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Inter-pregnancy interval and pregnancy outcomes among women with delayed childbearing: protocol for a… Asgharpour, Mani; Villarreal, Sofia; Schummers, Laura; Hutcheon, Jennifer; Shaw, Dorothy; Norman, Wendy V Apr 8, 2017

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PROTOCOL Open AccessInter-pregnancy interval and pregnancyoutcomes among women with delayedchildbearing: protocol for a systematicreviewMani Asgharpour1, Sofia Villarreal1, Laura Schummers2, Jennifer Hutcheon3, Dorothy Shaw4 and Wendy V. Norman1*AbstractBackground: Women in high resource nations are increasingly delaying childbearing until their thirties. Delayedchildbearing poses challenges for the spacing of a woman’s pregnancies. Inter-pregnancy intervals <12 months areassociated with risk for adverse pregnancy outcome, yet increased maternal age at delivery is linked with increasedrisk. The optimal inter-pregnancy interval for older mothers is uncertain. This systematic review will aim to assessthe relation between inter-pregnancy interval and perinatal and maternal health outcomes in women who delaychildbearing to age 30 and older.Methods: We will search MEDLINE, CINAHL, and EMBASE databases for peer-reviewed articles on the effects ofinter-pregnancy interval on perinatal and maternal health outcomes among women over 29 years at the time offirst birth, in high-income countries. To assess the quality of studies, the Cochrane’s Collaboration tool for assessingrisk of bias will be used for randomized controlled trials, and the Newcastle-Ottawa tool to assess quality of casecontrol and cross-sectional studies. The quality of the findings on each outcome will be assessed across studies,using the GRADE approach. The decision to conduct meta-analyses will be based on the concordance in definitionsused for inter-pregnancy intervals, age groups studied, or outcomes measured among selected studies. We willreport odds ratios and/or relative risks and/or risk differences for different inter-pregnancy intervals and perinataland maternal outcomes as well as pregnancy complications.Discussion: This systematic review will summarize existing data on the relation between inter-pregnancy intervaland perinatal and maternal health outcomes among women who delay childbearing to age 30 and older. Findingswill inform clinical best practices to assist mothers over age 30 to space their pregnancies appropriately.Systematic review registration: Prospero CRD42015019057Keywords: Advanced maternal age, Birth interval, Birth spacing, Inter-pregnancy interval, Maternal outcome,Pregnancy complication, Perinatal outcome, Pregnancy spacing* Correspondence: wendy.norman@ubc.ca1Department of Family Practice, University of British Columbia, E204- 4500Oak Street, Vancouver, BC V6H 3N1, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Asgharpour et al. Systematic Reviews  (2017) 6:75 DOI 10.1186/s13643-017-0464-0BackgroundThere is a growing trend in developed nations forwomen to delay childbearing to older ages [1–3]. In theUSA, the average age of first-time mothers increased3.6 years from 1970 to 2006, from 21.4 to 25.0 years[1]. The dramatic increase in women having their firstbirth at the age of 35 years and over has played thelargest role in the increased average age of first-timemothers. For example, the US National Center forHealth Statistics data indicated that the proportion offirst births to women aged 35 years or older increasedfrom one out of 100 in 1970 to one out of 12 in 2006 [1].Women who delay childbearing are at increased risk of in-fertility and obstetrical and perinatal complications [4].As more women have their first birth at older ages com-pared with several decades ago, they have fewer childrenand complete their childbearing in a relatively short timespan [1]. In one study in the USA, mothers aged 35 yearsand above at first pregnancy had significantly higher oddsof having a short interval between first and secondpregnancies compared to mothers of 20–29 years [5]. Thisis partly due to women being aware of the negative effectof the so-called “biological clock” [6]. As a result, theymay be inclined to accelerate subsequent pregnancies inan attempt to minimize the effects of the decliningfecundability that is characteristic of advanced maternalage. However, both short (<18 months) and long (>5 years)inter-pregnancy intervals are associated with higher risksof adverse pregnancy outcomes such as preterm birth, lowbirth weight, and small for gestational age birth [7–9].Delayed childbearing poses important challenges forplanning the spacing of a woman’s pregnancies. Atpresent, the optimal inter-pregnancy interval for womenof advanced maternal age at first birth is uncertain. Thissystematic review study will examine the association be-tween inter-pregnancy interval and perinatal and maternalhealth outcomes in women age 30 and older at the time ofbirth, with the aim to provide evidence and recommenda-tions on optimal inter-pregnancy intervals for this particu-lar age group of women.MethodsThis systematic review protocol adheres to the PreferredReporting Items for Systematic Review and Meta-AnalysisProtocols (PRISMA-P) 2015 statement [10] (Additionalfile 1) and was registered with the International ProspectiveRegister of Systematic Reviews (PROSPERO) (registrationnumber