The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial.

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. METHODS: This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. DISCUSSION: The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. TRIAL REGISTRATION NUMBER: The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Treatment effect of oil-based contrast is related to experienced pain at HSG: a post-hoc analysis of the randomised H2Oil study.

STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

The capacity of hysterosalpingography and laparoscopy to predict natural conception.

BACKGROUND: Laparoscopy has been claimed to be superior to hysterosalpingography (HSG) in predicting fertility. Whether this conclusion is applicable to a general subfertile population can be questioned as data in support of this claim were collected in third line centres. The aim of this study was to assess the prognostic capacity of HSG and laparoscopy in a general subfertile population. METHODS: In 38 centres, we prospectively studied a cohort of patients referred for subfertility between 2002 and 2004, who underwent HSG and/or laparoscopy as part of their subfertility work-up. Follow-up started immediately after tubal testing and ended 12 months thereafter. Time to pregnancy was censored at the of date last contact, when the woman was not pregnant or at the start of treatment. Kaplan-Meier curves for the occurrence of spontaneous intrauterine pregnancy were constructed for patients without tubal pathology, for those with unilateral tubal pathology and for patients with bilateral tubal pathology at HSG or laparoscopy. Multivariable Cox regression analysis was used to calculate fecundity rate ratios (FRRs) to express associations between tubal pathology and the occurrence of an intrauterine pregnancy. RESULTS: Of the 3301 included patients, 2043 underwent HSG only, 747 underwent diagnostic laparoscopy only and 511 underwent both. At HSG, 322 (13%) patients showed unilateral tubal pathology and 135 (5%) showed bilateral tubal pathology. At laparoscopy, 167 (13%) showed unilateral tubal pathology and 215 (17%) showed bilateral tubal pathology. Multivariable analysis resulted in FRRs of 0.81 [95% confidence interval (CI): 0.59-1.1] for unilateral, and 0.28 (95% CI: 0.13-0.59) for bilateral, tubal pathology at HSG. The FRRs at laparoscopy were 0.85 (95% CI: 0.47-1.52) for unilateral, and 0.24 (95% CI: 0.11-0.54) for bilateral, tubal pathology. CONCLUSIONS: Patients with unilateral tubal pathology at HSG and laparoscopy had a moderate reduction in pregnancy chances, whereas those with bilateral tubal pathology at HSG and laparoscopy had a severe reduction in pregnancy chances. This reduction was similar for HSG and laparoscopy, suggesting that HSG and laparoscopy have a comparable predictive capacity for natural conception.

Five-year follow up of a randomised controlled trial comparing NovaSure and ThermaChoice endometrial ablation.

OBJECTIVE: We have previously reported that NovaSure was more effective than balloon ablation at 12 months follow up in the treatment of menorrhagia. In this paper, we report the 5-year outcome of this study. The objective was to evaluate amenorrhoea rates, hysterectomy rate, and quality of life associated with the bipolar impedance-controlled endometrial ablation technique (NovaSure) in comparison with balloon ablation technique (ThermaChoice) at 5 years after administration. DESIGN: Double-blind randomised controlled trial, 2:1 randomisation NovaSure versus ThermaChoice. SETTING: A teaching hospital with 500 beds in The Netherlands. POPULATION: A total of 126 premenopausal women suffering from menorrhagia with a pictorial blood loss assessment count > or = 150 without intracavitary abnormalities. METHODS: Women were randomly allocated to bipolar radio-frequency ablation and balloon ablation in a 2:1 ratio. MAIN OUTCOME MEASURES: The main outcome measures were amenorrhoea rate, hysterectomies, and health-related quality of life (HRQol) as reported at 5 year follow up. RESULTS: At 5 years of follow up, the total response rate was 96% in the bipolar group and 90% in the balloon group. Amenorrhoea was reported in the bipolar group by 48% of women and in the balloon arm by 32% (relative risk 1.6 [.93-2.6]). There were eight women in the bipolar group (9.8%) and five in the balloon group (12.9%) who had undergone a hysterectomy. Furthermore, there was a significant equal improvement of HRQoL over time in both groups. CONCLUSIONS: At 5 years follow up, bipolar thermal ablation was superior over balloon ablation in the treatment of menorrhagia.

