Neurodevelopmental outcomes of school-age children conceived after hysterosalpingography with oil-based or water-based iodinated contrast: long-term follow-up of a nationwide randomized controlled trial.

STUDY QUESTION: Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER: Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY: HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION: This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012-2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study included 69 children aged 6-9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE: School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION: The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05168228.

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.

Single-layer vs double-layer uterine closure during cesarean delivery: 3-year follow-up of a randomized controlled trial (2Close study).

BACKGROUND: The rising rate of cesarean deliveries has led to an increased incidence of long long-term complications, including niche formation in the uterine scar. Niche development is associated with various gynecologic complaints and complications in subsequent pregnancies, such as uterine rupture and placenta accreta spectrum disorders. Although uterine closure technique is considered a potential risk factor for niche development, consensus on the optimal technique remains elusive. OBJECTIVE: We aimed to evaluate the effect of single-layer vs double-layer closure of the uterine incision on live birth rate at a 3-year follow-up with secondary objectives focusing on gynecologic, fertility, and obstetrical outcomes at the same follow-up. STUDY DESIGN: A multicenter, double-blind, randomized controlled trial was performed at 32 hospitals in the Netherlands. Women ≥18 years old undergoing a first cesarean delivery were randomly assigned (1:1) to receive either single-layer or double-layer closure of the uterine incision. The primary outcome of the long-term follow-up was the live birth rate; with secondary outcomes, including pregnancy rate, the need for fertility treatment, mode of delivery, and obstetrical and gynecologic complications. This trial is registered on the International Clinical Trials Registry Platform www.who.int (NTR5480; trial finished). RESULTS: Between 2016 and 2018, the 2Close study randomly assigned 2292 women, with 830 of 1144 and 818 of 1148 responding to the 3-year questionnaire in the single-layer and double-layer closure. No differences were observed in live birth rates; also there were no differences in pregnancy rate, need for fertility treatments, mode of delivery, or uterine ruptures in subsequent pregnancies. High rates of gynecologic symptoms, including spotting (30%-32%), dysmenorrhea (47%-49%), and sexual dysfunction (Female Sexual Function Index score, 23) are reported in both groups. CONCLUSION: The study did not demonstrate the superiority of double-layer closure over single-layer closure in terms of reproductive outcomes after a first cesarean delivery. This challenges the current recommendation favoring double-layer closure, and we propose that surgeons can choose their preferred technique. Furthermore, the high risk of gynecologic symptoms after a cesarean delivery should be discussed with patients.

Psychological sequelae following second-trimester termination of pregnancy: A longitudinal study.

INTRODUCTION: The decision to terminate a pregnancy due to fetal anomalies can have a significant emotional impact, especially in second-trimester terminations. Previous studies on the psychological consequences of pregnancy termination have had limitations, and little is known about the outcomes for partners and the impact of fetal donation. Therefore, we aimed to investigate the psychological effects of second-trimester pregnancy termination and identify factors associated with outcomes in both women and men, including donation of fetal remains to science. MATERIAL AND METHODS: A longitudinal cohort study was conducted at the Amsterdam UMC in the Netherlands, involving women and partners who underwent termination at or before 23 weeks and 6 days of gestation. Questionnaires were administered at termination, 6 weeks, and 4 months after. We utilized validated questionnaires to assess psychological morbidity (grief, post-traumatic stress and postnatal depression and quality of life [QoL]), and factors that could potentially influence outcomes. RESULTS: Of 241 participants, women displayed more pronounced psychological distress than men, though both groups improved over time. Four months after termination, 27.4% of women and 9.1% of men showed signs of pathological grief. Scores indicative for postnatal depression occurred in 19.8% women and 4.1% of men. A prior psychiatric history was a consistent predictor of poorer outcomes. Fetal donation to the Dutch Fetal Biobank was associated with reduced likelihood of symptoms of complicated grief four months after termination. CONCLUSIONS: Second-trimester termination of pregnancy for fetal anomalies can lead to psychological morbidity, particularly in women. However, there is a notable improvement over time for both groups. Individuals with prior psychiatric history appear more vulnerable post-termination. Also, fetal donation to science did not have a negative impact on psychological well-being.

