Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.

STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

Unplanned cesarean sections in advanced maternal age: A predictive model.

INTRODUCTION: As maternal age during pregnancy is rising all over the world, there is a growing need for prognostic factors that determine maternal and perinatal outcomes in older women. MATERIAL AND METHODS: This study is a retrospective cohort study of women aged 40 years or older at the time of delivery in four Santeon hospitals across the Netherlands between January 2016 and December 2019. Outcomes were compared between women of 40-44 years (advanced maternal age) and 45 years and older (very advanced maternal age). Primary outcome was unplanned cesarean section, secondary outcomes included postpartum hemorrhage and neonatal outcomes. Multivariate regression analysis was performed to analyze predictive factors for unplanned cesarean sections in women who attempted vaginal delivery. Subsequently, a predictive model and risk scores were constructed to predict unplanned cesarean section. RESULTS: A cohort of 1660 women was analyzed; mean maternal age was 41.4 years, 4.8% of the women were 45 years and older. In both groups, more than half of the women had not delivered vaginally before. Unplanned cesarean sections were performed in 21.1% of the deliveries in advanced maternal age and in 29.1% in very advanced maternal age. Four predictive factors were significantly correlated with unplanned cesarean sections: higher body mass index (BMI), no previous vaginal delivery, spontaneous start of delivery and number of days needed for cervical priming. A predictive model was constructed from these factors with an area under the curve of 0.75 (95% confidence interval 0.72-0.78). A sensitivity analysis in nulliparous women proved that BMI, days of cervical priming, age, and gestational age were risk factors, whereas spontaneous start of delivery and induction were protective factors. There was one occurrence of neonatal death. CONCLUSIONS: Women of advanced maternal age and those of very advanced maternal age have a higher chance of having an unplanned cesarean section compared to the general obstetric population in the Netherlands. Unplanned cesarean sections can be predicted through use of our predictive model. Risk increases with higher BMI, no previous vaginal delivery, and increasing number of days needed for cervical priming, whereas spontaneous start of labor lowers the risk. In nulliparous women, age and gestational age also increase risk, but induction lowers the risk of having an unplanned cesarean section.

Childhood outcomes after induction of labor or expectant management for preterm prelabor rupture of membranes: a 10-year follow-up of the PPROMEXIL trials.

BACKGROUND: Management of late preterm prelabor rupture of membranes between 34+0 and 36+6 weeks' gestation balances the risks of preterm birth with the risks of infection for both the mother and the neonate. Expectant management to prolong pregnancy showed similar risks of neonatal sepsis, but children at 2 years of age showed more neurodevelopmental delay when compared with induction of labor. Long-term outcomes on child development after 2 years of age are unknown. OBJECTIVE: This study aimed to assess the long-term outcomes of children born after singleton pregnancies complicated by late preterm prelabor rupture of membranes managed by induction of labor in comparison with expectant management. STUDY DESIGN: This was a follow-up study of the Preterm Prelabor Rupture of Membranes Expectant Management Versus Induction of Labor (PPROMEXIL) trials (randomized controlled trials between 2007 to 2011) evaluating children at 10 to 12 years of age (Netherlands Trial Register 6953). The primary outcomes were cognition, motor function, and behavior as assessed by the Wechsler Intelligence Scale for Children-V-NL, Movement Assessment Battery for Children-2, and Child Behavior Checklist, respectively. The secondary outcomes were sensory processing, respiratory problems, educational attainment, and general health. Mild delay was defined as -1 standard deviation or corresponding percentile. The relative risk and confidence intervals were calculated using standard methods. RESULTS: This follow-up study invited 711 surviving children of the 714 singleton pregnancies randomized in the original trials. In total, 248 (35%) children participated (127 induction of labor, 121 expectant management). Children born after induction of labor had no significant differences in the primary outcomes when compared with those born after expectant management. Mild cognitive delay was observed in 7 of 122 (5.7%) children born after induction of labor in comparison with in 12 of 120 (10.0%) children born after expectant management (relative risk, 0.57; 95% confidence interval, 0.23-1.41). A mild delay in motor function was observed in 42 of 122 (34.4%) children born after induction of labor vs in 55 of 120 (45.8%) children born after expectant management (relative risk, 0.75; 95% confidence interval, 0.55-1.03). Mild abnormal behavior was observed in 37 of 125 (29.6%) children born after induction of labor compared with in 33 of 118 (28.0%) children born after expectant management (relative risk, 1.05; 95% confidence interval, 0.71-1.57). Secondary outcomes were also comparable between the induction of labor and the expectant management groups except that more children born after expectant management had a hospital admission (relative risk, 0.68; 95% confidence interval, 0.52-0.89) or a surgery (relative risk, 0.58; 95% confidence interval, 0.41-0.82). CONCLUSION: In children born after pregnancies with late preterm prelabor rupture of membranes, expectant management did not improve long-term outcomes at 10 to 12 years when compared with induction of labor.

