Marcel van Hooff

Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin

STUDY OBJECTIVE To evaluate the possible role of inappropriate LH secretion, hyperandrogenism, and hyperinsulinemia in the development of polycystic ovaries (PCO) and the polycystic ovary syndrome. DESIGN Observational. SETTING General population samples. PARTICIPANTS 58 adolescents with regular menstrual cycles, 50 with irregular menstrual cycles, and 29 with oligomenorrhea (age 16.7+/-0.9 years). INTERVENTIONS Transabdominal pelvic ultrasonography and vena puncture. MAIN OUTCOME MEASURES PCO; LH, androstenedione, and testosterone levels; overnight fasting insulin concentrations; and oligomenorrhea. RESULTS The prevalence of PCO increased significantly with the irregularity of the menstrual cycle pattern, as illustrated by the study, finding PCO in 9% of the girls with regular menstrual cycles, 28% of those with irregular menstrual cycles, and 45% of oligomenorrheic girls. The LH and androgen concentrations were significantly higher in girls with PCO; the insulin levels and the glucose-insulin ratio did not differ when the girls with PCO were compared with girls with normal ovaries. Oligomenorrheic girls with PCO had the highest androgen and LH concentrations; their insulin concentrations and glucose-insulin ratio were in the same range as girls with regular menstrual cycles and normal ovaries; and both their hip and waist girths were wider, although their waist-hip ratio was normal. CONCLUSIONS PCO in adolescents is associated with irregular menstrual cycles, oligomenorrhea, and/or high androgen and LH levels; but no relationship was found with the insulin level or glucose-insulin ratio. Thus, it is doubtful that hyperinsulinemia is an important factor in the development of PCO or polycystic ovary syndrome.

Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries

OBJECTIVE To compare obstetrical outcome of twin pregnancies after assisted reproduction with that of natural twin pregnancies. DESIGN Retrospective national database study. SETTING Academic Medical Centre. PATIENT(S) One thousand ninety-three primiparous mothers registered in the Dutch National Birth Registry who gave birth to a dizygotic (DZ) twin (male/female) in 1994, 1995, and 1996. We compared 613 natural twin pregnancies and 480 twin pregnancies born after assisted reproduction. MAIN OUTCOME MEASURE(S) Gestational length, mode of delivery, mode of presentation of the children, birth weight, APGAR score, congenital anomalies, perinatal mortality rate, highest recorded maternal diastolic blood pressure, and maternal postpartum complications. RESULT(S) Rates of perinatal mortality and very premature parturition (<29 weeks) were lower in natural twin mothers. Overall, induced DZ twins were born 3.5 days earlier with a lower birth weight and APGAR score compared with controls. Rates of congenital anomalies and incidence of cesarean section were not different. The highest recorded diastolic blood pressure was lower in induced twinning with a 30% lower incidence of diastolic blood pressure >90 mm Hg. CONCLUSION(S) Obstetric outcome for induced DZ twin pregnancy is less optimal than in natural DZ twin pregnancy. Twinning in assisted reproduction is known for its contribution to the high rate of premature deliveries, but in addition being a subfertile patient undergoing treatment makes an intrinsic contribution to adverse events as well.

PREDICTIVE VALUE OF BASAL FOLLICLE-STIMULATING HORMONE CONCENTRATIONS IN A GENERAL SUBFERTILITY POPULATION

OBJECTIVE To assess the predictive value of elevated basal FSH concentrations during the initial subfertility workup with respect to fecundity in a general subfertility population with ovulatory menstrual cycles. DESIGN Nested case-control study. SETTING Fertility center of a university hospital. PATIENT(S) Fifty subfertile women with basal FSH levels >10.0 IU/L and 50 age-matched controls. INTERVENTION(S) Long-term follow-up (3-7 years). MAIN OUTCOME MEASURE(S) Pregnancies, deliveries, and time to pregnancy. RESULT(S) Patients with elevated basal FSH levels and controls were comparable with regard to basic characteristics, clinical diagnoses, and subfertility treatment. Long-term follow-up showed that 52% of the women with elevated basal FSH concentrations became pregnant (positive predictive value 48%) versus 62% of the controls, and 42% versus 46% eventually delivered a child, respectively. The mean time to pregnancy was 3.0 years in the elevated-FSH group and 3.4 years in controls. Most of the pregnancies in both groups occurred after spontaneous conceptions. CONCLUSION(S) The results of this study suggest that screening for elevated basal FSH concentrations is of no additional value in a general subfertility population with ovulatory menstrual cycles.

Transmural migration of retained surgical sponges: a systematic review.

