Review of the safety, efficacy, costs and patient acceptability of recombinant follicle-stimulating hormone for injection in assisting ovulation induction in infertile women

Anovulation is a common cause of female subfertility. Treatment of anovulation is aimed at induction of ovulation. In women with clomiphene-citrate resistant WHO group II anovulation, one of the treatment options is ovulation induction with exogenous follicle-stimulating hormone (FSH or follitropin). FSH is derived from urine or is produced as recombinant FSH. Two forms of recombinant FSH are available – follitropin alpha and follitropin beta. To evaluate the efficacy, safety, costs and acceptability of recombinant FSH, we performed a review to compare recombinant FSH with urinary-derived FSH products. Follitropin alpha, beta and urinary FSH products appeared to be equally effective in terms of pregnancy rates. Patient safety was also found to be comparable, as the incidence of side effects including multiple pregnancies was similar for all FSH products. In practice follitropin alpha and beta may be more convenient to use due to the ease of self-administration, but they are also more expensive than the urinary products

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

Review of the safety, efficacy, costs and patient acceptability of recombinant follicle-stimulating hormone for injection in assisting ovulation induction in infertile women

Marleen Nahuis1,2,3, Fulco van der Veen1, Jur Oosterhuis2, Ben Willem Mol1, Peter Hompes3, Madelon van Wely11Center for Reproductive Medicine, Department of Obstetrics and Gynaecology (H4-205), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede, The Netherlands; 3Department of Obstetrics and Gynaecology, Free Medical University, Amsterdam, The NetherlandsAbstract: Anovulation is a common cause of female subfertility. Treatment of anovulation is aimed at induction of ovulation. In women with clomiphene-citrate resistant WHO group II anovulation, one of the treatment options is ovulation induction with exogenous follicle-stimulating hormone (FSH or follitropin). FSH is derived from urine or is produced as recombinant FSH. Two forms of recombinant FSH are available – follitropin alpha and follitropin beta. To evaluate the efficacy, safety, costs and acceptability of recombinant FSH, we performed a review to compare recombinant FSH with urinary-derived FSH products. Follitropin alpha, beta and urinary FSH products appeared to be equally effective in terms of pregnancy rates. Patient safety was also found to be comparable, as the incidence of side effects including multiple pregnancies was similar for all FSH products. In practice follitropin alpha and beta may be more convenient to use due to the ease of self-administration, but they are also more expensive than the urinary products.Keywords: follitropin apha, follitropin beta, urinary gonadotropins, polycystic ovary syndrom

Maternal characteristics associated with referral to obstetrician-led care in low-risk pregnant women in the Netherlands: A retrospective cohort study

Background In the Netherlands, maternity care is divided into midwife-led care (for low-risk women) and obstetrician-led care (for high-risk women). Referrals from midwife-led to obstetrician-led care have increased over the past decade. The majority of women are referred during their pregnancy or labour. Referrals are based on a continuous risk assessment of the health and characteristics of mother and child, yet referral for non-medical factors and characteristics remain unclear. This study investigated which maternal characteristics are associated with women’s referral from midwife-led to obstetrician-led care. Materials and methods A retrospective cohort study in one midwife-led care practice in the Netherlands included 1096 low-risk women during January 2015–17. The primary outcomes were referral from midwife-led to obstetrician-led care in (1) the antepartum period and (2) the intrapartum period. In total, 11 maternal characteristics were identified. Logistic regression models of referral in each period were fitted and stratified by parity. Results In the antepartum period, referral among nulliparous women was associated with an older maternal age (aOR, 1.07; 95%CI, 1.05–1.09), being underweight (0.45; 0.31–0.64), overweight (2.29; 1.91–2.74), or obese (2.65; 2.06–3.42), a preconception period >1 year (1.34; 1.07–1.66), medium education level (0.76; 0.58–1.00), deprivation (1.87; 1.54–2.26), and sexual abuse (1.44; 1.14–1.82). Among multiparous women, a referral was associated with being underweight (0.40; 0.26–0.60), obese (1.61; 1.30–1.98), a preconception period >1 year (1.71; 1.27–2.28), employment (1.38; 1.19–1.61), deprivation (1.23; 1.03–1.46), highest education level (0.63; 0.51–0.80), psychological problems (1.24; 1.06–1.44), and one or multiple consultations with an obstetrician (0.68; 0.58–0.80 and 0.64; 0.54–0.76, respectively). In the intrapartum period, referral among nulliparous women was associated with an older maternal age (1.02; 1.00–1.05), being underweight (1.67; 1.15–2.42), a preconception period >1 year (0.42; 0.31–0.57), medium or high level of education (2.09; 1.49–2.91 or 1.56; 1.10–2.22, respectively), sexual abuse (0.46; 0.33–0.63), and multiple consultations with an obstetrician (1.49; 1.15–1.94). Among multiparous women, referral was associated with an older maternal age (1.02; 1.00–1.04), being overweight (0.65; 0.51–0.83), a preconception period >1 year (0.33; 0.17–0.65), non-Dutch ethnicity (1.98; 1.61–2.45), smoking (0.75; 0.57–0.97), sexual abuse (1.49; 1.09–2.02), and one or multiple consultations with an obstetrician (1.34; 1.06–1.70 and 2.09; 1.63–2.69, respectively). Conclusions This exploratory study showed that several non-medical maternal characteristics of low-risk pregnant women are associated with referral from midwife-led to obstetrician-led care, and how these differ by parity and partum period