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. METHODS AND FINDINGS: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. CONCLUSIONS: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. TRIAL REGISTRATION: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) lead to similar pregnancy outcomes, compared with hysterosalpingography (HSG), as first-choice tubal patency test in infertile couples? SUMMARY ANSWER: HyFoSy and HSG produce similar findings in a majority of patients and clinical management based on the results of either HyFoSy or HSG, leads to comparable pregnancy outcomes. HyFoSy is experienced as significantly less painful. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during fertility work-up is performed by HSG. HyFoSy is an alternative imaging technique lacking ionizing radiation and iodinated contrast medium exposure which is less expensive than HSG. Globally, there is a shift towards the use of office-based diagnostic methods, such as HyFoSy. STUDY DESIGN, SIZE, DURATION: This multicentre, prospective, comparative study with a randomized design was conducted in 26 hospitals in The Netherlands. Participating women underwent both HyFoSy and HSG in randomized order. In case of discordant results, women were randomly allocated to either a management strategy based on HyFoSy or one based on HSG. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male infertility or a known iodine contrast allergy were excluded. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 women underwent HyFoSy and HSG. HyFoSy was inconclusive in 97 of them (9.5%), HSG was inconclusive in 30 (2.9%) and both were inconclusive in 9 (0.9%). In 747 women (73%) conclusive tests results were concordant. Of the 143/1026 (14%) with discordant results, 105 were randomized to clinical management based on the results of either HyFoSy or HSG. In this group, 22 of the 54 women (41%) allocated to management based on HyFoSy and 25 of 51 women (49%) allocated to management based on HSG had an ongoing pregnancy leading to live birth (Difference -8%; 95% CI: -27% to 10%). In total, clinical management based on the results of HyFoSy was estimated to lead to a live birth in 474 of 1026 women (46%) versus 486 of 1026 (47%) for management based on HSG (Difference -1.2%; 95% CI: -3.4% to 1.5%). Given the pre-defined margin of -2%, statistically significant non-inferiority of HyFoSy relative to HSG could not be demonstrated (P = 0.27). The mean pain score for HyFoSy on the 1-10 Visual Analogue Scale (VAS) was 3.1 (SD 2.2) and the mean VAS pain score for HSG was 5.4 (SD 2.5; P for difference < 0.001). LIMITATIONS, REASONS FOR CAUTION: Since all women underwent both tubal patency tests, no conclusions on a direct therapeutic effect of tubal flushing could be drawn. WIDER IMPLICATIONS OF THE FINDINGS: HyFoSy or HSG produce similar tubal pathology findings in a majority of infertile couples and, where they differ, a difference in findings does not lead to substantial difference in pregnancy outcome, while HyFoSy is associated with significantly less pain. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foam® kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports travel and speaker fees from Guerbet. F.J.M.B. reports personal fees as a member of the external advisory board for Merck Serono, The Netherlands, and a research support grant from Merck Serono, outside the submitted work. C.B.L. reports speakers' fee from Ferring in the past, and his department receives research grants from Ferring, Merck and Guerbet. J.S. reports a research agreement with Takeda on MR of motility outside the submitted work. M.V.W. reports leading The Netherlands Satellite of the Cochrane Gynaecology and Fertility Group. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet and research funding from Merck and Guerbet. V.M. reports non-financial support from IQ medicals ventures, during the conduct of the study; grants and personal fees from Guerbet, outside the submitted work. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: NTR4746/NL4587 (https://www.trialregister.nl). TRIAL REGISTRATION DATE: 19 August 2014. DATE OF FIRST PATIENT'S ENROLMENT: 7 May 2015.