CRD42015019057).Data sources and search strategyWe will conduct computerized searches in MEDLINE,EMBASE, and CINAHL, using a combination of med-ical subject headings (MeSH) and keywords related tointer-pregnancy interval without any restrictions on timeperiod, language, or study type. A search strategy has beendeveloped in consultation with a research librarian (seeTable 1 for the search criteria). The search strategy waspiloted across each database to improve the effectivenessof the final search. The bibliographies of all priorsystematic reviews and meta-analyses as well as all eligibleprimary studies will also be reviewed for additional rele-vant articles. Only peer-reviewed original research articlesand conducted in humans will be included. Near the endof the review process, the search will be rerun to identifyany potential studies that have been published since theinitial search.Eligibility criteriaStudies meeting all of the following criteria will be in-cluded: (i) human study, (ii) studies conducted in highresource countries (we will use the definition of “HighIncome OECD Countries” defined by the World Bank)[11], (iii) studies with analysis or sub-analyses of resultsamong women age 30 or older, and (iv) studies on therelationship between inter-pregnancy interval and peri-natal, maternal, or pregnancy health outcomes. The pri-mary outcomes are perinatal health outcomes (pretermbirth, low birth weight, small for gestational age, stillbirth,NICU admission, neonatal and infant mortality). Second-ary outcomes are (i) maternal health outcomes (cesareandelivery, uterine rupture, maternal ICU admission, severeTable 1 Search strategyDatabase Search termMedline Subject heading (MeSH): Birth intervalKeywords: “birth interval*” or “pregnancy interval*” or “birth spacing*” or “pregnancy spacing*” or “interpregnancy interval*” or“interpregnancy spacing*”Birth adj3 IntervalCINAHL Subject heading (MeSH): Birth intervalKeywords: “birth interval*” or “pregnancy interval*” or “birth spacing*” or “pregnancy spacing*” or “interpregnancy interval*” or“interpregnancy spacing*”Embase Keywords: “birth interval*” or “pregnancy interval*” or “birth spacing*” or “pregnancy spacing*” or “interpregnancy interval*” or“interpregnancy spacing*”Birth adj3 IntervalAsgharpour et al. Systematic Reviews  (2017) 6:75 Page 2 of 4maternal morbidity, or maternal mortality), (ii) pregnancycomplications (preeclampsia, gestational diabetes), and(iii) complications of labor and delivery (dystocia, post-partum hemorrhage).Study selection and data managementAll papers identified from the initial electronic searchprocess will be imported into a Refworks library [12],and duplicates will be removed. Titles and abstracts willbe screened by two investigators (MA and SV). Discrep-ancies will be resolved through consultation with a thirdreviewer (WN). Following the screening process, the fulltext of potentially eligible studies will be retrieved. Twoindependent reviewers will screen at the full text stageaccording to the eligibility criteria. Any discrepanciesbetween the two reviewers for included or excludedstudies will be discussed, and if an agreement cannot bereached, two senior reviewers will be used to reach con-sensus (JH and WN). The reason for excluding eachstudy will be recorded. At this stage, the reference listsof included studies will be scanned, and if any relevantstudies are identified, the full text will be retrieved andreviewed for inclusion by both reviewers. We will decidewhether to conduct a meta-analysis based on whetherthe individual studies differed considerably in definitionsused for inter-pregnancy intervals, age groups studied,or outcomes measured. We will report odds ratios and/or relative risks and/or risk differences for differentinter-pregnancy intervals and perinatal and maternaloutcomes as well as pregnancy complications. We willdocument whether eligible studies have controlled for,or otherwise taken into consideration, potential con-founders, such as socioeconomic status, pre-existingmedical conditions, previous gynecological, or obstetricalhistory, while examining the relationship between inter-pregnancy interval and perinatal, maternal, or pregnancyhealth outcomes.Quality assessmentThe quality of studies included in this review will beassessed by two researchers (WN and MA) using a toolappropriate for the study design. Any discrepanciesbetween the two reviewers will be discussed, and if a con-sensus on study quality rating cannot be reached, advicewill be sought from a third reviewer (JH). For RCTs,Cochrane’s Collaboration tool for assessing risk of bias inrandomized trials [13] will be used. This tool includes sixdomains to assess bias (i.e., selection bias, performancebias, detection bias, attrition bias, and reporting bias)which are assigned as either “low risk of bias,” “unclearrisk of bias,” or “high risk of bias” [13]. This informationwill be presented as a risk of bias summary figure. To as-sess the study quality of prospective and cross-sectionalstudies, the Newcastle-Ottawa Scale (NOS) for cohortstudies will be used [14]. This tool assigns stars to indicatehigher quality based on three broad criteria, specific to thestudy design (i.e., selection of study groups, comparabilityand outcome assessment). This information will be pre-sented in a summary