Gonadotrophins for ovulation induction in women with polycystic ovary syndrome

BACKGROUND: Ovulation induction with follicle stimulating hormone (FSH) is a second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate. OBJECTIVES: To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with clomiphene citrate-resistant polycystic ovary syndrome (PCOS), and women who do not ovulate or conceive after clomiphene citrate. SEARCH METHODS: In January 2018, we searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, the World Health Organisation clinical trials register, Clinicaltrials.gov, LILACs, and PubMed databases, and Google Scholar. We checked references of in all obtained studies. We had no language restrictions. SELECTION CRITERIA: All randomised controlled trials reporting data on clinical outcomes in women with PCOS who did not ovulate or conceive on clomiphene citrate, and undergoing ovulation induction with urinary-derived gonadotrophins, including urofollitropin (uFSH) in purified FSH (FSH-P) or highly purified FSH (FSH-HP) form, human menopausal gonadotropin (HMG) and highly purified human menopausal gonadotrophin (HP-HMG), or recombinant FSH (rFSH), or continuing clomiphene citrate. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that described co-treatment with clomiphene citrate, metformin, luteinizing hormone, or letrozole. DATA COLLECTION AND ANALYSIS: Three review authors (NW, EK, and MvW) independently selected studies for inclusion, assessed risk of bias, and extracted study data. Primary outcomes were live birth rate per woman and multiple pregnancy per woman. Secondary outcomes were clinical pregnancy, miscarriage, incidence of ovarian hyperstimulation syndrome (OHSS) per woman, total gonadotrophin dose, and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the risk ratio (RR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria. MAIN RESULTS: The review included 15 trials with 2387 women. Ten trials compared rFSH with urinary-derived gonadotrophins (three compared rFSH with human menopausal gonadotrophin, and seven compared rFSH with FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P. One trial compared FSH with continued clomiphene citrate.Recombinant FSH (rFSH) versus urinary-derived gonadotrophinsThere may be little or no difference in the birth rate between rFSH and urinary-derived gonadotrophins (RR 1.21, 95% confidence interval (CI) 0.83 to 1.78; five trials, N = 505; I² = 9%; low-quality evidence). This suggests that for the observed average live birth per woman who used urinary-derived FSH of 16%, the chance of live birth with rFSH is between 13% and 28%. There may also be little or no difference between groups in incidence of multiple pregnancy (RR 0.86, 95% CI 0.46 to 1.61; eight trials, N = 1368; I² = 0%; low-quality evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88 to 1.27; eight trials, N = 1330; I² = 0; low-quality evidence), or miscarriage rate (RR 1.20, 95% CI 0.71 to 2.04; seven trials, N = 970; I² = 0; low-quality evidence). We are uncertain whether rFSH reduces the incidence of OHSS (RR 1.48, 95% CI 0.82 to 2.65, ten trials, n=1565, I² = 0%, very low-quality evidence).Human menopausal gonadotrophin (HMG) or HP-HMG versus uFSHWhen compared to uFSH, we are uncertain whether HMG or HP-HMG improves live birth rate (RR 1.28, 95% CI 0.65 to 2.52; three trials, N = 138; I² = 0%; very low quality evidence), or reduces multiple pregnancy rate (RR 2.13, 95% CI 0.51 to 8.91; four trials, N = 161; I² = 0%; very low quality evidence). We are also uncertain whether HMG or HP-HMG improves clinical pregnancy rate (RR 1.31, 95% CI 0.66 to 2.59; three trials, N = 102; I² = 0; very low quality evidence), reduces miscarriage rate (RR 0.33, 95% CI 0.06 to 1.97; two trials, N = 98; I² = 0%; very low quality evidence), or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42 to 117.81; two trials, N = 53; very low quality evidence) when compared to uFSH.Gonadotrophins versus continued clomiphene citrateGonadotrophins resulted in more live births than continued clomiphene citrate (RR 1.24, 95% CI 1.05 to 1.46; one trial, N = 661; I² = 0%; moderate-quality evidence). This suggests that for a woman with a live birth rate of 41% with continued clomiphene citrate, the live birth rate with FSH was between 43% and 60%. There is probably little or no difference in the incidence of multiple pregnancy between treatments (RR 0.89, 95% CI 0.33 to 2.44; one trial, N = 661; I² = 0%; moderate-quality evidence). Gonadotrophins resulted in more clinical pregnancies than continued clomiphene citrate (RR 1.31, 95% CI 1.13 to 1.52; one trial, N = 661; I² = 0%; moderate-quality evidence), and more miscarriages (RR 2.23, 95% CI 1.11 to 4.47; one trial, N = 661; I² = 0%; moderate-quality evidence). None of the women developed OHSS. AUTHORS' CONCLUSIONS: There may be little or no difference in live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate between urinary-derived gonadotrophins and recombinant follicle stimulating hormone in women with polycystic ovary syndrome. For human menopausal gonadotropin or highly purified human menopausal gonadotrophin versus urinary follicle stimulating hormone we are uncertain whether one or the other improves or lowers live birth, incidence of multiple pregnancy, clinical pregnancy rate, or miscarriage rate. We are uncertain whether any of the interventions reduce the incidence of ovarian hyperstimulation syndrome. We suggest weighing costs and convenience in the decision to use one or the other gonadotrophin. In women with clomiphene citrate failure, gonadotrophins resulted in more live births than continued clomiphene citrate without increasing multiple pregnancies