Retained surgical sponges have been reported to occur after a diversity of surgical procedures, but transmural migration is a very unusual sequela. This article reports a case in which a retained surgical sponge eroded from the intra-abdominal space into the intestinal lumen, migrated distally, and spontaneously passed with defecation 12 weeks after the cesarean section. We performed a systematic review of the literature in Pubmed and found 64 cases of transmural migration of retained surgical sponges. Sixty-four cases have been reported of transmural migration, mainly after intra-abdominal surgery. The most frequent site of impaction is the intestine (75%), but we also found 2 cases that describe migration into the stomach and 7 into the bladder. Five more cases have been published describing transdiaphragmic migration. Only 4 cases describe a sponge spontaneously expelled through the rectum, whereas more than 93% needed re-intervention. We strongly advise only the use sponges with radiopaque markers during surgery and additional methodical wound/body cavity examination. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to describe the occurrence of transmural migration of a sponge left behind during an abdominal surgery including the rate of occurrence, possible pathways of migration, physical reaction, treatment options, and preventive measures.

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

BackgroundCosts of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime.Methods/DesignMulticentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT.DiscussionThe results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines.Trial registrationNTR2657

Hysteroscopy before in-vitro fertilisation (inSIGHT): a multicentre, randomised controlled trial

BACKGROUND Hysteroscopy is often done in infertile women starting in-vitro fertilisation (IVF) to improve their chance of having a baby. However, no data are available from randomised controlled trials to support this practice. We aimed to assess whether routine hysteroscopy before the first IVF treatment cycle increases the rate of livebirths. METHODS We did a pragmatic, multicentre, randomised controlled trial in seven university hospitals and 15 large general hospitals in the Netherlands. Women with a normal transvaginal ultrasound of the uterine cavity and no previous hysteroscopy who were scheduled for their first IVF treatment were randomly assigned (1:1) to either hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF (hysteroscopy group) or immediate start of the IVF treatment (immediate IVF group). Randomisation was done with web-based concealed allocation and was stratified by centre with variable block sizes. Participants, doctors, and outcome assessors were not masked to the assigned group. The primary outcome was ongoing pregnancy (detection of a fetal heartbeat at >12 weeks of gestation) within 18 months of randomisation and resulting in livebirth. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01242852. FINDINGS Between May 25, 2011, and Aug 27, 2013, we randomly assigned 750 women to receive either hysteroscopy (n=373) or immediate IVF (n=377). 209 (57%) of 369 women eligible for assessment in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group had a livebirth from a pregnancy during the trial period (relative risk 1·06, 95% CI 0·93-1·20; p=0·41). One (<1%) woman in the hysteroscopy group developed endometritis after hysteroscopy. INTERPRETATION Routine hysteroscopy does not improve livebirth rates in infertile women with a normal transvaginal ultrasound of the uterine cavity scheduled for a first IVF treatment. Women with a normal transvaginal ultrasound should not be offered routine hysteroscopy. FUNDING The Dutch Organisation for Health Research and Development (ZonMW).

The inSIGHT study : costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial

BackgroundIn in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment a large drop is present between embryo transfer and occurrence of pregnancy. The implantation rate per embryo transferred is only 30%. Studies have shown that minor intrauterine abnormalities can be found in 11–45% of infertile women with a normal transvaginal sonography or hysterosalpingography. Two randomised controlled trials have indicated that detection and treatment of these abnormalities by office hysteroscopy after two failed IVF cycles leads to a 9–13% increase in pregnancy rate. Therefore, screening of all infertile women for intracavitary pathology prior to the start of IVF/ICSI is increasingly advocated. In absence of a scientific basis for such a policy, this study will assess the effects and costs of screening for and treatment of unsuspected intrauterine abnormalities by routine office hysteroscopy, with or without saline infusion sonography (SIS), prior to a first IVF/ICSI cycle.Methods/designMulticenter randomised controlled trial in asymptomatic subfertile women, indicated for a first IVF/ICSI treatment cycle, with normal findings at transvaginal sonography. Women with recurrent miscarriages, prior hysteroscopy treatment and intermenstrual blood loss will not be included. Participants will be randomised for a routine fertility work-up with additional (SIS and) hysteroscopy with on-the-spot-treatment of predefined intrauterine abnormalities versus the regular fertility work-up without additional diagnostic tests. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months of IVF/ICSI treatment after randomisation. Secondary study outcome parameters are the cumulative implantation rate; cumulative miscarriage rate; patient preference and patient tolerance of a SIS and hysteroscopy procedure. All data will be analysed according to the intention-to-treat principle, using univariate and multivariate logistic regression and cox regression. Cost-effectiveness analysis will be performed to evaluate the costs of the additional tests as routine procedure. In total 700 patients will be included in this study.DiscussionThe results of this study will help to clarify the significance of hysteroscopy prior to IVF treatment.Trial registrationNCT01242852

