Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH).

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.

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.

Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study: a randomized controlled trial (NTR 5342).

BACKGROUND: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. METHOD: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12 months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. DISCUSSION: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. TRIAL REGISTRATION: NTR 5342 , registered July 31st, 2015. PROTOCOL VERSION: Version 4.10, January 4th, 2017.

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.

Parasitic myoma after laparoscopic morcellation: a systematic review of the literature.

BACKGROUND: Laparoscopic morcellation is frequently used for tissue removal after laparoscopic hysterectomy or myomectomy and may result in parasitic myomas, due to seeding of remained tissue fragments in the abdominal cavity. However, little is known about the incidence and risk factors of this phenomenon. OBJECTIVES: To identify the incidence and risk factors for the development of parasitic myoma after laparoscopic morcellation. SEARCH STRATEGY: A systematic review of the literature in Pubmed (MEDLINE) and Embase was conducted. Reference lists of identified relevant articles were checked for missing case reports. SELECTION CRITERIA: Studies reporting on incidence or cases of parasitic myoma diagnosed after laparoscopic morcellation were selected. Studies were excluded when history of laparoscopic morcellation was lacking or final pathology demonstrated a malignancy or endometriosis. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed on incidence of parasitic myomas and characteristics of case reports. MAIN RESULTS: Fourty-four studies were included. Sixty-nine women diagnosed with parasitic myomas after laparoscopic morcellation were identified. Mean age was 40.8 (± 7.5) years (range 24-57), median time between surgery and diagnosis was 48.0 months (range 1-192) and mean number of parasitic myomas was 2.9 (± 3.3) (range 1-16). The overall incidence of parasitic myomas after laparoscopic morcellation was 0.12-0.95%. CONCLUSION: Although the incidence is relatively low, it is important to discuss the risk of parasitic myoma after laparoscopic morcellation with women and balance towards alternative treatment options. The duration of steroid exposure after laparoscopic morcellation might be a risk factor for development of parasitic myomas. TWEETABLE ABSTRACT: Systematic review on the incidence and risk factors for parasitic myoma after laparoscopic morcellation.

Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study).

BACKGROUND: Thyroid peroxidase antibodies (TPO-Ab) in euthyroid women are associated with recurrent miscarriage (RM) and other pregnancy complications such as preterm birth. It is unclear if treatment with levothyroxine improves pregnancy outcome. AIM: The aim of this study is to determine the effect of levothyroxine administration on live birth rate in euthyroid TPO-Ab positive women with recurrent miscarriage. METHODS/DESIGN: We will perform a multicenter, placebo controlled randomized trial in euthyroid women with recurrent miscarriage and TPO-Ab. Recurrent miscarriage is defined as two or more miscarriages before the 20th week of gestation. The primary outcome is live birth, defined as the birth of a living fetus beyond 24weeks of gestation. Secondary outcomes are ongoing pregnancy at 12weeks, miscarriage, preterm birth, (serious) adverse events, time to pregnancy and survival at 28days of neonatal life. The analysis will be performed according to the intention to treat principle. We need to randomize 240 women (120 per group) to demonstrate an improvement in live birth rate from 55% in the placebo group to 75% in the levothyroxine treatment group. This trial is a registered trial (NTR 3364, March 2012). Here we discuss the rationale and design of the T4-LIFE study, an international multicenter randomized, double blind placebo controlled, clinical trial aimed to assess the effectiveness of levothyroxine in women with recurrent miscarriage and TPO-Ab.

The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis.

BACKGROUND: Milder ovarian stimulation protocols for in vitro fertilization (IVF) are being developed to minimize adverse effects. Mild stimulation regimens result in a decreased number of oocytes at retrieval. After conventional ovarian stimulation for IVF, a low number of oocytes are believed to represent poor ovarian reserve resulting in reduced success rates. Recent studies suggest that a similar response following mild stimulation is associated with better outcomes. METHODS: This review investigates whether the retrieval of a low number of oocytes following mild ovarian stimulation is associated with impaired implantation rates. Three randomized controlled trials comparing the efficacy of the mild ovarian stimulation regimen (involving midfollicular phase initiation of FSH and GnRH co-treatment) for IVF with a conventional long GnRH agonist co-treatment stimulation protocol could be identified by means of a systematic literature search. RESULTS: These studies comprised a total of 592 first treatment cycles. Individual patient data analysis showed that the mild stimulation protocol results in a significant reduction of retrieved oocytes compared with conventional ovarian stimulation (median 6 versus 9, respectively, P < 0.001). Optimal embryo implantation rates were observed with 5 oocytes retrieved following mild stimulation (31%) versus 10 oocytes following conventional stimulation (29%) (P = 0.045). CONCLUSIONS: The optimal number of retrieved oocytes depends on the ovarian stimulation regimen. After mild ovarian stimulation, a modest number of oocytes is associated with optimal implantation rates and does not reflect a poor ovarian response. Therefore, the fear of reducing the number of oocytes retrieved following mild ovarian stimulation appears to be unjustified.

Mild ovarian stimulation for IVF.

BACKGROUND: Mild ovarian stimulation for in vitro fertilization (IVF) aims to achieve cost-effective, patient-friendly regimens which optimize the balance between outcomes and risks of treatment. METHODS: Pubmed and Medline were searched up to end of January 2008 for papers on ovarian stimulation protocols for IVF. Additionally, references to related studies were selected wherever possible. RESULTS: Studies show that mild interference with the decrease in follicle-stimulating hormone levels in the mid-follicular phase was sufficient to override the selection of a single dominant follicle. Gonadotrophin-releasing hormone antagonists compared with agonists reduce length and dosage of gonadotrophin treatment without a significant reduction in the probability of live birth (OR 0.86, 95% CI 0.72-1.02). Mild ovarian stimulation may be achieved with limited gonadotrophins or with alternatives such as anti-estrogens or aromatase inhibitors. Another option is luteinizing hormone or human chorionic gonadotrophin administration during the late follicular phase. Studies regarding these approaches are discussed individually; small sample size of single studies along with heterogeneity in patient inclusion criteria as well as outcomes analysed does not allow a meta-analysis to be performed. Additionally, the implications of mild ovarian stimulation for embryo quality, endometrial receptivity, cost and the psychological impact of IVF treatment are discussed. CONCLUSIONS: Evidence in favour of mild ovarian stimulation for IVF is accumulating in recent literature. However, further, sufficiently powered prospective studies applying novel mild treatment regimens are required and structured reporting of the incidence and severity of complications, the number of treatment days, medication used, cost, patient discomfort and number of patient drop-outs in studies on IVF is encouraged.

Why do couples drop-out from IVF treatment? A prospective cohort study.

BACKGROUND: Cumulative IVF pregnancy rates are compromised by the large number of couples who drop-out of treatment before achieving pregnancy. The aim of this study was to identify the role of the treatment strategy applied, and potential other factors that influence the decision of couples to discontinue treatment. METHODS: The incidence of drop-out from IVF treatment and factors related to drop-out were studied in a cohort of IVF patients aged <38 years embarking on IVF treatment either with a mild or a standard treatment strategy for a planned maximum number of treatment cycles. RESULTS: Of the 384 couples studied, 17% dropped out of IVF treatment. The physical or psychological burden of treatment was the most frequent cause of drop-out (28%). The application of a mild treatment strategy (mild ovarian stimulation along with the transfer of a single embryo) significantly reduced the chance of drop-out (hazard ratio (HR) 0.55; 95% confidence interval (CI), 0.31-0.96). When a mild IVF strategy was employed, the association between the baseline anxiety score and drop-out was reduced by >50%. The presence of severe male subfertility (HR 4.80; 95% CI, 1.63-14.13) and the failure to achieve embryo transfer (odds ratio 0.41; 95% CI, 0.24-0.72) were also related to drop-out. CONCLUSIONS: Reducing drop-out rate is crucial to further improve the efficacy and cost-effectiveness of IVF treatment. An important factor determining the risk of drop-out is the burden of the treatment strategy. The application of a mild treatment strategy and managing patient's expectations might reduce drop-out rates.

Predictors of low response to mild ovarian stimulation initiated on cycle day 5 for IVF.

BACKGROUND: Milder stimulation protocols are being developed to minimize adverse effects of ovarian stimulation in in vitro fertilization (IVF) programs. A drawback is the possibility of an increased rate of insufficient ovarian response. This study aimed to develop a prognostic model for the prediction of cycle cancellation due to insufficient response to mild stimulation. METHODS: A total of 174 IVF patients aged<38 years and with a body mass index (BMI)<28 Kg/m2 were treated with mild ovarian stimulation using a fixed daily dose (150 IU) of recombinant follicle-stimulating hormone (rFSH) from cycle day 5 and GnRH antagonist from the late follicular phase. In women with mono- or bifollicular growth (17%), the cycle was cancelled and the treatment was adjusted in a second treatment cycle by starting rFSH on cycle day 2. RESULTS: In a multivariable logistic regression analysis, duration of infertility, menstrual cycle length, secondary infertility and BMI were included in the prediction model. The area under the receiver-operating characteristics curve of the model was 0.69. A probability cut-off for cancellation of 0.3 yielded an expected sensitivity of 33% and specificity of 92%. Analysis of ovarian response in the subsequent treatment cycle showed an improved ovarian response and a significant reduction in the cancellation rate. CONCLUSIONS: With the presented model, it is possible to identify patients at risk for cycle cancellation, during mild ovarian stimulation, due to insufficient response. The contributing factors of the model suggest that ovarian aging and BMI are related to insufficient response to mild stimulation.

ART: iatrogenic multiple pregnancy?

Assisted reproductive technologies (ART) are now widely accepted as effective treatment for most causes of infertility. With improving success rates, attention has turned to the problem of multiple pregnancies, which are associated with a poor perinatal outcome, maternal complications and significant financial consequences. The challenge is to reduce multigestational pregnancies while maintaining good treatment outcomes. Methods to prevent multiple pregnancy include restrictive use of ART in couples with a good chance of spontaneous pregnancy, cautious use of gonadotrophins, and increased use of natural-cycle intra-uterine insemination and elective single embryo transfer in in-vitro fertilization and intracytoplasmic sperm injection. The aim of this article is to review the contribution of fertility treatment to multiple pregnancies and strategies for reducing multiples in ART.

Hyperemesis gravidarum, a literature review.

Hyperemesis gravidarum (HG) is a condition causing severe nausea and vomiting in early pregnancy often resulting in hospital admission. The incidence of HG is approximately 0.5% of live births, said to be higher in multiple pregnancies, hydatidiform mole and other conditions associated with increased pregnancy hormone levels. Both the aetiology and pathogenesis of HG remain unknown. We conducted a literature review (1966-now) to summarize the current evidence on the aetiology and pathogenesis of HG. The potential role of pregnancy-related hormones such as progesterone, estrogen and HCG has been widely studied; however, various other hormones such as leptin, placental growth hormone, prolactin, thyroid and adrenal cortical hormones have been implicated in the aetiology of HG. In addition to endocrinological hypotheses, the rationale and evidence considering infectious, immunological, psychological, metabolic and anatomical causes for HG have been analysed here. Many studies suffer from the low number of patients included, the variable definition used for HG and varying assay methodology used in studies of hormone measurement. This review highlights the need for more extensive studies addressing the pathogenesis and aetiology of HG.