Gonadotrophins for ovulation induction in women with polycystic ovarian syndrome

BACKGROUND: Ovulation induction with follicle stimulating hormone (FSH) is the second-line treatment in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate (CC). OBJECTIVES: To compare the effectiveness and safety of gonadotrophins as a second-line treatment for ovulation induction in women with CC-resistant PCOS. SEARCH METHODS: We searched the Menstrual Disorders & Subfertility Group's Specialist Register of controlled trials, the Cochrane Central Register of Controlled Trials, MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014), CINAHL (1982 to October 2014), National Research Register and web-based trials databases such as Current Controlled Trials. There was no language restriction. SELECTION CRITERIA: All randomised controlled trials reporting data on comparing clinical outcomes in women with PCOS who did not ovulate or conceive on CC, and undergoing ovulation induction with urinary FSH (uFSH: FSH-P or FSH-HP), HMG/HP-HMG or recombinant FSH. We included trials reporting on ovulation induction followed by intercourse or intrauterine insemination. We excluded studies that used co-treatment with CC, metformin, LH or letrozole. DATA COLLECTION AND ANALYSIS: Three review authors (NW, MN and MvW) independently selected studies for inclusion, assessed study quality and extracted study data. Primary outcomes were live birth rate per woman (effectiveness outcome) and incidence of ovarian hyperstimulation syndrome (OHSS) per woman (safety outcome). Secondary outcomes were clinical pregnancy, miscarriage, multiple pregnancy, total gonadotrophin dose and total duration of stimulation per woman. We combined data using a fixed-effect model to calculate the odds ratio (OR). We summarised the overall quality of evidence for the main outcomes using GRADE criteria. MAIN RESULTS: The review includes 14 trials with 1726 women. Ten trials compared rFSH versus urinary-derived gonadotrophins (three rFSH versus HMG and seven rFSH versus FSH-HP), four trials compared FSH-P with HMG. We found no trials that compared FSH-HP with FSH-P.We found no evidence of a difference in live birth for rFSH versus urinary-derived gonadotrophins (OR 1.26, 95% CI 0.80 to 1.99, 5 trials, 505 women, I² = 0%, low-quality evidence) or clinical pregnancy rate (OR 1.08, 95% CI 0.83 to 1.39, 8 trials, 1330 women, I² = 0, low-quality evidence). This suggests that for the observed average live birth per woman with urinary-derived FSH of 16%, the chance of live birth following rFSH is between 13% and 26%.For the comparison HMG or HP-HMG versus FSH-P there was also no difference in the evidence on live birth rate (OR 1.36, 95% CI 0.58 to 3.18, 3 trials, 138 women, I² = 0%, low-quality evidence). This suggests that for a woman with a live birth rate of 18% with HMG or HP-HMG, the chance of live birth following uFSH is between 9% and 37%.Trial authors used various definitions for OHSS. Pooling the data, we found no evidence of a difference for rFSH versus urinary-derived gonadotrophins (OR 1.52, 95% CI 0.81 to 2.84, 10 trials, 1565 women, I(2) = 0%, very low-quality evidence) and for HMG or HP-HMG versus FSH-P (OR 9.95, 95% CI 0.47 to 210.19, 2 trials, 53 women, I² = 0%, very low-quality evidence). AUTHORS' CONCLUSIONS: In women with PCOS and CC resistance or CC failure, we found no evidence of a difference in live birth and OHSS rates between urinary-derived gonadotrophins and rFSH or HMG/HP-HMG. Evidence for all outcomes was of low or very low quality. We suggest weighing costs and convenience in the decision to use one or the other