Maternal and perinatal complications in triplet compared with twin pregnancy.

OBJECTIVE: To compare maternal and perinatal complications in triplet and twin pregnancies. STUDY DESIGN: Case-controlled study in the setting of a University Hospital. Each pregnancy of a consecutive series of 40 triplet pregnancies of 20 weeks or more was matched for parity and maternal age with two sets of twins delivered in the same year. Primary end points of the analysis were maternal complications and perinatal outcome. RESULTS: Of the triplets 82% and of the twins 36% were a result of assisted reproduction. Pre-term labor occurred significantly more often in triplet than in twin gestation. Triplets had a significantly lower median birth-weight (1478 vs. 2030 g) and gestational age at delivery (32 vs. 35.5 weeks). The mean neonatal hospital stay was significantly longer in triplets, mainly related to the lower birth-weight, but there was no significant difference between triplets and twins in the incidence of major neonatal complications. CONCLUSION: This data of the anticipated perinatal outcome in triplet and twin pregnancies may be used to counsel women with a triplet pregnancy considering selective reduction to twins. All methods of assisted reproduction should aim at prevention of multifetal gestation.

Routine Chlamydia antibody testing is of limited use in subfertile women with anovulation.

The Chlamydia antibody titre (CAT) is a test used to identify subfertile couples at increased risk for tubal pathology. The usefulness of the routine performance of CAT was evaluated in a multicentre prospective cohort study, in women without regular ovulation. Consecutive couples presenting with subfertility due to an irregular menstrual cycle or amenorrhoea were included. A total of 711 women were studied, all of whom underwent CAT. Tubal status was verified in 190 of these women. Two-sided tubal pathology was found in 5% of these women, and one-sided occlusion in 10%. Of all the women in the study group, 33 (4.6%) had an abnormal CAT, of which 21 underwent further tubal testing. Tubal pathology was found in two (10%) of these 21 patients. The sensitivity and specificity of CAT were respectively 20% and 89%. Correction for verification bias increased the specificity to 96% with a drop of the sensitivity to 9%. In subfertile couples with anovulation, the performance of CAT is not useful. It is proposed that testing for tubal disease in these women is delayed until treatment with clomiphene citrate has failed.

Ropivacaine 0.25% versus bupivacaine 0.25% for continuous epidural analgesia in labor: a double-blind comparison.

We compared the effects of continuous epidural infusion of ropivacaine 0.25% with bupivacaine 0.25% on pain relief and motor block during labor, and on the neonate. Seventy-six full-term parturients in active labor requiring epidural analgesia were randomly allocated to receive either bupivacaine 0.25% or ropivacaine 0.25%. Fifteen minutes after a loading dose of 10 mL of the study drug, an epidural infusion with the same drug was started at 6-12 mL/h to maintain an adequate block. Top-up doses of 6-10 mL were given as required. At full cervical dilation, the epidural infusion was discontinued. The onset of pain relief (verbal scale), contraction pain (visual analog scale), intensity of motor block (modified Bromage scale), and duration of motor block were not statistically different between the groups. Apgar scores at 1 and 5 min after delivery were comparable. There was a higher proportion of the neonates in the ropivacaine group (26/31 = 84%) who had a neurologic and adaptive capacity score (NACS) > or = 35 2 h after delivery than in the bupivacaine group (18/29 = 62%). We conclude that ropivacaine 0.25% and bupivacaine 0.25% are equally effective for epidural pain relief during labor. Ropivacaine may have an advantage over bupivacaine regarding neonatal neurobehavioral performance during the first few hours after delivery, although further studies will be required to substantiate this.