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood.

This study aimed to investigate the association between hyperemesis gravidarum (HG) severity and early enteral tube feeding on cardiometabolic markers in offspring cord blood. We included women admitted for HG, who participated in the MOTHER randomised controlled trial (RCT) and observational cohort. The MOTHER RCT showed that early enteral tube feeding in addition to standard care did not affect symptoms/birth outcomes. Among RCT and cohort participants, we assessed how HG severity affected lipid, c-peptide, glucose and free thyroxine cord blood levels. HG severity measures were severity of vomiting at inclusion and 3 weeks after inclusion, pregnancy weight gain and 24-h energy intake at inclusion, readmissions and duration of hospital admissions. Cord blood measures were also compared between RCT participants allocated to enteral tube feeding and those receiving standard care. Between 2013-2016, 215 women were included: 115 RCT and 100 cohort participants. Eighty-one cord blood samples were available. Univariable not multivariable regression analysis showed that lower maternal weight gain was associated with higher cord blood glucose levels (ß: -0·08, 95% CI -0·16, -0·00). Lower maternal weight gain was associated with higher Apo-B cord blood levels in multivariable regression analysis (ß: -0·01, 95% CI -0·02, -0·01). No associations were found between other HG severity measures or allocation to enteral tube feeding and cord blood cardiometabolic markers. In conclusion, while lower maternal weight gain was associated with higher Apo-B cord blood levels, no other HG severity measures were linked with cord blood cardiometabolic markers, nor were these markers affected by enteral tube feeding.

Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: Follow up of the MOTHER study.

INTRODUCTION: Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG's long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies. MATERIAL AND METHODS: We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies. RESULTS: Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3-130.5, p = 0.03). CONCLUSIONS: High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning.

Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: A prospective cohort study.

INTRODUCTION: Little is known about the pathophysiology of hyperemesis gravidarum (HG). Proposed underlying causes are multifactorial and thyroid function is hypothesized to be causally involved. In this study, we aimed to assess the utility of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) as a marker and predictor for the severity and clinical course of HG. MATERIAL AND METHODS: We conducted a prospective cohort study including women admitted for HG between 5 and 20 weeks of gestation in 19 hospitals in the Netherlands. Women with a medical history of thyroid disease were excluded. TSH and FT4 were measured at study entry. To adjust for gestational age, we calculated TSH multiples of the median (MoM). We assessed HG severity at study entry as severity of nausea and vomiting (by the Pregnancy Unique Quantification of Emesis and nausea score), weight change compared with prepregnancy weight, and quality of life. We assessed the clinical course of HG as severity of nausea and vomiting and quality of life 1 week after inclusion, duration of hospital admissions, and readmissions. We performed multivariable regression analysis with absolute TSH, TSH MoMs, and FT4. RESULTS: Between 2013 and 2016, 215 women participated in the cohort. TSH, TSH MoM, and FT4 were available for, respectively, 150, 126, and 106 of these women. Multivariable linear regression analysis showed that lower TSH MoM was significantly associated with increased weight loss or lower weight gain at study entry (ΔKg; ß = 2.00, 95% CI 0.47-3.53), whereas absolute TSH and FT4 were not. Lower TSH, not lower TSH MoM or FT4, was significantly associated with lower nausea and vomiting scores 1 week after inclusion (ß = 1.74, 95% CI 0.36-3.11). TSH and FT4 showed no association with any of the other markers of the severity or clinical course of HG. Twenty-one out of 215 (9.8%) women had gestational transient thyrotoxicosis. Women with gestational transient thyrotoxicosis had a lower quality of life 1 week after inclusion than women with no gestational transient thyrotoxicosis (p = 0.03). CONCLUSIONS: Our findings show an inconsistent role for TSH, TSH MoM, or FT4 at time of admission and provide little guidance on the severity and clinical course of HG.