Maternal characteristics associated with referral to obstetrician-led care in low-risk pregnant women in the Netherlands: A retrospective cohort study

Background In the Netherlands, maternity care is divided into midwife-led care (for low-risk women) and obstetrician-led care (for high-risk women). Referrals from midwife-led to obstetrician-led care have increased over the past decade. The majority of women are referred during their pregnancy or labour. Referrals are based on a continuous risk assessment of the health and characteristics of mother and child, yet referral for non-medical factors and characteristics remain unclear. This study investigated which maternal characteristics are associated with women’s referral from midwife-led to obstetrician-led care. Materials and methods A retrospective cohort study in one midwife-led care practice in the Netherlands included 1096 low-risk women during January 2015–17. The primary outcomes were referral from midwife-led to obstetrician-led care in (1) the antepartum period and (2) the intrapartum period. In total, 11 maternal characteristics were identified. Logistic regression models of referral in each period were fitted and stratified by parity. Results In the antepartum period, referral among nulliparous women was associated with an older maternal age (aOR, 1.07; 95%CI, 1.05–1.09), being underweight (0.45; 0.31–0.64), overweight (2.29; 1.91–2.74), or obese (2.65; 2.06–3.42), a preconception period >1 year (1.34; 1.07–1.66), medium education level (0.76; 0.58–1.00), deprivation (1.87; 1.54–2.26), and sexual abuse (1.44; 1.14–1.82). Among multiparous women, a referral was associated with being underweight (0.40; 0.26–0.60), obese (1.61; 1.30–1.98), a preconception period >1 year (1.71; 1.27–2.28), employment (1.38; 1.19–1.61), deprivation (1.23; 1.03–1.46), highest education level (0.63; 0.51–0.80), psychological problems (1.24; 1.06–1.44), and one or multiple consultations with an obstetrician (0.68; 0.58–0.80 and 0.64; 0.54–0.76, respectively). In the intrapartum period, referral among nulliparous women was associated with an older maternal age (1.02; 1.00–1.05), being underweight (1.67; 1.15–2.42), a preconception period >1 year (0.42; 0.31–0.57), medium or high level of education (2.09; 1.49–2.91 or 1.56; 1.10–2.22, respectively), sexual abuse (0.46; 0.33–0.63), and multiple consultations with an obstetrician (1.49; 1.15–1.94). Among multiparous women, referral was associated with an older maternal age (1.02; 1.00–1.04), being overweight (0.65; 0.51–0.83), a preconception period >1 year (0.33; 0.17–0.65), non-Dutch ethnicity (1.98; 1.61–2.45), smoking (0.75; 0.57–0.97), sexual abuse (1.49; 1.09–2.02), and one or multiple consultations with an obstetrician (1.34; 1.06–1.70 and 2.09; 1.63–2.69, respectively). Conclusions This exploratory study showed that several non-medical maternal characteristics of low-risk pregnant women are associated with referral from midwife-led to obstetrician-led care, and how these differ by parity and partum period