Surgery versus sclerotherapy versus combined therapy in head and neck lymphatic malformations in the pediatric population: systematic review and meta-analysis.

PURPOSE: To systematically review current literature on the treatment of lymphatic malformations (LMs) of the head and neck to guide treatment strategy. METHODS AND MATERIALS: A systematic review and meta-analysis of literature until 16 November 2021 was performed on treatments of LMs in the head and neck. RESULTS: Out of 9044 articles, 54 studies were eligible for inclusion with 26 studies providing detailed participant data. A total number of 1573 patients with a mean age of 21.22 months were analysed. Comparative meta-analysis did not reveal significant differences two proportions of volume reduction (≥ 50% and 100%) between sclerotherapy and surgical treatment. Regression demonstrated that positive predictors for volume reduction were surgery 17 (95% CI 0.26-34; p = 0.047) and treatment of macrocystic lesions 19 (95% CI 5.5-32; p = 0.006). Treatment of mixed lesions also demonstrated a trend towards achieving a greater volume reduction (p = 0.052). A higher de Serres stage of the lesion had a negative effect on the amount of volume reduction - 3.7 (95% CI - 7.0 to - 0.35; p = 0.030). CONCLUSION: This comprehensive meta-analysis demonstrated no significant difference in volume reduction between various treatment modalities at study level. However, individual patient data indicated that surgery and larger cyst types are associated with a significant higher percentage of volume reduction, whereas a higher de Serres stage negatively impacted the amount of volume reduction. These findings can be used for patient counseling and treatment planning based on cyst type and de Serres stage. However volume reduction constitutes just one objective within a more complex treatment spectrum.

Continuous glucose monitoring metrics and pregnancy outcomes in insulin-treated diabetes: A post-hoc analysis of the GlucoMOMS trial.

AIM: To investigate the association between continuous glucose monitoring (CGM) metrics and perinatal outcomes in insulin-treated diabetes mellitus in pregnancy. MATERIALS AND METHODS: In a post-hoc analysis of the GlucoMOMS randomized controlled trial, we investigated the association between the metrics of an offline, intermittent CGM, glycated haemoglobin (HbA1c) and perinatal outcomes per trimester in different types of diabetes (type 1, 2 or insulin-treated gestational diabetes mellitus [GDM]). Data were analysed using multivariable binary logistic regression. Outcomes of interest were neonatal hypoglycaemia, pre-eclampsia, preterm birth, large for gestational age (LGA) and Neonatal Intensive Care Unit (NICU) admission. The glucose target range was defined as 3.5-7.8 mmol/L (63-140 mg/dL). RESULTS: Of the 147 participants (N = 50 type 1 diabetes, N = 94 type 2 diabetes/insulin-treated GDM) randomized to the CGM group of the GlucoMOMS trial, 115 participants had CGM metrics available and were included in the current study. We found that, in pregnancies with type 1 diabetes, a higher second trimester mean glucose was associated with LGA (odds ratio 2.6 [95% confidence interval 1.1-6.2]). In type 2 and insulin-treated gestational diabetes, an increased area under the curve above limit was associated with LGA (odds ratio 10.0 [95% confidence interval 1.4-72.8]). None of the CGM metrics were associated with neonatal hypoglycaemia, pre-eclampsia, shoulder dystocia, preterm birth and NICU admission rates for pregnancies complicated by any type of diabetes. CONCLUSION: In this study, in type 2 diabetes or insulin-treated GDM, the glucose increased area under the curve above limit was associated with increased LGA. In type 1 diabetes, the mean glucose was the major determinant of LGA. Our study found no evidence that other CGM metrics determined adverse pregnancy outcomes.

Cost-effectiveness of urethral bulking polydimethylsiloxane-Urolastic® compared with mid-urethral sling surgery for stress urinary incontinence: A two-arm cohort study.

