Follicle stimulating hormone versus clomiphene citrate in intrauterine insemination for unexplained subfertility: a randomized controlled trial.

STUDY QUESTION: Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER: In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN: FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IU FSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION: We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE: 1 July 2013. DATE OF FIRST PATIENT'S ENROLMENT: The first patient was randomized at 27 August 2013.

The SUPER study: protocol for a randomised controlled trial comparing follicle-stimulating hormone and clomiphene citrate for ovarian stimulation in intrauterine insemination.

OBJECTIVE: To study the effectiveness of four cycles of intrauterine insemination (IUI) with ovarian stimulation (OS) by follicle-stimulating hormone (FSH) or by clomiphene citrate (CC), and adherence to strict cancellation criteria. SETTING: Randomised controlled trial among 22 secondary and tertiary fertility clinics in the Netherlands. PARTICIPANTS: 732 women from couples diagnosed with unexplained or mild male subfertility and an unfavourable prognosis according to the model of Hunault of natural conception. INTERVENTIONS: Four cycles of IUI-OS within a time horizon of 6 months comparing FSH 75 IU with CC 100 mg. The primary outcome is ongoing pregnancy conceived within 6 months after randomisation, defined as a positive heartbeat at 12 weeks of gestation. Secondary outcomes are cancellation rates, number of cycles with a monofollicular or with multifollicular growth, number of follicles >14 mm at the time of ovulation triggering, time to ongoing pregnancy, clinical pregnancy, miscarriage, live birth and multiple pregnancy. We will also assess if biomarkers such as female age, body mass index, smoking status, antral follicle count and endometrial aspect and thickness can be used as treatment selection markers. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on Research involving Human Subjects (CCMO NL 43131-018-13). Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NTR4057.

General practitioners' adherence to work-up and referral recommendations in fertility care.

STUDY QUESTION: What is the current guideline adherence by general practitioners (GPs) for work-up and subsequent referral from primary to secondary care for patients suffering from infertility? SUMMARY ANSWER: Guideline adherence by GPs concerning infertility was 9.2% in couples referred. WHAT IS KNOWN ALREADY: Adherence to recommendations can decrease unnecessary referral, diagnostics and treatments, and consequently result in lower expenditures. Moreover, patients can be saved from unnecessary hospital visits, emotional burden and out of pocket costs. STUDY DESIGN, SIZE, AND DURATION: A retrospective cohort study among 306 patients referred for basic fertility work-up between January 2011 and June 2013 from primary care to a secondary care teaching hospital or a tertiary hospital with IVF facilities. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Couples were eligible to participate when there was no previous referral for fertility problems and the duration of the child wish was <2 years. Data to assess guideline adherence were collected from the referral letter and the medical records. A patient questionnaire was used to determine patients' general and fertility-related characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The GP performed a Chlamydia Antibody Titre (CAT) testing and semen analysis as recommended in 15.9% and 42.2% of the referred patients, respectively. According to the guideline, 39% of the couples were under referred (i.e. not immediately referred as recommended), 8.8% were unnecessarily referred and the CAT and semen analysis were unnecessarily repeated in secondary care in 80.0% and 57.1% of cases, respectively. LIMITATIONS REASONS FOR CAUTION: We could not include non-referred patients with expectant management in primary care, an unknown number of whom became pregnant in this period. This may have resulted in an underestimation of primary care performance. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that guideline adherence concerning work-up and subsequent referral for fertility problems is low. The influence of patient demands for referral remains largely unknown. Barriers and facilitators for guideline adherence should be determined to develop interventions to improve guideline adherence in the areas of work-up and referral for fertility care and to diminish duplicate tests in secondary care. STUDY FUNDING/COMPETING INTEREST(S): Funded by CZ, a Dutch healthcare insurer (grant number AFVV 11-232). CZ had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: None. TRIAL REGISTRATION NUMBER: Not applicable.

Fetal habituation to vibroacoustic stimulation in uncomplicated postterm pregnancies.