Gonadotrophins or clomiphene citrate in couples with unexplained infertility undergoing intrauterine insemination: a cost-effectiveness analysis.

RESEARCH QUESTION: What is the cost-effectiveness of gonadotrophins compared with clomiphene citrate in couples with unexplained subfertility undergoing intrauterine insemination (IUI) with ovarian stimulation under strict cancellation criteria? DESIGN: A cost-effectiveness analysis alongside a randomized controlled trial (RCT). Between July 2013 and March 2016, 738 couples were randomized to gonadotrophins (369) or clomiphene citrate (369) in a multicentre RCT in the Netherlands. The direct medical costs of both strategies were compared. Direct medical costs included costs of medication, cycle monitoring, insemination and, if applicable, pregnancy monitoring. Non-parametric bootstrap resampling was used to investigate the effect of uncertainty in estimates. The cost-effectiveness analysis was performed according to intention-to-treat. The incremental cost-effectiveness ratio (ICER) between gonadotrophins and clomiphene citrate for ongoing pregnancy and live birth was assessed. RESULTS: The mean costs per couple were €1534 for gonadotrophins and €1067 for clomiphene citrate (mean difference of €468; 95% confidence interval [CI] €464-472). As ongoing pregnancy rates were 31% in women allocated to gonadotrophins and 26% in women allocated to clomiphene citrate (relative risk 1.16, 95% CI 0.93-1.47), the ICER was €21,804 (95% CI €11,628-31,980) per additional ongoing pregnancy with gonadotrophins and €17,044 (95% CI €8998-25,090) per additional live birth with gonadotrophins. CONCLUSIONS: Gonadotrophins are more expensive compared with clomiphene citrate in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria, without being significantly more effective.

Kidney Function After a Hypertensive Disorder of Pregnancy: A Longitudinal Study.

BACKGROUND: Registry-based studies report an increased risk for end-stage kidney disease after hypertensive disorders of pregnancy (HDPs). It is unclear whether HDPs lead to an increased incidence of chronic kidney disease (CKD) and/or progression of kidney function decline. STUDY DESIGN: Subanalysis of the Prevention of Renal and Vascular Endstage Disease (PREVEND) Study, a Dutch population-based cohort with follow-up of 5 visits approximately 3 years apart. SETTING & PARTICIPANTS: Women without and with patient-reported HDPs (non-HDP, n=1,805; HDP, n=977) were identified. Mean age was 50 years at baseline and median follow-up was 11 years. FACTOR: An HDP. OUTCOMES: (1) The incidence of CKD using Cox regression and (2) the course of kidney function (estimated glomerular filtration rate [eGFR] and 24-hour albuminuria) over 5 visits using generalized estimating equation analysis adjusted for age, mean arterial pressure, and renin-angiotensin system (RAS) blockade. CKD was defined as eGFR<60mL/min/1.73m2 and/or 24-hour albuminuria with albumin excretion > 30mg, and end-stage kidney disease was defined as receiving dialysis or kidney transplantation. RESULTS: During follow-up, none of the women developed end-stage renal disease and the incidence of CKD during follow-up was similar across HDP groups (HR, 1.04; 95% CI, 0.79-1.37; P=0.8). Use of RAS blockade was higher after HDP at all visits. During a median of 11 years, we observed a decrease in eGFR in both groups, with a slightly steeper decline in the HDP group (98±15 to 88±16 vs 99±17 to 91±15mL/min/1.73m2; Pgroup<0.01, Pgroup*visit<0.05). The group effect remained significant after adjusting for mean arterial pressure, but disappeared after adjusting for RAS blockade. The 24-hour albuminuria did not differ between groups. LIMITATIONS: No obstetric records available. HDPs defined by patient report rather than health records. CONCLUSIONS: HDPs did not detectably increase the incidence of CKD. During follow-up, we observed no differences in albuminuria, but observed a marginally lower eGFR after HDP that was no longer statistically significant after adjusting for the use of RAS blockers. In this population, we were unable to identify a significant risk for kidney function decline after patient-reported HDP.

The FOAM study: is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial.