OBJECTIVE: To investigate the cost-effectiveness of urethral bulking polydimethylsiloxane-Urolastic® (PDMS-U) compared with mid-urethral sling (MUS) surgery for stress urinary incontinence (SUI) at 1-year follow-up. DESIGN: Prospective, two-arm cohort study with 2-year follow-up. SETTING: International multicentre. POPULATION: Women with moderate to severe SUI. MAIN OUTCOME MEASURES: Primary outcome was subjective cure (Patient Global Impression of Improvement). SECONDARY OUTCOMES: objective cure (negative cough stress test), Urogenital Distress Inventory (UDI-6), complications and re-interventions. Cost-effectiveness outcomes: total costs, quality-adjusted life year (QALY) using IIQ7-scores (Incontinence Impact Questionnaire) and EQ-5D-5L, incremental cost-effectiveness ratio (ICER) and monetary benefit (adjusted for baseline confounders). RESULTS: In all, 131 PDMS-U and 153 MUS surgery patients were treated. Subjective cure rates for MUS surgery and PDMS-U were, respectively: 101/112 (90%) versus 40/87 (46%), adjusted odds ratio (aOR; for age, body mass index [BMI], severity, type of urinary incontinence and previous SUI procedure) was 4.9. Objective cure rates for MUS surgery and PDMS-U were respectively: 98/109 (90%) versus 58/92 (63%), aOR 5.4. Average total costs for PDMS-U and MUS surgery were €3567 and €6688. ICER for MUS surgery cost €15 598 per IIQ QALY and €37 408 per EQ-5D-5L QALY. With a willingness to pay (WTP) of €25 000, MUS has a 84% chance of being cost-effective using IIQ, whereas PDMS-U has a 99% chance of being cost-effective using EQ-5D-5L. CONCLUSION: MUS surgery is more cost-effective in realising improved disease-specific quality of life (QoL), while PDMS-U is more cost-effective in realising improved generic QoL.

Tell me what you want, what you really really want: Estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies.

PURPOSE: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process. METHODS: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population-level summary measure. RESULTS: Different estimands were defined for case studies representing three types of pharmacological treatments: (1) single-dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of ≥60 years of age; (2) sustained-treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon-like peptide-1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as-needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris. CONCLUSIONS: The case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data-analysis and clarify how to interpret study findings.

The Effect of a Myomectomy on Myoma-related Symptoms and Quality of Life: A Retrospective Cohort Study.

STUDY OBJECTIVE: Although it is assumed that myomectomy improves uterine myoma-related symptoms such as pelvic pain and heavy menstrual bleeding (HMB), validated measures are rarely reported. This study aimed to verify the effect of myomectomy on myoma-related symptoms. DESIGN: A retrospective cohort study. SETTING: A university-affiliated hospital. PATIENTS: Our study included 241 patients with a myoma diagnosis and received a myomectomy between 2004 and 2018. Data were collected from the patient medical file and patients responded in 1 questionnaire. INTERVENTIONS: Transcervical resection of myoma (TCRM) and laparoscopic or abdominal myomectomy (LAM). MEASUREMENTS AND MAIN RESULTS: One year after TCRM, a significant number of women experienced symptom improvement for pelvic pain (79% [19/24, p = .01]) and HMB (89% [46/52, p <.001]). For other myoma-related symptoms, abdominal pressure (43%, 10/23), sexual complaints (67%, 2/3), infertility (56%, 10/18), and other complaints (83%, 5/6), improvements were not statistically significant. One year after LAM, a significant number of women experienced symptom improvement for pelvic pain (80%, 74/93), HMB (83%, 94/113), abdominal pressure (85%, 79/93), sexual complaints (77%, 36/47), and other complaints (91%, 40/44). One year after myomectomy, 47% (30/64) (TCRM) and 44% of women (78/177) (LAM) described no myoma-related symptoms. Most women (82% [172/217]) were satisfied with the postoperative result after 1 year and 53% (114/217) would have liked to receive the myomectomy earlier in life. Average quality of life (measured on a 10-point Likert scale) increased from 6.3 at baseline to 8.0 at 1 year after TCRM and from 6.2 to 8.0 1 year after LAM, resulting in a difference of 1.7 points (p <.001; 95% confidence interval, 1.1-2.3) and 1.9 points (p <.001; 95% confidence interval, 1.4-2.3), respectively. CONCLUSION: One year after myomectomy, most women have benefited from myomectomy, concluded by a significant number of women who experienced myoma-related symptom improvement, positive patient satisfaction, and a significant improvement in reported quality of life. Validation of results after conventional treatment such as myomectomy is essential in counseling patients for surgical treatment in today's evidence based practice. In addition, it is necessary to make an adequate comparison with new treatment options for myomas. To provide this, further research should preferably be conducted prospectively or by randomization.

A Clinical Learning Curve Study of Polydimethylsiloxane Urolastic for Stress Urinary Incontinence: Does Safety Improve when Expertise Grow?

OBJECTIVES: The aim of the study was to characterize the learning curve of bulk injection therapy polydimethylsiloxane Urolastic (PDMS-U) for stress urinary incontinence. DESIGN: Secondary analysis from three clinical studies on efficacy and safety outcomes of PDMS-U was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: PDMS-U-certified physicians who performed ≥4 procedures were included. The primary outcome was the number of PDMS-U procedures needed to achieve acceptable failure rates for "complications overall," "urinary retention," and "excision," using the LC-CUSUM method. For the primary outcome, physicians who performed ≥20 procedures were used. For the secondary outcome, logistic and linear regression analysis was used to assess the relationship between number of procedures, complications (complications overall, urinary retention, pain, exposure, excision of PDSM-U), and duration of treatment. RESULTS: In total, 203 PDMS-U procedures were performed by nine physicians. Five physicians were used for the primary outcome. For "complications overall," "urinary retention," and "excision," two physicians reached a level of competence: one at procedure 20 and one at procedure 40. The secondary outcome showed no statistically significant association between procedure number and complications. There was a statistically significant increase in the duration of treatment with more physician experience (mean difference 0.83 min per 10 additional procedures, 95% CI: 0.16-1.48). LIMITATIONS: One limitation is that retrospectively collected data might have underreported the number of complications. Secondly, there was variation in the way the technique was applied between physicians. CONCLUSIONS: Physicians' experience in the PDMS-U procedure did not influence safety outcomes. There was large inter-physician variability and most physicians did not reach acceptable failure rates. There was no relationship between PDMS-U complications and the number of performed procedures.

The effect of myomectomy on reproductive outcomes in patients with uterine fibroids: A retrospective cohort study.

RESEARCH QUESTION: What is the effect of myomectomy in women with uterine fibroids on time to live birth and other reproductive outcomes? DESIGN: This was a monocentric retrospective cohort study of 311 women with fibroids, of whom 165 eventually received myomectomy and 146 remained on expectant management. To assess the primary outcome time to live birth, a Cox proportional hazards model with a time-varying covariate for myomectomy was used. In the sensitivity analyses, this was combined with an approach to account for confounders via a cloning/censoring/weighting that aimed to emulate a randomized controlled trial. RESULTS: Notable differences in baseline characteristics between the myomectomy and expectant management group were fibroid size (fibroid >7 cm: myomectomy 48%; expectant management 15%) and whether the patient had fibroid-related complaints (myomectomy 85%, expectant management 67%). The adjusted hazard ratio for the effect of myomectomy compared with expectant management on live birth was 1.26 (95% CI 0.87-1.81). Sensitivity analyses yielded similar results, but secondary outcomes showed that women remaining on expectant management had more often received assisted reproductive technology (63%) compared with those who eventually received myomectomy (38%). CONCLUSIONS: The study did not find a significant difference in time to live birth after myomectomy compared with expectant management in women with fibroids and a wish to conceive, despite more, larger and more symptomatic fibroids in the myomectomy group. The results after myomectomy encourage the execution of a randomized controlled trial in women with large (symptomatic) fibroids not or minimally distorting the intrauterine cavity, and infertility or a desire to conceive.

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.

Day 5 versus day 3 embryo biopsy for preimplantation genetic testing for monogenic/single gene defects.

