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 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.

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.

Cost-effectiveness of treatment strategies in women with PCOS who do not conceive after six cycles of clomiphene citrate.

This study evaluated the cost-effectiveness of treatments for women with polycystic ovary syndrome (PCOS) who ovulate on clomiphene citrate but do not conceive after six cycles. A decision-analytic framework was developed for six scenarios: (1) three cycles of IVF; (2) continuation of clomiphene citrate for six cycles, followed by three cycles of IVF in case of no birth; (3) six cycles of gonadotrophins and three cycles of IVF; (4) 12 cycles of gonadotrophins and three cycles of IVF; (5) continuation of clomiphene citrate for six cycles, six cycles of gonadotrophins and three cycles of IVF; (6) continuation of clomiphene citrate for six cycles, 12 cycles of gonadotrophins and three cycles of IVF. Two-year cumulative birth rates were 58%, 74%, 89%, 97%, 93% and 98% and costs per couple were € 9518, € 7530, € 9711, € 9764, € 7651 and € 7684 for scenarios 1-6, respectively. Scenario 2 was the lowest cost option. The extra cost for at least one live birth in scenario 5 was € 629 and in scenario 6 € 630. In these subjects, continuation of treatment for six cycles of clomiphene citrate, 6 or 12 cycles of gonadotrophins and IVF is potentially cost-effective. These results should be confirmed in a randomized clinical trial.

Pregnancy complications and metabolic disease in women with clomiphene citrate-resistant anovulation randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotropins: a 10-year follow-up.

OBJECTIVE: To assess long-term effects of laparoscopic electrocautery of the ovaries compared with ovulation induction with gonadotropins in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS) on the incidence of pregnancy complications like gestational diabetes, hypertensive disorders, and metabolic or cardiovascular disease. DESIGN: Long-term follow-up study. SETTING: Twenty-eight hospitals within the Netherlands. PATIENT(S): One hundred sixty-eight CC-resistant women who had participated in a randomized controlled trial between 1998 and 2001 comparing electrocautery and gonadotropins. INTERVENTION(S): Postal questionnaire, search in medical files. MAIN OUTCOME MEASURE(S): Pregnancy complications, metabolic or cardiovascular disease. RESULT(S): Eighty-two percent of follow-up data were obtained. Thirteen of 68 women (19%) allocated to electrocautery, and 14 of 63 women (22%) allocated to gonadotropins had evidence for pregnancy complications (relative risk 0.86; 95% confidence interval 0.43-1.7). At follow-up, 12 of 69 (17%) women allocated to electrocautery, and 13 of 69 (19%) women allocated to gonadotropins had evidence for metabolic or cardiovascular disease (relative risk 0.90; 95% confidence interval 0.39-2.1). The risk of these was modified by body mass index (BMI), but not by female age or treatment allocation. This study is based on questionnaires and data from medical files. In the absence of routine screening, under-reporting in our follow-up study is likely. CONCLUSION(S): Electrocautery in women with CC-resistant PCOS does not affect pregnancy complications or metabolic or cardiovascular disease later in life compared with ovulation induction with gonadotropins.

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate - a randomised controlled trial.

BACKGROUND: Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. METHODS/DESIGN: We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). DISCUSSION: The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women. TRIAL REGISTRATION NUMBER: Netherlands Trial register NTR1449.

The basic fertility workup in women with polycystic ovary syndrome: a systematic review.

OBJECTIVE: To summarize the evidence for the use of commonly accepted fertility tests in subfertile women with ovulation problems. DESIGN: Systematic review. SETTING: Not applicable. PATIENT(S): The study population included women starting with clomiphene citrate (CC) as first-line treatment, women starting with second-line treatment if CC failed to result in pregnancy, and women starting with second-line treatment if CC failed to result in ovulation (CC resistant). INTERVENTION(S): Performance of a semen analysis or tubal patency test before or during treatment. MAIN OUTCOME MEASURE(S): Prevalence of abnormal tests as well as the diagnostic and prognostic performance of these tests. RESULT(S): Four studies reported on 3,017 women starting with CC as first-line treatment. The prevalence of male factor infertility was 10%, and in 0.3% of couples azoospermia was found (two studies). Semen parameters were not associated with pregnancy chance (one study). The prevalence of bilateral tubal disease was 4% (two studies). Three studies reported on 462 women starting with second-line treatment if CC failed to result in a pregnancy. Semen parameters were not predictive for pregnancy (one study). The prevalence of bilateral tubal disease in these women was 8% (three studies). Two studies reported on 168 CC-resistant women and total motile sperm count did not predict live birth (two studies). For all other outcomes, no studies were available. CONCLUSION(S): Data on the basic fertility workup in subfertile women with anovulation are scarce. Based on the available data, the workup should contain a semen analysis, and, for women who need to start second-line treatment if CC failed to result in pregnancy or women with CC resistance, assessment of tubal patency.