Maternal characteristics associated with referral to obstetrician-led care in low-risk pregnant women in the Netherlands: A retrospective cohort study.

BackgroundIn the Netherlands, maternity care is divided into midwife-led care (for low-risk women) and obstetrician-led care (for high-risk women). Referrals from midwife-led to obstetrician-led care have increased over the past decade. The majority of women are referred during their pregnancy or labour. Referrals are based on a continuous risk assessment of the health and characteristics of mother and child, yet referral for non-medical factors and characteristics remain unclear. This study investigated which maternal characteristics are associated with women's referral from midwife-led to obstetrician-led care.Materials and methodsA retrospective cohort study in one midwife-led care practice in the Netherlands included 1096 low-risk women during January 2015-17. The primary outcomes were referral from midwife-led to obstetrician-led care in (1) the antepartum period and (2) the intrapartum period. In total, 11 maternal characteristics were identified. Logistic regression models of referral in each period were fitted and stratified by parity.ResultsIn the antepartum period, referral among nulliparous women was associated with an older maternal age (aOR, 1.07; 95%CI, 1.05-1.09), being underweight (0.45; 0.31-0.64), overweight (2.29; 1.91-2.74), or obese (2.65; 2.06-3.42), a preconception period >1 year (1.34; 1.07-1.66), medium education level (0.76; 0.58-1.00), deprivation (1.87; 1.54-2.26), and sexual abuse (1.44; 1.14-1.82). Among multiparous women, a referral was associated with being underweight (0.40; 0.26-0.60), obese (1.61; 1.30-1.98), a preconception period >1 year (1.71; 1.27-2.28), employment (1.38; 1.19-1.61), deprivation (1.23; 1.03-1.46), highest education level (0.63; 0.51-0.80), psychological problems (1.24; 1.06-1.44), and one or multiple consultations with an obstetrician (0.68; 0.58-0.80 and 0.64; 0.54-0.76, respectively). In the intrapartum period, referral among nulliparous women was associated with an older maternal age (1.02; 1.00-1.05), being underweight (1.67; 1.15-2.42), a preconception period >1 year (0.42; 0.31-0.57), medium or high level of education (2.09; 1.49-2.91 or 1.56; 1.10-2.22, respectively), sexual abuse (0.46; 0.33-0.63), and multiple consultations with an obstetrician (1.49; 1.15-1.94). Among multiparous women, referral was associated with an older maternal age (1.02; 1.00-1.04), being overweight (0.65; 0.51-0.83), a preconception period >1 year (0.33; 0.17-0.65), non-Dutch ethnicity (1.98; 1.61-2.45), smoking (0.75; 0.57-0.97), sexual abuse (1.49; 1.09-2.02), and one or multiple consultations with an obstetrician (1.34; 1.06-1.70 and 2.09; 1.63-2.69, respectively).ConclusionsThis exploratory study showed that several non-medical maternal characteristics of low-risk pregnant women are associated with referral from midwife-led to obstetrician-led care, and how these differ by parity and partum period

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

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