BACKGROUND: Assisted reproductive technology (ART) has allowed couples with a family history of a monogenic genetic disease, or a disease-carrying gene, to reduce the chance of them having a child with the genetic disorder. This is achieved by genetically testing the embryos using an advanced process called preimplantation genetic testing for monogenic or single gene disorders (PGT-M), such as Huntington's disease or cystic fibrosis. This current terminology (PGT-M) has replaced the formerly-known preimplantation genetic diagnosis (PGD). During PGT-M, one or more embryo cells are biopsied and analysed for genetic or chromosomal anomalies before transferring the embryos to the endometrial cavity. Biopsy for PGT-M can be performed at day 3 of cleavage-stage embryo development when the embryo is at the six- to the eight-cell stage, with either one or two blastomeres being removed for analysis. Biopsy for PGT-M can also be performed on day 5 of the blastocyst stage of embryo development when the embryo has 80 to 100 cells, with five to six cells being removed for analysis. Day 5 biopsy has taken over from day 3 biopsy as the most widely-used biopsy technique; however, there is a lack of summarised evidence from randomised controlled trials (RCTs) that assesses the effectiveness and safety of day 5 biopsy compared to day 3 biopsy. Since biopsy is an invasive process, whether it is carried out at day 3 or day 5 of embryo development may have different impacts on further development, implantation, pregnancy, live birth and perinatal outcomes. OBJECTIVES: To assess the benefits and harms of day 5 embryo biopsy, in comparison to day 3 biopsy, in PGT-M in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles. SEARCH METHODS: We searched the following electronic bibliographic databases in December 2021 to identify relevant RCTs: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Trials Register; CENTRAL, MEDLINE, Embase and PsycINFO. We also handsearched grey literature, such as trial registers, relevant journals, reference lists, Google Scholar, and published conference abstracts. SELECTION CRITERIA: Eligible RCTs compared day 5 versus day 3 embryo biopsy for PGT-M.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live births and miscarriages. We calculated outcomes per woman/couple randomised and reported odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS: We included one RCT involving 20 women. The evidence was of very low certainty; the main limitations of the study were serious risk of bias due to lack of blinding of study personnel, and imprecision. We are uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on live births (OR 1.50, 95% CI 0.26 to 8.82; 1 RCT, 20 women; very low-certainty evidence). The evidence suggests that if the chance of live birth following day 3 biopsy was assumed to be 40%, then the chance with day 5 biopsy is between 15% and 85%. It is also uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on miscarriages (OR 1.00, 95% CI 0.05 to 18.57; 1 RCT, 20 women; very low-certainty evidence).  We are uncertain whether day 5 embryo biopsy compared to day 3 biopsy has an effect on other secondary outcome measures, including viable intrauterine pregnancies (OR 2.25, 95% CI 0.38 to 13.47; 1 RCT, 20 women; very low-certainty evidence), ectopic pregnancies (OR 0.16, 95% CI 0.01 to 3.85; 1 RCT, 20 women; very low-certainty evidence), stillbirths (OR not estimable as no events in either group; 1 RCT, 20 women; very low-certainty evidence) or termination of pregnancies (OR 3.32, 95% CI 0.12 to 91.60; 1 RCT, 20 women; very low-certainty evidence). No studies reported on gestational age at birth, birthweight, neonatal mortality and major congenital anomaly. AUTHORS' CONCLUSIONS: We are uncertain if there is a difference in live births and miscarriages, viable intrauterine pregnancies, ectopic pregnancies, stillbirths or termination of pregnancies between day 5 and day 3 embryo biopsy for PGT-M. There was insufficient evidence to draw any conclusions regarding other adverse outcomes. The results should be interpreted with caution, as the evidence was of very low certainty due to limited studies, high risk of bias in the included study, and an overall low level of precision.

Prioritizing IVF treatment in the post-COVID 19 era: a predictive modelling study based on UK national data.