The reliability, acceptability and applications of basal body temperature (BBT) records in the diagnosis and treatment of infertility

The possibilities and limitations of basal body temperature (BBT) records as an adjunct in the management of infertility were re-evaluated. To assess its accuracy as an index of ovulation, 172 charts were analyzed by three different physicians. While the average true positive rate was 90%, the false negative rate was only 2%. The remaining graphs (8%) were classified as non-interpretable, probably reflecting measurement problems. Retrospective assessment of 210 biphasic records showed the thermal nadir to occur within 1 day of the urinary luteinizing hormone (LH) surge in 75% of the cases, and in 90% when 2 days where considered. This confirms BBT as a relatively accurate guide for retrospective identification of the periovulatory period. Moreover, results of a study conducted to investigate how patients experienced daily recording of BBT graphs suggest that the method is well accepted by a high proportion of women. From all these it appears that there are many indications where BBT graphs can still be applied. Development of new electronic devices may further improve the reliability, acceptability and applications of the BBT records in the fertility investigation.

Individualized versus standard FSH dosing in women starting IVF/ICSI: An RCT. Part 1: The predicted poor responder

STUDY QUESTION Does an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI? SUMMARY ANSWER In women with a predicted poor ovarian response (AFC < 11) undergoing IVF/ICSI, an increased FSH dose (225/450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day). WHAT IS KNOWN ALREADY In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered. STUDY DESIGN, SIZE, DURATION Between May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC < 11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha-error 0.05, power 80%). PARTICIPANTS/MATERIALS, SETTING, METHODS Women with an AFC ≤ 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8-10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE In total, 511 women were randomized, 234 with an AFC ≤ 7 and 277 with an AFC 8-10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78-1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: €1099 (95%CI, 562-1591)], standard FSH dosing was the dominant strategy in our economic analysis. LIMITATIONS, REASONS FOR CAUTION Despite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy. WIDER IMPLICATIONS OF THE FINDINGS Since an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC < 11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number NTR2657. TRIAL REGISTRATION DATE 20 December 2010. DATE OF FIRST PATIENT’S ENROLMENT 12 May 2011.

Hysteroscopy before In-Vitro Fertilisation (inSIGHT): A Multicentre, Randomised Controlled Trial

Since the first successful live birth after in vitro fertilization (IVF) was reported in 1978, more than 5 million children have been born with the help of this and intracytoplasmic sperm injection (ICSI) procedures. However, only approximately 25% to 30% of cycles of IVF and ICSI lead to the birth of a child. The reasons for implantation failure are poorly understood. One major cause of implantation failure is abnormalities of the uterine cavity such as polyps, myoma, and adhesions. Hysteroscopy has been generally regarded as the standard procedure to detect these uterine abnormalities. It is thought to improve pregnancy rates in women scheduled for IVF by detection and surgical removal of uterine cavity abnormalities, dilatation of the cervical canal, or induction of inflammatory reactions in the endometriumby the procedure itself. Hysteroscopy is often performed routinely in infertile women scheduled for their first IVF cycle. However, there are no data from well-designed randomized controlled trials to support this practice. The inSIGHT trial is a pragmatic multicenter randomized clinical trial designed to determine whether routine hysteroscopy before the first IVF treatment cycle increases the live birth rate. The trial was conducted in 7 university hospitals and 15 large general hospitals in the Netherlands. Women eligible for the trial were infertile, scheduled to start their first IVF or ICSI treatment, had no previous hysteroscopy, and had a normal transvaginal ultrasound of the uterine cavity. Subjects were randomly assigned in a 1: 1 ratio to hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF followed by IVF (hysteroscopy group) or to immediate start of IVF treatment (immediate IVF group). Web-based randomization was done with a variable block size to allocate patients to groups and was stratified by center. The doctors, outcome assessors, and participants were not masked to the assigned group. The primary study outcome was an ongoing pregnancy (detection of a fetal heartbeat at > 12weeks of gestation) within 18 months of randomization and a live birth. Analysis was done according to intention to treat. Between May 25, 2011, and August 27, 2013, 750 women were randomized: 373 to the hysteroscopy group and 377 to the immediate IVF group. A live birth occurred during the trial period in 209 (57%) of 369 women in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group; the relative riskwas 1.06, with a 95% confidence interval of 0.93 to 1.20; P = 0.41. These findings demonstrate that hysteroscopy does not improve live birth rates in infertile women scheduled for their first IVF cycle, who have a normal transvaginal ultrasound of the uterine cavity. Therefore, routine hysteroscopy should not be performed in women with a normal transvaginal ultrasound.