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Background: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function., Methods: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or β2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 μg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39., Results: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure., Interpretation: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function., Funding: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders., Competing Interests: Declaration of interests MG received research and educational grants from Guerbet, Merck, and Ferring, not related to the presented work, paid to their institution. AH reports an unrestricted educational grant from Ferring, not related to the presented work, paid to their institution. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

Objective: To evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups., Design: Authors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy., Setting: In vitro fertilization clinics., Patient(s): A total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs., Intervention(s): None., Main Outcome Measure(s): Excessive response prediction., Result(s): We included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same., Conclusion(s): We demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine and compare the diagnostic accuracy of the lecithin/sphingomyelin (L/S) ratio and lamellar body count (LBC) in the prediction of neonatal respiratory distress syndrome (RDS)., Study Design: A systematic review was performed to identify studies comparing either the L/S ratio or the LBC with the occurrence of RDS published between January 1999 and February 2009. Two independent reviewers performed study selection and data extraction. For each study sensitivity and specificity were calculated. Summary receiver-operating characteristics (ROC) curves, assessing the diagnostic performance of both tests, were constructed. A subgroup analysis was performed to estimate the sensitivity and specificity of the various cut-off values., Results: 13 studies were included. The ROC curves of the collected data illustrate that the LBC and L/S ratio perform equally well in the prediction of RDS. Comparison of the two summary ROC curves of each test indicates that the diagnostic performance of LBC might even have a slight advantage over L/S ratio. Due to the wide cut-off range it was not possible to define specific cut-off values with the best accuracy., Conclusion: We recommend replacing the L/S ratio as gold standard with the lamellar body count since the LBC is easy to perform, rapid, inexpensive, and available to all hospitals 24h per day., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Study Question: Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients?, Summary Answer: The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women., What Is Known Already: Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion., Study Design, Size, Duration: We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n = 131 treated with aspirin, n = 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected., Participants/materials, Setting, Methods: All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n = 187) and preterm delivery (n = 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression., Main Results and the Role of Chance: There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30-0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22-1.7) and OR 0.52 (95% CI 0.16-1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35-4.4) and OR 1.6 (95% CI 0.51-5.0), respectively., Limitations, Reasons for Caution: We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis., Wider Implications of the Findings: Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted.

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

Background: Tubal patency tests are routinely performed in the diagnostic work-up of subfertile patients, but it is unknown whether these diagnostic tests add value beyond the information obtained by medical history taking and findings at physical examination. We used individual patient data meta-analysis to assess this question., Methods: We approached authors of primary studies for data sets containing information on patient characteristics and results from tubal patency tests, such as Chlamydia antibody test (CAT), hysterosalpingography (HSG) and laparoscopy. We used logistic regression to create models that predict tubal pathology from medical history and physical examination alone, as well as models in which the results of tubal patency tests are integrated in the patient characteristics model. Laparoscopy was considered to be the reference test., Results: We obtained data from four studies reporting on 4883 women. The duration of subfertility, number of previous pregnancies and a history of previous pelvic inflammatory disease (PID), pelvic surgery or Chlamydia infection qualified for the patient characteristics model. This model showed an area under the receiver operating characteristic curve (AUC) of 0.63 [95% confidence interval (CI) 0.61-0.65]. For any tubal pathology, the addition of HSG significantly improved the predictive performance to an AUC of 0.74 (95% CI 0.73-0.76) (P < 0.001). For bilateral tubal pathology, the addition of both CAT and HSG increased the predictive performance to an AUC of 0.76 (95% CI 0.74-0.79)., Conclusions: In the work-up for subfertile couples, the combination of patient characteristics with CAT and HSG results gives the best diagnostic performance for the diagnosis of bilateral tubal pathology.

Background: The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays., Methods: We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction., Results: We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology., Conclusions: In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice.

Background: Conventional meta-analysis has estimated the sensitivity and specificity of hysterosalpingography (HSG) to be 65% and 83%. The impact of patient characteristics on the accuracy of HSG is unknown. The aim of this study was to assess by individual patient data meta-analysis whether the accuracy of HSG is associated with different patient characteristics., Methods: We approached authors of primary studies reporting on the accuracy of HSG using findings at laparoscopy as the reference. We assessed whether patient characteristics such as female age, duration of subfertility and a clinical history without risk factors for tubal pathology were associated with the accuracy of HSG, using a random intercept logistic regression model., Results: We acquired data of seven primary studies containing data of 4521 women. Pooled sensitivity and specificity of HSG were 53% and 87% for any tubal pathology and 46% and 95% for bilateral tubal pathology. In women without risk factors, the sensitivity of HSG was 38% for any tubal pathology, compared with 61% in women with risk factors (P = 0.005). For bilateral tubal pathology, these rates were 13% versus 47% (P = 0.01). For bilateral tubal pathology, the sensitivity of HSG decreased with age [factor 0.93 per year (P = 0.05)]. The specificity of HSG was very stable across all subgroups., Conclusions: The accuracy of HSG in detecting tubal pathology was similar in all subgroups, except for women without risk factors in whom sensitivity was lower, possibly due to false-positive results at laparoscopy. HSG is a useful tubal patency screening test for all infertile couples.

Background: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine., Methods/design: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians., Discussion: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

Background: Regional differences in resting myocardial blood flow (MBF) have been observed in patients with hypertrophic cardiomyopathy (HCM), but their determinants are currently unknown. This study verifies whether MBF at rest in HCM is related to delayed contrast enhancement (DCE) or regional systolic function (or both) as determined by magnetic resonance imaging., Methods and Results: Fourteen patients with HCM were studied. MBF was measured with positron emission tomography by use of oxygen 15-labeled water. DCE and tissue tagging, to calculate end-systolic circumferential shortening (Ecc), were obtained with magnetic resonance imaging. The mean resting MBF was 0.78 +/- 0.19 mL x min(-1) x mL(-1), and there was a trend toward reduced MBF in the septum (0.72 +/- 0.11 mL x min(-1) x mL(-1)) compared with that in the lateral wall (0.84 +/- 0.29 mL x min(-1) x mL(-1)) (P = .092). The distribution patterns of DCE and Ecc were both heterogeneous, displaying significantly increased enhancement and impaired regional systolic function in the hypertrophic septum compared with the lateral wall (both P < .001). Resting MBF was inversely related to the extent of DCE (r = -0.30, P < .001), whereas MBF was not significantly related to Ecc (r = -0.15, P = .072)., Conclusions: Regional heterogeneity of resting perfusion in HCM is related to the extent of DCE but not to regional systolic function.