To study the source of human papillomavirus (HPV) in semen. DESIGN: Observational study (CCMO-NL3248800010). SETTING: Academic hospital-based laboratory. PATIENT(S): Healthy male volunteers (n = 213). INTERVENTION(S): One penile scrape and three semen samples were obtained per participant for HPV-DNA testing by both GP5+/6+ polymerase chain reaction (PCR) and SPF10-PCR to detect moderate/high and low viral loads, respectively; flat penile lesions (FPL) were detected by penoscopy. MAIN OUTCOME MEASURE(S): HPV-DNA presence in semen and penile scrapes, and the presence of FPL. RESULT(S): HPV-DNA at moderate/high viral loads (i.e., GP5+/6+ PCR-positive) was detected in ≥1 semen sample(s) in 27% of participants. Most men with moderate/high viral loads in the penile scrape also had moderate/high viral loads in semen (85%). Men with a HPV-negative penile scrape were very unlikely to have moderate/high viral loads in semen (3%). The presence of HPV in semen was associated with the presence of HPV in the penile scrape also on a genotype-specific level. Having FPL was a risk factor for HPV presence in semen. CONCLUSION(S): HPV-DNA presence in semen of healthy men is common and associated with HPV infections of the penile epithelium. HPV-DNA presence in semen may result from desquamation of HPV-infected penile cells.

Cost-effectiveness of assisted conception for male subfertility.

Intrauterine insemination (IUI), with or without ovarian stimulation, IVF and intracytoplasmatic sperm injection (ICSI) are frequently used treatments for couples with male subfertility. No consensus has been reached on specific cut-off values for semen parameters, at which IVF would be advocated over IUI and ICSI over IVF. The aim of this study was to evaluate the cost-effectiveness of interventions for male subfertility according to total motile sperm count (TMSC). A computer-simulated cohort of subfertile women aged 30 years with a partner was analysed with a pre-wash TMSC of 0 to 10 million. Three treatments were evaluated: IUI with and without controlled ovarian stimulation; IVF; and ICSI. Main outcome was expected live birth; secondary outcomes were cost per couple and the incremental cost-effectiveness ratio. The choice of IVF over IUI with ovarian stimulation and ICSI over IVF depends on the willingness to pay for an extra live birth. If only cost per live birth is considered for each treatment, above a pre-wash TMSC of 3 million, IUI is less costly than IVF and, below a pre-wash, TMSC of 3 million ICSI is less costly. Effectiveness needs to be confirmed in a large randomized controlled trial.

Diagnostic accuracy of hysterosalpingo-foam-sonography to confirm tubal occlusion after Essure® placement as treatment for hydrosalpinges.

Consensus globally is that hydrosalpinges need to be treated before IVF owing to their negative influence on outcomes. The current standard treatment is laparoscopic salpingectomy. A potential less invasive treatment is proximal occlusion of a hydrosalpinx by hysteroscopic placement of an Essure® device. Tubal occlusion after Essure® placement needs to be verified by hysterosalpingography (HSG). However, this is a painful examination, that exposes patients to radiation. Hysterosalpingo-foam sonography (HyFoSy) is a less invasive alternative test to confirm proximal tubal occlusion. This prospective diagnostic accuracy study evaluated if HyFoSy is as accurate as HSG to confirm proximal tubal occlusion after placement of an Essure® device as treatment for a hydrosalpinx before IVF. Thirty-eight treated hydrosalpinges in 26 women were evaluated. Proximal occlusion was verified by HyFoSy (index test) and HSG (standard reference). The accuracy of HyFoSy was 97.4% (95% CI 92.3% to 100.0%). Sensitivity and specificity were 97.1% (95% CI.84.6% to 99.5%) and 100.0% (95% CI 40.2% to 100.0%), respectively. After an Essure® device is placed as treatment for a hydrosalpinx before IVF, HyFoSy is as able as HSG to confirm proximal tubal occlusion. If HyFoSy demonstrates tubal patency, a subsequent HSG needs to be carried out to validate this finding.

Impact of assisted reproductive technology on the incidence of multiple-gestation infants: a population perspective.

OBJECTIVE: To study the value of a population view in assessing assisted reproductive technology (ART) multiple-gestation infants. DESIGN: Descriptive comparison of ART treatment and population statistics in seven developed countries (United States [U.S.], South Korea, United Kingdom, the Netherlands, Australia, Belgium, Denmark) with varying ART utilization and single-embryo transfer (SET) rates. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The contribution of ART multiple-gestation infants to the total number of multiple-gestation infants in a population was calculated in relation to utilization of ART and SET rates. RESULT(S): The number of ART treatments leading to embryo transfer varied from 304 per million inhabitants in the U.S. to 1,518 in Denmark. The percentage of ART cycles that utilized SET varied from 8.8% in South Korea to 53.3% in Australia. Reflecting both utilization rates and SET rates, the percentage of multiple-gestation infants in the population attributed to ART ranged from 14.7% in South Korea to 29.0% in Denmark. CONCLUSION(S): In seven countries, the contribution of ART multiple-gestation infants to all multiple-gestation infants varies from 14.7% to 29.0%, a percentage that was influenced by both the SET rate per cycle and ART utilization rates. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient.