Esme I. Kamphuis

Are we overusing IVF

The indications for IVF have expanded from tubal disorders to many causes of subfertility, including unexplained. But with limited evidence underpinning its extended remit Esme Kamphuis and colleagues explain how the risks could outweigh the benefits

How are neonatal and maternal outcomes reported in randomised controlled trials (RCTs) in reproductive medicine

STUDY QUESTION How do randomised controlled trials (RCTs) in reproductive medicine report maternal and neonatal outcomes, specifically singleton live birth? SUMMARY ANSWER Despite the widespread appeal to use singleton live birth as the outcome measure in subfertility trials, 80% of RCTs fail to do so, and fail to report on neonatal and maternal outcomes. WHAT IS KNOWN ALREADY The aim of reproductive medicine is to assist subfertile couples in their wish to have children. A decade ago it was proposed to use singleton live birth as the outcome measure. We assessed whether clinical research has followed this recommendation, and how neonatal/maternal outcomes are reported. STUDY DESIGN, SIZE, DURATION A review of the published literature from 1 January 1966 to 31 December 2012 was performed using the Cochrane database. We compared the time periods before and after 2004; the year after ESHRE recommended the use of singleton live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS We searched the Cochrane database for RCTs in reproductive medicine, and recorded the number of studies that used singleton live birth as the outcome measure. We also recorded the reporting neonatal and maternal outcomes. MAIN RESULTS AND THE ROLE OF CHANCE We identified 910 RCTs that reported on fertility treatments, of which 182 RCTs (20%) reported on singleton live birth [before 2004 96/518 (19%); after 2003 86/392 RCTs (22%)]. Singleton live birth was the primary outcome in 68 RCTs (7.4%). Only 44 RCTs (4.8%) reported on neonatal outcome, while 52 RCTs (5.7%) reported on maternal outcome. LIMITATIONS, REASONS FOR CAUTION We only included Cochrane reviews, thus report here only on the higher quality studies. The actual reporting on maternal and neonatal outcome may even be lower when studies of lower quality are included. WIDER IMPLICATIONS OF THE FINDINGS Although a decade ago singleton live birth was recommended as the outcome measure of reproductive medicine research, this has not been followed; currently most clinical research in reproductive medicine does not report beyond the occurrence of pregnancy. STUDY FUNDING/COMPETING INTEREST(S) No funding was received for the study. The authors have no conflicts of interest to declare.

Ongoing pregnancy qualifies best as the primary outcome measure of choice in trials in reproductive medicine: an opinion paper.

The most appropriate primary outcome measure for reproductive medicine has been discussed frequently. In 2003 the European Society for Human Reproduction and Embryology recommended that the outcome measure of assisted reproductive technology (ART) and non-ART should be singleton live birth. Although live birth is indeed the aim of clinical practice, and there is no discussion that it should be reported in infertility trials, we hereby provide arguments that plead for using ongoing pregnancy as the primary outcome in such trials. We feel that ongoing pregnancy best serves the many purposes of a primary outcome and best reflects the effectiveness of a treatment.

The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women

BACKGROUND The combination of the qualitative fetal fibronectin test and cervical length measurement has a high negative predictive value for preterm birth within 7 days; however, positive prediction is poor. A new bedside quantitative fetal fibronectin test showed potential additional value over the conventional qualitative test, but there is limited evidence on the combination with cervical length measurement. OBJECTIVE The purpose of this study was to compare quantitative fetal fibronectin and qualitative fetal fibronectin testing in the prediction of spontaneous preterm birth within 7 days in symptomatic women who undergo cervical length measurement. STUDY DESIGN We performed a European multicenter cohort study in 10 perinatal centers in 5 countries. Women between 24 and 34 weeks of gestation with signs of active labor and intact membranes underwent quantitative fibronectin testing and cervical length measurement. We assessed the risk of preterm birth within 7 days in predefined strata based on fibronectin concentration and cervical length. RESULTS Of 455 women who were included in the study, 48 women (11%) delivered within 7 days. A combination of cervical length and qualitative fibronectin resulted in the identification of 246 women who were at low risk: 164 women with a cervix between 15 and 30 mm and a negative fibronectin test (<50 ng/mL; preterm birth rate, 2%) and 82 women with a cervix at >30 mm (preterm birth rate, 2%). Use of quantitative fibronectin alone resulted in a predicted risk of preterm birth within 7 days that ranged from 2% in the group with the lowest fibronectin level (<10 ng/mL) to 38% in the group with the highest fibronectin level (>500 ng/mL), with similar accuracy as that of the combination of cervical length and qualitative fibronectin. Combining cervical length and quantitative fibronectin resulted in the identification of an additional 19 women at low risk (preterm birth rate, 5%), using a threshold of 10 ng/mL in women with a cervix at <15 mm, and 6 women at high risk (preterm birth rate, 33%) using a threshold of >500 ng/mL in women with a cervix at >30 mm. CONCLUSION In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.

The Effect of Interpregnancy Interval on the Recurrence Rate of Spontaneous Preterm Birth: A Retrospective Cohort Study

Objective We assessed, in women with a previous spontaneous preterm birth, the effect of interpregnancy interval on the subsequent preterm birth rate. Design Retrospective cohort study. Setting A nationwide longitudinal dataset of the the Netherlands Perinatal Registry. Population Women with three sequential singleton pregnancies between 1999 and 2009 and a spontaneous preterm birth <37 weeks in the first pregnancy. Methods We evaluated the impact of interpregnancy interval on the course of the next pregnancies. Antenatal death and/or congenital abnormalities were excluded. Conventional and conditional logistic regression analysis were applied. We adjusted for maternal age, ethnicity, socioeconomic status, artificial reproductive techniques, and year of birth. Main Outcome Measures Outcomes studied were preterm birth <37 weeks, <32 weeks, low birth weight <2500 g, and small for gestational age <10th percentile. Results Among 2,361 women with preterm birth in the first pregnancy, logistic regression analysis indicated a significant effect of a short interpregnancy interval (0‐5 mo) on recurrent preterm birth <37 weeks (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.62‐3.05), <32 weeks (OR, 2.90; 95% CI, 1.43‐5.87), and low birth weight (OR, 2.69; 95% CI, 1.79‐4.03). In addition, a long interval (≥60 mo) had a significant effect on preterm birth <37 weeks (OR, 2.19; 95% CI, 1.29‐3.74). Conditional logistic regression analysis confirmed the effect of a short interval on the recurrence of preterm birth rate <37 weeks and low birth weight. Conclusion In women with a previous spontaneous preterm birth, a short interpregnancy interval has a strong impact on the risk of preterm birth before 37 weeks and low birth weight in the next pregnancy, irrespective of the type of analysis performed.

The risk of preterm birth of treated versus untreated cervical intraepithelial neoplasia (CIN): a systematic review and meta-analysis

Cervical surgery is associated with preterm birth (PTB) and neonatal morbidity. However, it is unknown whether this increased risk is due to the surgery itself or to the cervical intraepithelial neoplasia (CIN) underlying the surgery. Our objective was to assess the risk for PTB in women with treated and untreated CIN. We performed an electronic literature search in MEDLINE, Embase and CENTRAL for studies that reported on pregnancy outcome after treated and untreated CIN. The methodological quality was scored using the STROBE combined checklist for observational studies. We extracted data on PTB<37 weeks, very PTB<32 weeks, spontaneous PTB<37 weeks, (preterm) premature rupture of membranes ((P)PROM), perinatal mortality and section caesarean each before and after treatment for CIN. We used the Mantel-Haenszel method to estimate summarizing odds ratios. Our search identified 620 studies, of which 20 were reporting on pregnancy outcome for a total of 12,159,293 women. There were 20,832 women who gave birth after treatment for CIN before pregnancy, 52 women who gave birth after treatment for CIN during pregnancy, 64,237 women with CIN who gave birth before treatment, and 8,902,865 women who gave birth without CIN. Compared to women with untreated CIN, women treated for CIN before or during pregnancy, had a significantly higher risk of PTB<37 weeks (OR 1.7, 95% CI 1.0-2.7). When comparing women treated for CIN before pregnancy (n=20,832) to women with untreated CIN (n=64,162), we found an OR of 1.4 with a 95% confidence interval of 0.85-2.3. Women treated during pregnancy had a clearly increased risk for PTB (OR 6.5, 95% CI 1.1-37), and (P)PROM (OR 1.8, 95% CI 1.4-2.2). In women with cervical surgery, the risks for spontaneous PTB<37 weeks (OR 0.87, 95% CI 0.54-1.4), caesarean section (OR 1.0, 95% CI 0.71-1.5) and perinatal mortality (OR 1.0, 95% CI 0.38-2.8) were not increased. The increased risk of PTB in women who underwent cervical surgery for CIN is especially increased when performed during pregnancy. When performed before pregnancy the risk of PTB is increased, although insignificant.