STUDY QUESTION: Can we use prediction modelling to estimate the impact of coronavirus disease 2019 (COVID 19) related delay in starting IVF or ICSI in different groups of women? SUMMARY ANSWER: Yes, using a combination of three different models we can predict the impact of delaying access to treatment by 6 and 12 months on the probability of conception leading to live birth in women of different age groups with different categories of infertility. WHAT IS KNOWN ALREADY: Increased age and duration of infertility can prejudice the chances of success following IVF, but couples with unexplained infertility have a chance of conceiving naturally without treatment whilst waiting for IVF. The worldwide suspension of IVF could lead to worse outcomes in couples awaiting treatment, but it is unclear to what extent this could affect individual couples based on age and cause of infertility. STUDY DESIGN, SIZE, DURATION: A population-based cohort study based on national data from all licensed clinics in the UK obtained from the Human Fertilisation and Embryology Authority Register. Linked data from 9589 women who underwent their first IVF or ICSI treatment in 2017 and consented to the use of their data for research were used to predict livebirth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three prediction models were used to estimate the chances of livebirth associated with immediate treatment versus a delay of 6 and 12 months in couples about to embark on IVF or ICSI. MAIN RESULTS AND THE ROLE OF CHANCE: We estimated that a 6-month delay would reduce IVF livebirths by 0.4%, 2.4%, 5.6%, 9.5% and 11.8% in women aged <30, 30-35, 36-37, 38-39 and 40-42 years, respectively, while corresponding values associated with a delay of 12 months were 0.9%, 4.9%, 11.9%, 18.8% and 22.4%, respectively. In women with known causes of infertility, worst case (best case) predicted chances of livebirth after a delay of 6 months followed by one complete IVF cycle in women aged <30, 30-35, 36-37, 38-39 and 40-42 years varied between 31.6% (35.0%), 29.0% (31.6%), 23.1% (25.2%), 17.2% (19.4%) and 10.3% (12.3%) for tubal infertility and 34.3% (39.2%), 31.6% (35.3%) 25.2% (28.5%) 18.3% (21.3%) and 11.3% (14.1%) for male factor infertility. The corresponding values in those treated immediately were 31.7%, 29.8%, 24.5%, 19.0% and 11.7% for tubal factor and 34.4%, 32.4%, 26.7%, 20.2% and 12.8% in male factor infertility. In women with unexplained infertility the predicted chances of livebirth after a delay of 6 months followed by one complete IVF cycle were 41.0%, 36.6%, 29.4%, 22.4% and 15.1% in women aged <30, 30-35, 36-37, 38-39 and 40-42 years, respectively, compared to 34.9%, 32.5%, 26.9%, 20.7% and 13.2% in similar groups of women treated without any delay. The additional waiting period, which provided more time for spontaneous conception, was predicted to increase the relative number of babies born by 17.5%, 12.6%, 9.1%, 8.4% and 13.8%, in women aged <30, 30-35, 36-37, 38-39 and 40-42 years, respectively. A 12-month delay showed a similar pattern in all subgroups. LIMITATIONS, REASONS FOR CAUTION: Major sources of uncertainty include the use of prediction models generated in different populations and the need for a number of assumptions. Although the models are validated and the bases for the assumptions are robust, it is impossible to eliminate the possibility of imprecision in our predictions. Therefore, our predicted live birth rates need to be validated in prospective studies to confirm their accuracy. WIDER IMPLICATIONS OF THE FINDINGS: A delay in starting IVF reduces success rates in all couples. For the first time, we have shown that while this results in fewer babies in older women and those with a known cause of infertility, it has a less detrimental effect on couples with unexplained infertility, some of whom conceive naturally whilst waiting for treatment. Post-COVID 19, clinics planning a phased return to normal clinical services should prioritize older women and those with a known cause of infertility. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy work for ObsEva, Merck, Merck KGaA, Guerbet and iGenomics. S.B. is Editor-in-Chief of Human Reproduction Open. None of the other authors declare any conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

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.

How long does the fertility-enhancing effect of hysterosalpingography with oil-based contrast last?

RESEARCH QUESTION: Does the fertility-enhancing effect of tubal flushing during hysterosalpingography (HSG) with oil-based contrast change over time? DESIGN: This was a secondary analysis of the H2Oil (long-term follow-up) study, a multicentre randomized controlled trial evaluating the effectiveness of oil-based and water-based contrast during HSG. The main outcome was ongoing pregnancy. Cox proportional hazards models for time to ongoing pregnancy were fitted over 3 years of follow-up. RESULTS: Data on 1107 couples were available; 550 couples had oil-based contrast and 557 water-based contrast at HSG. Ongoing pregnancy rates after 3 years were 77% and 71%, respectively. Median follow-up was 9-10 months (5th-95th percentile: <1 to 36). The hazard ratio for ongoing pregnancy for oil versus water over 3 years of follow-up was 1.26 (95% confidence interval [CI] 1.10-1.45). The scaled Schoenfeld residual plots showed a decrease in hazard ratio that was linear with log-transformed time. After including an interaction with log-transformed time, the hazard ratio immediately after HSG was 1.71 (95% CI 1.27-2.31) and reduced to no effect (hazard ratio of 1) at approximately 2 years. There was no evidence for a change in hazard ratio over time in a subgroup of women who experienced pain during HSG. CONCLUSIONS: The hazard ratio for ongoing pregnancy of oil-based versus water-based contrast was 1.71 immediately after HSG, gradually decreasing and plateauing towards a hazard ratio of 1 (indicating no effect) after approximately 2 years. This supports the hypothesis that oil-based contrast might dislodge debris or mucus plugs from the Fallopian tubes, but this has yet to be definitively proved.

