Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF: a meta-analysis with individual patient data.

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.

Treatment should be considered a competing risk when predicting natural conception in subfertile women.

BACKGROUND: Prediction of natural conception in subfertile couples can help to differentiate between couples who should have immediate treatment and couples who can aim for natural conception for some time. Natural conception rates are often estimated using standard techniques such as Kaplan-Meier or Cox proportional hazard models. These estimates can be biased by incorrect handling of data from women who start assisted reproductive technology therapy before the end of the follow-up period. This paper discusses the validity and the impact of the assumption of non-informative censoring as used in the Kaplan-Meier and Cox models. METHODS: In a cohort of 5360 subfertile couples with suspected tubal pathology, the probability of natural conception and the prognostic value of additional tests for tubal pathology were estimated using traditional methods and with a competing risks analysis. RESULTS: The estimated probability of natural conception within 3 years was almost 2-fold higher when assuming non-informative censoring compared with the competing risks model, 41 versus 22%. The prognostic value of tests was more conservative using the competing risks model than with the traditional methods, the fecundity rate ratio for Chlamydia antibody testing was 0.72 versus 0.67, for hysterosalpingography, 0.83 versus 0.71 and for diagnostic laparoscopy, 0.89 versus 0.74. CONCLUSIONS: Given the improbable validity of the non-informative censoring assumption, the predictions of natural conception and of the prognostic value of tests are likely to be overestimated by the traditional analytic methods. We suggest the use of competing risks models as an alternative, more conservative, form of analysis when predicting natural conception and evaluating prognostic fertility tests.

Integration of patient characteristics and the results of Chlamydia antibody testing and hysterosalpingography in the diagnosis of tubal pathology: an individual patient data meta-analysis.

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.

Is aspirin effective in women undergoing in vitro fertilization (IVF)? Results from an individual patient data meta-analysis (IPD MA).

BACKGROUND: Aspirin is believed to improve the outcome of IVF, but previous conventional meta-analyses on the subject are conflicting. Therefore, we performed a meta-analysis with individual patient data (IPD MA) of randomized clinical trials (RCTs) on the subject. METHODS: A systematic literature search was conducted to identify RCTs assessing the effectiveness of aspirin in IVF. Authors were asked to share their original data. In a one step meta-analytic approach, the treatment effect of aspirin was estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression, based on the intention to treat principle. RESULTS: Ten studies fulfilled the inclusion criteria. Authors of six studies provided IPD, including 1119 patients (562 placebo and 557 aspirin). There were 160 clinical pregnancies in the aspirin (28.8%) and 179 (31.9%) in the placebo group [OR 0.86, 95% CI (0.69-1.1)]. There were 129 ongoing pregnancies in the aspirin (23.6%) and 147 in the placebo group (26.7%) [OR 0.85, 95% CI (0.65-1.1)]. Whereas the conventional meta-analysis limited to studies that could provide IPD showed an OR of 0.89 (95% CI 0.69-1.2), the conventional meta-analysis limited to the eight studies of which method of randomization could be confirmed showed an OR of 0.94 (95% CI 0.76-1.17) and the conventional meta-analysis including all 10 eligible RCTs identified with our search changed the OR to 1.07 (95% CI 0.81-1.41). This difference in direction of effect, derived from the studies not able to share IPD of which quality of randomization could not be confirmed. CONCLUSIONS: Aspirin does not improve pregnancy rates after IVF.

Are patient characteristics associated with the accuracy of hysterosalpingography in diagnosing tubal pathology? An individual patient data meta-analysis.

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.

Chlamydia antibody testing and diagnosing tubal pathology in subfertile women: an individual patient data meta-analysis.

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.