BACKGROUND: Tubal pathology is a causative factor in 20% of subfertile couples. Traditionally, tubal testing during fertility work-up is performed by hysterosalpingography (HSG). Hysterosalpingo-foam sonography (HyFoSy) is a new technique that is thought to have comparable accuracy as HSG, while it is less expensive and more patient friendly. HyFoSy would be an acceptable alternative for HSG, provided it has similar effectiveness in terms of patient outcomes. METHODS/DESIGN: We aim to compare the effectiveness and costs of management guided by HyFoSy or by HSG. Consenting women will undergo tubal testing by both HyFoSy and HSG in a randomized order during fertility work-up. The study group will consist of 1163 subfertile women between 18 and 41 years old who are scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male subfertility or a known contrast (iodine) allergy will be excluded. We anticipate that 7 % (N = 82) of the participants will have discordant test results for HyFoSy and HSG. These participants will be randomly allocated to either a management strategy based on HyFoSy or a management strategy based on HSG, resulting in either a diagnostic laparoscopy with chromopertubation or a strategy that assumes tubal patency (intrauterine insemination or expectant management). The primary outcome is ongoing pregnancy leading to live birth within 12 months after randomization. Secondary outcomes are patient pain scores, time to pregnancy, clinical pregnancy, miscarriage rate, multiple pregnancy rate, preterm birth rate and number of additional treatments. Costs will be estimated by counting resource use and calculating unit prices. DISCUSSION: This trial will compare the effectiveness and costs of HyFoSy versus HSG in assessing tubal patency in subfertile women. TRIAL REGISTRATION: Dutch Trial Register (NTR 4746, http://www.trialregister.nl ). Date of registration: 19 August 2014.

Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome.

BACKGROUND: Current management of preterm prelabour rupture of the membranes (PPROM) involves either initiating birth soon after PPROM or, alternatively, adopting a 'wait and see' approach (expectant management). It is unclear which strategy is most beneficial for mothers and their babies. This is an update of a Cochrane review published in 2010 (Buchanan 2010). OBJECTIVES: To assess the effect of planned early birth versus expectant management for women with preterm prelabour rupture of the membranes between 24 and 37 weeks' gestation for fetal, infant and maternal well being. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 September 2016), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing planned early birth with expectant management for women with PPROM prior to 37 weeks' gestation. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated trials for inclusion into the review and for methodological quality. Two review authors independently extracted data. We checked data for accuracy. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 12 trials in the review (3617 women and 3628 babies). For primary outcomes, we identified no clear differences between early birth and expectant management in neonatal sepsis (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30, 12 trials, 3628 babies, evidence graded moderate), or proven neonatal infection with positive blood culture (RR 1.24, 95% CI 0.70 to 2.21, seven trials, 2925 babies). However, early birth increased the incidence of respiratory distress syndrome (RDS) (RR 1.26, 95% CI 1.05 to 1.53, 12 trials, 3622 babies, evidence graded high). Early birth was also associated with an increased rate of caesarean section (RR 1.26, 95% CI 1.11 to 1.44, 12 trials, 3620 women, evidence graded high).Assessment of secondary perinatal outcomes showed no clear differences in overall perinatal mortality (RR 1.76, 95% CI 0.89 to 3.50, 11 trials, 3319 babies), or intrauterine deaths (RR 0.45, 95% CI 0.13 to 1.57, 11 trials, 3321 babies) when comparing early birth with expectant management. However, early birth was associated with a higher rate of neonatal death (RR 2.55, 95% CI 1.17 to 5.56, 11 trials, 3316 babies) and need for ventilation (RR 1.27, 95% CI 1.02 to 1.58, seven trials, 2895 babies, evidence graded high). Babies of women randomised to early birth were delivered at a gestational age lower than those randomised to expectant management (mean difference (MD) -0.48 weeks, 95% CI -0.57 to -0.39, eight trials, 3139 babies). Admission to neonatal intensive care was more likely for those babies randomised to early birth (RR 1.16, 95% CI 1.08 to 1.24, four trials, 2691 babies, evidence graded moderate).In assessing secondary maternal outcomes, we found that early birth was associated with a decreased rate of chorioamnionitis (RR 0.50, 95% CI 0.26 to 0.95, eight trials, 1358 women, evidence graded moderate), and an increased rate of endometritis (RR 1.61, 95% CI 1.00 to 2.59, seven trials, 2980 women). As expected due to the intervention, women randomised to early birth had a higher chance of having an induction of labour (RR 2.18, 95% CI 2.01 to 2.36, four trials, 2691 women). Women randomised to early birth had a decreased total length of hospitalisation (MD -1.75 days, 95% CI -2.45 to -1.05, six trials, 2848 women, evidence graded moderate).Subgroup analyses indicated improved maternal and infant outcomes in expectant management in pregnancies greater than 34 weeks' gestation, specifically relating to RDS and maternal infections. The use of prophylactic antibiotics were shown to be effective in reducing maternal infections in women randomised to expectant management.Overall, we assessed all 12 studies as being at low or unclear risk of bias. Some studies lacked an adequate description of methods and the risk of bias could only be assessed as unclear. In five of the studies there were one and/or two domains where the risk of bias was judged as high. GRADE profiling showed the quality of evidence across all critical outcomes to be moderate to high. AUTHORS' CONCLUSIONS: With the addition of five randomised controlled trials (2927 women) to this updated review, we found no clinically important difference in the incidence of neonatal sepsis between women who birth immediately and those managed expectantly in PPROM prior to 37 weeks' gestation. Early planned birth was associated with an increase in the incidence of neonatal RDS, need for ventilation, neonatal mortality, endometritis, admission to neonatal intensive care, and the likelihood of birth by caesarean section, but a decreased incidence of chorioamnionitis. Women randomised to early birth also had an increased risk of labour induction, but a decreased length of hospital stay. Babies of women randomised to early birth were more likely to be born at a lower gestational age.In women with PPROM before 37 weeks' gestation with no contraindications to continuing the pregnancy, a policy of expectant management with careful monitoring was associated with better outcomes for the mother and baby.The direction of future research should be aimed at determining which groups of women with PPROM would not benefit from expectant management. This could be determined by analysing subgroups according to gestational age at presentation, corticosteroid usage, and abnormal vaginal microbiological colonisation. Research should also evaluate long-term neurodevelopmental outcomes of infants.