A comparison of the beta-geometric model with landmarking for dynamic prediction of time to pregnancy.

We conducted a simulation study to compare two methods that have been recently used in clinical literature for the dynamic prediction of time to pregnancy. The first is landmarking, a semi-parametric method where predictions are updated as time progresses using the patient subset still at risk at that time point. The second is the beta-geometric model that updates predictions over time from a parametric model estimated on all data and is specific to applications with a discrete time to event outcome. The beta-geometric model introduces unobserved heterogeneity by modelling the chance of an event per discrete time unit according to a beta distribution. Due to selection of patients with lower chances as time progresses, the predicted probability of an event decreases over time. Both methods were recently used to develop models predicting the chance to conceive naturally. The advantages, disadvantages and accuracy of these two methods are unknown. We simulated time-to-pregnancy data according to different scenarios. We then compared the two methods by the following out-of-sample metrics: bias and root mean squared error in the average prediction, root mean squared error in individual predictions, Brier score and c statistic. We consider different scenarios including data-generating mechanisms for which the models are misspecified. We applied the two methods on a clinical dataset comprising 4999 couples. Finally, we discuss the pros and cons of the two methods based on our results and present recommendations for use of either of the methods in different settings and (effective) sample sizes.

Treatment-independent live birth after in-vitro fertilisation: a retrospective cohort study of 2,133 women.

STUDY QUESTION: What is the chance of a treatment-independent live birth following IVF (including ICSI) treatment? SUMMARY ANSWER: Over 5 years of follow-up, the treatment-independent live birth rate was 17% in unsuccessfully treated women and 15% in those who had a live birth after IVF. WHAT IS KNOWN ALREADY: A limited number of studies have investigated the chance of treatment-independent conception following completion of IVF, but most of them have been based on surveys with poor response rates and limited sample sizes. STUDY DESIGN, SIZE, DURATION: This is a population-based, retrospective cohort study of 2133 women who received IVF treatment between 1998 and 2011 at a single regional IVF Unit and were followed for a minimum of 1 year and maximum of 15 years after their last IVF or ICSI treatment cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included all women, residing in the north-east of the UK, who attended the Aberdeen Fertility Clinic and received IVF treatment between 1998 and 2011. Clinical and diagnostic information of all women was linked with treatment and pregnancy outcome data. A total of 2133 women were divided into two groups: (i) those who achieved a live birth following successful IVF or ICSI treatment (n = 1060) and (ii) those in whom treatment was unsuccessful i.e. resulted in either no pregnancy or pregnancy loss (n = 1073). The two groups were followed from the date of the last embryo transfer until the first treatment-independent live birth or 31 December 2012, whichever came first. The primary outcome was the treatment-independent live birth rate at 1, 2.5, 5 and 10 years of follow-up. Cox regression was used to determine factors associated with treatment-independent live birth in each group. MAIN RESULTS AND THE ROLE OF CHANCE: Within 5 years of follow-up, the treatment-independent live birth rate was 17% (95% CI, 15-19%) among women whose IVF or ICSI treatment was unsuccessful and 15% (95% CI, 12-17%) among women whose treatment resulted in live birth. In both groups, shorter duration of infertility, younger female age and IVF as compared to ICSI were associated with a higher chance of achieving treatment-independent live birth. Among unsuccessfully treated women, the chance of post-IVF live birth was reduced in those with tubal factor infertility. Three or more previous IVF or ICSI embryo transfers were associated with a lower chance of treatment-independent live birth among successfully treated women. LIMITATIONS, REASONS FOR CAUTION: The study was conducted in a single fertility centre, which could compromise the generalizability of the findings. Moreover, data were unavailable on the women's use of contraception or active attempts to get pregnant, both of which could influence treatment-independent live birth rates. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a better understanding of the long-term prognosis for treatment-independent live birth after completion of IVF or ICSI treatment. The results will inform women of their chances of a treatment-independent live birth following failed or successful treatment and the factors that are associated with it. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. The authors have no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

The risk of bias and sample size of trials of spinal manipulative therapy for low back and neck pain: analysis and recommendations.