OBJECTIVES: Testing of fetal habituation to repeated vibroacoustic stimulation might give additional information concerning the fetal condition and central nervous system (CNS) functioning in postterm pregnancies. This study is designed to investigate whether healthy postterm fetuses are able to habituate and if so, if the habituation pattern of postterm fetuses differs from that of term fetuses. STUDY DESIGN: Twenty women with an uncomplicated pregnancy beyond 41 weeks gestational age (GA) participated, and 37 women with a GA between 37 and 40 weeks served as controls. The vibroacoustic stimulus was repeatedly applied to the maternal abdomen above the fetal legs for a period of 1s every 30s. A fetal trunk movement within 1s of stimulus application was considered a positive response. Lack of response to four consecutive stimuli indicated habituation. The habituation rate is defined as the number of stimuli applied before the fetus stopped responding. Data were compared using Mann-Whitney U test. RESULTS: Of the 18 postterm fetuses in which the presence or absence of habituation could be established, 14 habituated and four persisted in responding. Twenty-six of the 32 term fetuses, in which the presence or absence of habituation could be established, habituated and six persisted in responding. The habituation rate varied widely in postterm (median of eight stimuli, quartile ranges of 6 and 18) as well as in term fetuses (median of 9.5 stimuli, quartile ranges of 6 and 15). There was no difference in median habituation rate between postterm and term fetuses. CONCLUSION: The ongoing maturation of the CNS in the last weeks of pregnancy appears not to be reflected in the fetal habituation pattern. Furthermore, the interfetal variability in habituation of healthy postterm fetuses is such that testing of habituation appears not to be suitable for the identification of the fetus at risk for an adverse neonatal outcome.

The responses to repeated vibroacoustic stimulation in a fetus with trisomy 18.

Observation of the fetal movement and fetal heart rate responses to repeated vibroacoustic stimulation might be useful as a measure to assess fetal well-being. Studies of abnormal fetuses are needed to gain insight in the spectrum of possible responses to stimulation. We present a case of a fetus with trisomy 18 that failed to respond to repeated stimulation.

Fetal habituation to vibroacoustic stimulation in relation to fetal states and fetal heart rate parameters.

OBJECTIVES: Fetal habituation to repeated stimulation has the potential to become a tool in the assessment of fetal condition and of the function of the fetal central nervous system (CNS). However, the influence of fetal quiescence and activity on habituation remains to be clarified. We studied habituation and the influence of fetal state and fetal heart rate (FHR) parameters on habituation in healthy term fetuses. SUBJECTS AND METHOD: We studied habituation in 37 healthy fetuses in two tests with an interval of 10 min. The vibroacoustic stimuli were applied to the maternal abdomen above the fetal legs for a period of 1 s every 30 s. A fetal trunk movement within 1 s after stimulation was defined as a positive response. Habituation rate is defined as the number of stimuli applied before an observed non-response to four consecutive stimuli. The FHR patterns (FHRP) of the 10 min observation period before and after the tests were visually classified. Fetal states were defined according to the FHRP. Baseline FHR, FHR variability and the number of accelerations were calculated in a subgroup of 25 fetuses. RESULTS: Of the 32 fetuses that responded normally during the first test, 26 habituated and six had persistent responses. The median habituation rate decreased significantly in the second test (P=0.001). There was no difference in habituation rate between fetuses that where initially in a quiet state and those in an active state. The FHR parameters before the first test and the difference between these FHR parameters before and after the test did not correlate with the habituation rate. CONCLUSIONS: Although the majority of healthy fetuses was able to habituate, the interfetal variability in habituation performance is such that testing of habituation seems not to be a sensitive tool for the assessment of the fetal CNS. This variability is neither the result of differences in fetal state nor of the various FHR parameters before testing, nor of the difference in change of FHR parameters arising from stimulation.

Fetal learning and memory.