Time efficiency of a web-based questionnaire in urogynecology: a randomized study.

INTRODUCTION AND HYPOTHESIS: Based on nationwide recommended questionnaires for women with pelvic floor dysfunction (PFD), we developed a web-based questionnaire (WBQ) that can be sent to women prior to their first visit. We hypothesized that using this WBQ would contribute to a more efficient first visit. Furthermore, we were interested in the satisfaction of patients who used the WBQ. METHODS: Women referred for PFD were randomized between WBQ and no questionnaire. Time spent per consultation was recorded in total and in split times for history taking, physical examination, counseling, and administration. Patient experience was evaluated by a standardized telephone interview. RESULTS: One hundred and twenty-eight women were randomized: 64 in the WBQ group and 64 in the control group. History taking was significantly shorter in the WBQ group [mean difference (MD) -1 m 32 s; 95 % confidence interval (CI) -2:41 to -0:23], and time for counseling was significantly longer (MD 1 m 21 s; 95 % CI 0:06-2:37). Overall time of the consultation was equal. The need for an additional visit tended to be less frequent in the WBQ group [53 % versus 64 %; relative risk (RR) 1.3, 95 % CI 0.8-2.0]. Forty-nine percent of women considered the WBQ time consuming without adding value. CONCLUSIONS: The WBQ contributed to a slightly more efficient use of the first consultation. While differences were small and patient satisfaction was low, other benefits of the WBQ should define whether the WBQ will be introduced.

Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL - III trial).

BACKGROUND: Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome. METHODS/DESIGN: Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. INTERVENTION: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, ß-error 0.2 and α-error 0.05). DISCUSSION: This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure. TRIAL REGISTRATION: NTR3492 Dutch Trial Register (http://www.trialregister.nl).

Economic analysis comparing induction of labor and expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks (PPROMEXIL trial).