Effectiveness and safety as outcome measures in reproductive medicine

The aim of reproductive medicine is to help couples with an unfulfilled child wish to have a child by offering them the best treatment option. The choice of treatment reflects effectiveness and safety. While effectiveness refers to the extent to which a treatment increases the chance of a couple in having a baby, safety relates to adverse effects associated with such a treatment. In an attempt to integrate effectiveness and safety, healthy singleton live birth (at term) has been suggested as the ideal outcome measure for evaluative research in reproductive medicine. Although intuitively desirable, this proposal overlooks the fact that assessment of effectiveness and safety in this context cannot be measured as a single outcome. In this paper, we explain why effectiveness and safety outcomes in reproductive medicine should be assessed independently, and later synthesized to inform clinical decision-making.

Fetal Gender of the First Born and the Recurrent Risk of Spontaneous Preterm Birth.

OBJECTIVE To study, in women with a spontaneous preterm birth (sPTB) in the first pregnancy, the effect of fetal sex in that first pregnancy on the recurrent sPTB risk. STUDY DESIGN A nationwide retrospective cohort study (data from National Perinatal Registry) on all women with two sequential singleton pregnancies (1999-2009) with the first delivery ending in sPTB <37 weeks. We used logistic regression analysis to study the association between fetal gender in the first pregnancy and the risk of recurrent sPTB. We repeated the analysis for sPTB < 32 weeks. RESULTS The overall incidence of sPTB <37 weeks in the first pregnancy was 4.5% (15,351/343,853). Among those 15,351 women, the risk of recurrent sPTB <37 weeks was increased when the first fetus was female compared when that fetus was male (15.8 vs. 15.2%; adjusted odds ratio [aOR] 1.2; 95% confidence interval [CI] 1.05-1.3). A similar effect was seen for sPTB <32weeks (8.2 vs. 5.9%; aOR 4.5; 95% CI 1.5-13). CONCLUSION Women who suffer sPTB of a female fetus have an increased risk of recurrent sPTB compared with women who suffer sPTB of a male fetus. This information provides proof for the hypothesis that sPTB is due to an independent maternal and fetal factor.

Should the individual preterm birth risk be incorporated into the embryo transfer policy in in vitro fertilisation? A decision analysis

To assess by proof of principle whether the individual risk for preterm birth (PTB) should be incorporated into the embryo transfer policy in in vitro fertilisation (IVF).

Effect of Cervical Cancer Screening Programs on Preterm Birth: A Decision and Cost-Effectiveness Analysis

OBJECTIVE To assess the effect of age at initiation and interval of cervical cancer screening in women of reproductive age on the risk of future preterm birth and subsequent adverse neonatal outcome relative to maternal life-years gained and cost of both screening and preterm birth. METHODS In this decision and cost-effectiveness analysis, we compared eight cytology-based screening programs varying in age of onset (21, 24, 25, 27, or 30 years) and screening interval (3 or 5 years) in a fictive cohort of 100,000 women. We used the microsimulation screening analysis model to estimate number of cervical intraepithelial neoplasia diagnoses, large loop excisions of the transformation zone (LLETZs), life-years gained, cervical cancer cases, deaths, and costs of screening and treatment. We used the number of LLETZs to calculate additional preterm births, subsequent neonatal morbidity, mortality, and associated costs. RESULTS The number of LLETZs per 100,000 women varied from 9,612 for the most intensive screening (every 3 years from age 21 years) to 4,646 for the least intensive screening (every 5 years from age 30 years). Compared with the least intensive program, the most intensive program increased maternal life-years gained by 9% (10,728 compared with 9,839), decreased cervical cancer cases by 67% (52 compared with 158), and cervical cancer deaths by 75% (four compared with 16) at the expense of 250% (158 compared with 45) more preterm births and 320% (four compared with one) more neonatal deaths while increasing total costs by