OBJECTIVE: The purpose of this study was to evaluate changes in methodological quality and sample size in randomized controlled trials (RCTs) of spinal manipulative therapy (SMT) for neck and low back pain over a specified period. A secondary purpose was to make recommendations for improvement for future SMT trials based upon our findings. METHODS: Randomized controlled trials that examined the effect of SMT in adults with neck and/or low back pain and reported at least 1 patient-reported outcome measure were included. Studies were identified from recent Cochrane reviews of SMT, and an update of the literature was conducted (March 2013). Risk of bias was assessed using the 12-item criteria recommended by the Cochrane Back Review Group. In addition, sample size was examined. The relationship between the overall risk of bias and sample size over time was evaluated using regression analyses, and RCTs were grouped into periods (epochs) of approximately 5 years. RESULTS: In total, 105 RCTs were included, of which 41 (39%) were considered to have a low risk of bias. There is significant improvement in the mean risk of bias over time (P < .05), which is the most profound for items related to selection bias and, to a lesser extent, attrition and selective outcome reporting bias. Furthermore, although there is no significant increase in sample size over time (overall P = .8), the proportion of studies that performed an a priori sample size calculation is increasing statistically (odds ratio, 2.1; confidence interval, 1.5-3.0). Sensitivity analyses suggest no appreciable difference between studies for neck or low back pain for risk of bias or sample size. CONCLUSION: Methodological quality of RCTs of SMT for neck and low back pain is improving, whereas overall sample size has shown only small and nonsignificant increases. There is an increasing trend among studies to conduct sample size calculations, which relate to statistical power. Based upon these findings, 7 areas of improvement for future SMT trials are suggested.

Cumulative Incidence, Risk Factors, and Overall Survival of Disease Recurrence after Curative Resection of Stage II-III Colorectal Cancer: A Population-based Study.

Real-world data are necessitated to counsel patients about the risk for recurrent disease after curative treatment of colorectal cancer. This study provided a population-based overview of the epidemiology of recurrent disease in patients with surgically resected stage II/III colorectal cancer.Patients diagnosed with stage II/III primary colorectal cancer between July and December 2015 were selected from the Netherlands Cancer Registry (N = 3,762). Cumulative incidence of recurrent disease was estimated, and multivariable competing risk regression was used to identify risk factors for recurrent disease in patients with primary colon and rectal cancer. Moreover, overall survival (OS) after diagnosis of recurrent colorectal cancer was estimated.Median clinical follow-up was 58 months (Q1-Q3: 22-62). Five-year cumulative incidence of recurrent disease was 21.6% [95% confidence interval (CI): 20.0-23.2] and 30.0% (95% CI: 28.3-33.5) for patients with primary colon and rectal cancer, respectively. Stage III disease and incomplete resection margin in patients with primary colon cancer and extramural vascular invasion in patients with primary rectal cancer were strongly (HR ≥ 2) associated with recurrent disease. Median OS of patients with distant, locoregional, or the synchronous combination of distant and locoregional recurrent disease was 29, 27, and 13 months, respectively (P < 0.001). Patients with distant recurrences limited to liver or lung showed a median OS of 46 and 48 months, respectively. The incidence of recurrent disease was higher in patients with rectal cancer than in patients with colon cancer, predominantly due to higher rates of distant recurrences. OS after recurrent disease was impaired, but subgroups of patients diagnosed with recurrent disease limited to one site showed statistically significantly longer OS. SIGNIFICANCE: Population-based data on recurrent colorectal cancer are rare, but crucial for counseling patients and their physicians. This large nationwide, population-based study provides an up-to-date overview of the epidemiology of recurrent disease in patients with stage II and III primary colon and rectal cancer treated with surgical resection.