Hypertensive disorders in pregnancies conceived by ART compared to spontaneous conceptions: a systematic review and meta-analysis of cohort studies.

Infertility, defined as a failure to conceive after 12 months of unprotected intercourse, is experienced by 10-15% of couples. Recent estimates of infertility in Canada suggest an increase in the prevalence, rising from 8.5% in 1992 to 11.5-14% in 2009/10. Nowadays, between 1 and 5% of children in industrialized countries are born following ART, and their number is destined to increase further. This is one of three reviews we are performing, which represents steps in a grander research program which has been planned to improve the quality and effectiveness of maternity care in Canada and elsewhere (PI Prof Maria Del Pilar Velez). The objective of this systematic review is to assess the hypertensive disorders in pregnancies conceived by assisted reproductive technology compared to spontaneous conceptions (SC). Methods * Searches. A search strategy has been developed by an experienced information specialist. The search covered the following electronic databases: EMBASE, MEDLINE and the Cochrane Library using OVID platform. Searching of grey literature was performed. The searches were imported to Covidence (Veritas Health Innovation, Melbourne, Australia. Available at www.covidence. org) and two reviewers screened independently Titles and abstract. Full-text reports of all relevant records will screened by two reviewers and a third reviewer was available to solve conflicts. All papers selected were exported to EndNote X8 (Clarivate Analytics, Philadelphia, USA). * Condition or domain being studied Hypertensive disorders in women becoming pregnant with ART * Participants/population: Pregnant women that became pregnant with ART, singleton pregnancies. * Intervention(s), exposure(s). Assisted reproductive technology (ART): In-vitro fertilization (IVF), or Intra-cytoplasmic sperm injection (ICSI),Fresh embryo transfer, Frozen (Cryopreservation, Thawed) embryo transfer, autologous or donation oocytes, sperm or surrogate pregnancy. Inclusion: 1. Were prospective or retrospective cohort studies. 2. Clearly separated enrolled patients into singleton pregnancy and non-singleton pregnancy groups (for example: twins, multiple gestations, vanishing twins). 3. Had IVF and/or ICSI as the exposure group. 4. Had gestational hypertension, pre-eclampsia, eclampsia, or pregnancy-induced hypertension in general as the outcomes of study. PS: Studies where it is not possible to define which ART includes, after making a question for authors Exclusion: 1. Were case-control studies, reviews, meta-analysis and cross-sectional articles, case reports, editorials, letters to the editor, abstracts, or unpublished studies. 2. Included ART other than IVF and ICSI. 3. Does not have spontaneous pregnancies as the control group. 4. Does not clearly separate patients into singleton pregnancy and non-singleton pregnancy groups. 5. Does not include gestational hypertension, pre-eclampsia, eclampsia, or pregnancy-induced hypertension in general as the outcomes of study. 6. Not in English, Chinese, French, Spanish, or Portuguese. * Comparator(s)/control: spontaneous conception from the general population or none comparator * Types of study to be included. Retrospective and prospective cohort studies Cohort studies addressing the topic included as primary studies in previous systematic reviews * Main outcome(s). - Pregnancy-induced hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mg after 20 weeks of gestation) - pre-eclampsia (hypertension and proteinuria after 20 weeks’ gestation), - eclampsia (gestational hypertension plus either proteinuria or 1 relevant target organ complication) - Confounding variables: previous conditions as hypertensive disorders, diabetes and smoking * Data extraction (selection and coding). Title and abstract screening were done by two reviewers independently. The full-text screening was performed by two reviewers independently of each reference. Conflicts were resolved by consensus or a third team member. * Risk of bias (quality) assessment. Newcastle Ottawa Scale for Cohorts Studies. The final scores will be summarized to provide an overview of the risk of bias in each study. These scores are classified from 0 to 9, for which a higher score indicates better quality (8 or 9 high, 6 or 7 moderate and less than 5 low quality). * Strategy for data synthesis. Data extraction forms will be developed in Microsoft Excel. One reviewer will extract data and a second reviewer will verify the information collected. For all identified studies, the following study characteristics will be extracted: - the authorship and date of publication - country - study design - study population - endpoints assessed (PIH, pre-eclampsia, eclampsia) - summary measures of association by outcome (e.g. odds ratios with corresponding 95% confidence intervals) - confounding variables: previous woman hypertensive disorders, diabetes and smoking - statistical methods used to assess association (e.g. univariate approaches such as contingency tables) Meta-analyses of measures of association will be perform using Review Manager (RevMan) [Computer program]. Version 5.3. The measures of association by outcome are reported as odds ratios (OR) with corresponding 95% confidence intervals calculated using random effects models. Analysis of subgroups or subsets Predictions of interest: a)Fresh embryo transfer or Frozen embryo transfer b)Advanced maternal age c)Vanishing twin d)Multiple pregnancies (control: spontaneous multiple pregnancies) e) Infertility causes

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