OBJECTIVE: To compare the costs of induction of labor and expectant management in women with preterm prelabor rupture of membranes (PPROM). DESIGN: Economic analysis based on a randomized clinical trial. SETTING: Obstetric departments of eight academic and 52 non-academic hospitals in the Netherlands. POPULATION: Women with PPROM near term who were not in labor 24 h after PPROM. METHODS: A cost-minimization analysis was done from a health care provider perspective, using a bottom-up approach to estimate resource utilization, valued with unit-costs reflecting actual costs. MAIN OUTCOME MEASURES: Primary health outcome was the incidence of neonatal sepsis. Direct medical costs were estimated from start of randomization to hospital discharge of mother and child. RESULTS: Induction of labor did not significantly reduce the probability of neonatal sepsis [2.6% vs. 4.1%, relative risk 0.64 (95% confidence interval 0.25-1.6)]. Mean costs per woman were €8094 for induction and €7340 for expectant management (difference €754; 95% confidence interval -335 to 1802). This difference predominantly originated in the postpartum period, where the mean costs were €5669 for induction vs. €4801 for expectant management. Delivery costs were higher in women allocated to induction than in women allocated to expectant management (€1777 vs. €1153 per woman). Antepartum costs in the expectant management group were higher because of longer antepartum maternal stays in hospital. CONCLUSIONS: In women with pregnancies complicated by PPROM near term, induction of labor does not reduce neonatal sepsis, whereas costs associated with this strategy are probably higher.

Meta-analysis shows that infants who have suffered neonatal sepsis face an increased risk of mortality and severe complications.

UNLABELLED: Infants suffering from neonatal sepsis face an increased risk of early death and long-term neurodevelopmental delay. This paper analyses and summarises the existing data on short-term and long-term outcomes of neonatal sepsis, based on 12 studies published between January 2000 and 1 April 2012 and covering 3669 neonates with sepsis. CONCLUSION: Infants who have suffered neonatal sepsis face an increased risk of mortality and severe complications such as brain damage and, or, neurodevelopmental delay.

Home telemonitoring versus hospital care in complicated pregnancies in the Netherlands: a randomised, controlled non-inferiority trial (HoTeL).

BACKGROUND: Women with complicated pregnancies often require hospital admission. Telemonitoring at home is a promising alternative that fulfils a worldwide need in obstetric health care. Moreover, the COVID-19 pandemic has accelerated the transformation to digital care. The aim of this study was to evaluate safety, clinical effectiveness, patient satisfaction, and costs of home telemonitoring against hospital care in complicated pregnancies. METHODS: We did a multicentre, randomised, controlled, non-inferiority trial in six hospitals (four general teaching hospitals and two university hospitals) in the Netherlands (located in Utrecht, Amsterdam, and Groningen). Women aged 18 years and older with singleton pregnancies (>26 weeks gestation) requiring monitoring for pre-eclampsia, fetal growth restriction, fetal anomaly, preterm rupture of membranes, reduced fetal movements, or history of fetal death were included in the study. Participants were randomly assigned to either hospital admission or telemonitoring in (1:1), stratified for the six diagnoses for inclusion and the six centres of inclusion, using block randomisation (block sizes of four and six). When assigned to telemonitoring, participants went home with devices for cardiotocography and blood pressure measurements and had daily contact with their care providers after digitally sending their home measurements. When assigned to hospital admission, participants received care as usual on the ward until the postpartum period. The primary outcome was a composite of adverse perinatal outcomes assessed after delivery, including mortality; an Apgar score below 7 after 5 min or an umbilical arterial pH at birth below 7·05; maternal morbidity; admission of the newborn to the neonatal intensive care unit; and rate of caesarean section. The primary outcome was assessed in the intention-to-treat population. The non-inferiority margin for the primary outcome was a 10% absolute increase in composite primary endpoint based on baseline 20% incidence. The study was registered at the Dutch Trial Registration (NL5888) and is now closed to new participants. FINDINGS: From Dec 1, 2016, to Nov 30, 2019, 201 pregnant women were randomly assigned to an intervention procedure. 101 women were allocated to the telemonitoring group and 100 to the hospital admission group. One participant in the telemonitoring group withdrew consent before the intervention was initiated, and 100 participants were analysed for the primary outcome. In the hospital admission group, four participants did not receive the allocated intervention because they did not accept hospital admission. 100 participants in each group were analysed for the primary outcome according to the intention-to-treat principal. No participants were lost to follow-up. The primary outcome occurred in 31 (31%) of 100 participants in the telemonitoring group and in 40 (40%) of 100 participants in the hospital admission group. Adjusted for centre of inclusion, diagnosis, and nulliparity, the risk difference in primary outcome between both groups was 10·3% (95% CI -22·4 to 2·2) lower in the telemonitoring group, below the pre-defined non-inferiority margin of 10% absolute increase. A similar distribution for each of the individual components within the composite primary outcome was seen between groups. Five serious adverse events were reported: one neonatal death in the hospital admission group, in addition to one intra-uterine fetal death, two neonatal deaths, and one case of eclampsia in the telemonitoring group, all unrelated to the study. INTERPRETATION: This non-inferiority trial shows the first evidence that telemonitoring might be as safe as hospital admission for monitoring complicated pregnancies. FUNDING: Stichting Achmea Gezondheidszorg and ICT Healthcare Technology Solutions.

Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial.

BACKGROUND: At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term. METHODS AND FINDINGS: We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34(+0) and 37(+0) wk of gestation. Participants were randomly allocated in a 1:1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate. From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported. Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM. CONCLUSIONS: In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29313500

Management of late-preterm premature rupture of membranes: the PPROMEXIL-2 trial.

OBJECTIVE: The evidence for the management of near term prelabor rupture of membranes is poor. From January 2007 until September 2009, we performed the PPROM Expectant Management versus Induction of Labor (PPROMEXIL) trial. In this trial, we showed that in women with preterm prelabor rupture of membranes (PPROM), the incidence of neonatal sepsis was low, and the induction of labor (IoL) did not reduce this risk. Because the PPROMEXIL trial was underpowered and because of a lower-than-expected incidence of neonatal sepsis, we performed a second trial (PPROMEXIL-2), aiming to randomize 200 patients to improve the evidence in near-term PPROM. STUDY DESIGN: In a nationwide multicenter study, nonlaboring women with PPROM between 34 and 37 weeks' gestational age were eligible for inclusion. Patients were randomized to IoL or expectant management (EM). The primary outcome measure was neonatal sepsis. RESULTS: From December 2009 until January 2011, we randomized 100 women to IoL and 95 to EM. Neonatal sepsis was seen in 3 neonates (3.0%) in the IoL-group versus 4 neonates (4.1%) in the EM group (relative risk, 0.74; 95% confidence interval, 0.17-3.2). One of the sepsis cases in the IoL group resulted in neonatal death because of asphyxia. There were no significant differences in secondary outcomes. CONCLUSION: The risk of neonatal sepsis after PPROM near term is low. Induction of labor does not reduce this risk.

Prelabour rupture of membranes: overview of diagnostic methods.

PURPOSE OF REVIEW: To evaluate diagnostic accuracy studies for rupture of the fetal membranes (ROM). RECENT FINDINGS: Sample sizes of recent studies are small and studies used different 'silver standard' definitions for ROM. Therefore, reported results should be interpreted with caution. Over the review period the focus of diagnostic studies has been on two bedside test strips: insulin-like growth factor-binding protein-1 (IGFBP-1) and placental α microglobulin-1 (PAMG-1). Bedside tests improve the confidence of the clinician about their diagnosis. Compared to nitrazine or ferning test alone, IGFBP-1 and PAMG-1 are more accurate. However, compared to the conventional testing (combination of history, ferning, nitrazine, speculum and ultrasound) no statistical difference in accuracy was found. In-vitro PAMG-1 is shown to be superior to IGFPB-1. Furthermore, soluble intercellular adhesion molecule-1 and Axl receptor tyrosine kinase (Axl) seem to be promising new specific biomarkers for diagnosing ROM. SUMMARY: IGFBP-1 and PAMG-1 are the most commonly used bedside tests for diagnosing ROM. Both tests seem to be sensitive and specific, however, evidence is lacking especially in equivocal cases and comparative studies against the real gold standard (amnio-dye) have still not been published. Further effectiveness research is needed before tests can be applied in practice.