We used fetal habituation to repeated vibroacoustic stimulation to assess fetal memory. After the initial stimulus, we assessed the fetuses 10 min later and again after 24 h. 16 of 19 fetuses habituated rapidly to the stimuli at 10 min (p=0.004) and 24 h (p=0.042) after the initial test. We conclude, therefore, that fetuses are able to learn: they have a short-term memory of at least 10 min, and a long-term memory of at least 24 h.

Responses to vibroacoustic stimulation in a fetus with an encephalocele compared to responses of normal fetuses.

BACKGROUND: Observation of fetal movement and fetal heart rate (FHR) responses to repeated vibroacoustic stimulation (VAS) might be useful as a measure to assess fetal well-being and to assess the integrity of the fetal central nervous system (CNS). We observed the movement and FHR responses to repeated VAS of a term fetus with a serious brain anomaly as compared to responses of normal term fetuses. SUBJECTS, METHODS, RESULTS: In 37 normal term fetuses and in a term fetus with an encephalocele we studied movement and FHR response to repeated VAS. All normal fetuses responded within 1 s after stimulation with general body movement and FHR acceleration. At 36 gestational weeks, no movement or FHR responses were seen in the fetus with an encephalocele. Repetition of the test in this fetus after one week still showed no response to repeated VAS. CONCLUSION: Normal fetuses showed movement and FHR responses to external stimulation. The fetus with an encephalocele did not respond to repeated VAS with a movement or FHR acceleration. Case studies in fetuses with structural anomalies of the CNS are needed to gain insight into the spectrum of possible responses to VAS.

[Discordant fetal growth in multiple pregnancy: intervention should be based on chorionicity]. / Discordante foetale groei bij meerlingen: beleid afstemmen op chorioniciteit.

In three women, aged 28, 35, and 38 years, with multiple pregnancies and discordant foetal growth, the question arose what to do in case of (threatening) intrauterine death of one twin. In one monochorionic pregnancy with single foetal death the survivor suffered irreversible neurological damage and died at the age of five months, in one monochorionic pregnancy the survivor was born healthy and in one dichorionic pregnancy both twins were born healthy although one twin showed severe intrauterine growth retardation. The problem concerning single foetal death in a monochorionic pregnancy is whether to terminate the pregnancy and accept the risk of premature birth to the surviving twin, or to continue the pregnancy and accept the risk of damage to the survivor. In a dichorionic pregnancy foetal death of one twin does not entail any great risk of damage to the survivor; in such a pregnancy single foetal death in a premature phase may be accepted and the pregnancy may be continued. Sonographic determination of the chorionicity in multiple pregnancy at an early stage is essential because it also determines the policy if foetal problems occur.

Risk for surviving twin after fetal death of co-twin in twin-twin transfusion syndrome.

OBJECTIVE: To determine neonatal outcome of surviving twins in pregnancies complicated by twin-twin transfusion syndrome and fetal deaths of co-twins. METHODS: We retrospectively reviewed medical records of 11 women seen during 1990-1996 in our hospital who had pregnancies complicated by twin-twin transfusion syndrome and death of one fetus. RESULTS: The median interval between fetal death and delivery (six by cesarean delivery and five vaginally) was 2 weeks (range, 1 day to 7 weeks). Three of the 11 surviving twins died soon after birth (gestational ages at birth 32, 31, and 34 weeks; fetal death-delivery intervals 3, 7, and 7 weeks, respectively). Two survivors were severely handicapped (gestational ages at birth 29 and 33 weeks; fetal death-delivery interval 1 and 2 weeks, respectively). Two children showed cerebral echodensities on ultrasound after birth but developed normally, and four did not show any abnormalities on cerebral and abdominal ultrasound and developed normally. Five of 11 surviving twins, each born 1 week or more after fetal death of the co-twin, either died or experienced serious morbidity. In the two infants born within 1 day of fetal death, no problems were detected. CONCLUSION: In monochorionic twin gestations complicated by twin-twin transfusion syndrome, approximately half of surviving twins will experience mortality or serious morbidity when co-twins die in utero.