table, indicating the star rating foreach individual study included in the review. For all stud-ies included in this review, the information on effect sizewill be recorded and assessed. Effect size will be either ex-tracted from the study or calculated if the study does notreport the information, using the mean values and stand-ard deviation retrieved from the study.Besides the quality assessment of individual studies,we will also assess the quality of the findings on pri-mary and secondary outcomes across studies, usingGRADE guidelines, which were developed by theGrading of Recommendations, Assessment, Develop-ment and Evaluations (GRADE) Working Group andadopted by BMJ Clinical Evidence [15]. The GRADEapproach will allow us to consider multiple key factorsto determine the quality of the evidence of each out-come, and therefore help appraise how confident weare in the body of evidence [16]. A Summary of Find-ings table will be generated to present the quality ofthe evidence, the magnitude of the effect, and reasonsbehind decisions.DiscussionThis will be the first systematic review to examine the as-sociation between inter-pregnancy interval and perinataland maternal health outcomes in women age 30 and olderat the time of birth. While it is already recognized thatboth short and long inter-pregnancy intervals increase therisk of adverse pregnancy outcomes [7, 8], a greaterunderstanding of these effects in women who delaychildbearing to age 30 and older would provide clinicalpractitioners and mothers a better knowledge base fordecision-making.Additional fileAdditional file 1: PRISMA-P 2015 checklist. (DOCX 70 kb)AbbreviationsCINAHL: Cumulative Index to Nursing and Allied Health Literature;EMBASE: Excerpta Medica database; MEDLINE: Medical Literature Analysisand Retrieval System OnlineAcknowledgementsWe are very grateful for the expert assistance of medical librarian, KathrynHornby, and our Research Manager Dr. Weihong Chen.FundingThe review is supported by Dr. Norman’s Chair in Applied Public HealthResearch, funded by the Canadian Institutes of Health Research, Instituteof Health Policy and Services Research (CPP-329455-107837).Asgharpour et al. Systematic Reviews  (2017) 6:75 Page 3 of 4Availability of data and materialsSupporting data can be found at our registration page at the InternationalProspective Register of Systematic Reviews (PROSPERO) web site, at ourregistration page- number CRD42015019057.Authors’ contributionsWN is the guarantor. MA registered the protocol with PROSPERO and draftedthe manuscript. All authors contributed to the initial question development,search strategy, criteria for study selection, assessment of risk bias instrument,and data extraction procedures. SV contributed to the development of theprotocol and manuscript. WN, DS, JH, and LS provided high level guidanceacross all aspects of the protocol procedures. All authors reviewed the finalmanuscript. All authors read and approved the final manuscript.Competing interestsThe authors declare they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participatePrior to commencing this study, IRB approval was obtained from theUniversity of British Columbia-Children’s and Women’s Research Ethics Board(H15-00968). No consent to participate, nor consent to publish participantdata, was applicable for this systematic review.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Family Practice, University of British Columbia, E204- 4500Oak Street, Vancouver, BC V6H 3N1, Canada. 2Department of Epidemiology,Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA02115, USA. 3Department of Obstetrics and Gynecology, BC Women’sHospital & Health Centre, University of British Columbia, Shaughnessy C408A,4500 Oak Street, Vancouver, BC V6H 3N1, Canada. 4Departments ofObstetrics and Gynecology and Medical Genetics, University of BritishColumbia, B2 West 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.Received: 30 September 2016 Accepted: 23 March 2017References1. Mathews TJ, Hamilton BE. Delayed childbearing: more women are havingtheir first child later in life. NCHS data brief, no 21. Hyattsville: NationalCenter for Health Statistics.; 2009. https://www.cdc.gov/nchs/data/databriefs/db21.pdf. Accessed 20 May 2016.2. Fertility rates. Births, Australia, 2014. Australian Bureau of Statistics. http://www.abs.gov.au/ausstats/abs@.nsf/Previousproducts/3301.0Main%20Features42014?opendocument&tabname=Summary&prodno=3301.0&issue=2014&num=&view=. Accessed 8 Feb 2016.3. Fertility Summary. Office for national statistics. 2010. http://www.ons.gov.uk/ons/rel/fertility-analysis/fertility-summary/2010/uk-fertility-summary.html.Accessed 8 Feb 2016.4. Johnson JA, Tough S. Society of Obstetricians and Gynaecologists ofCanada. Delayed child-bearing. J Obstet Gynaecol Can. 2012;34(1):80–93.5. Nabukera SK, Wingate MS, Salihu HM, Owen J, Swaminathan S, Alexander GR,Kirby RS. Pregnancy spacing among women delaying initiation of childbearing.Arch Gynecol Obstet. 2009;279(5):677–84. doi:10.1007/s00404-008-0793-2.6. Carolan M. The graying of the obstetric population: implications for theolder mother. J Obstet Gynecol Neonatal Nurs. 2003;32(1):19–27.7. Conde-Agudelo A, Rosas-Bermúdez A, Kafury-Goeta AC. Effects of birthspacing on maternal health: a systematic review. Am J Obstet Gynecol.2007;196(4):297–308.8. Conde-Agudelo A, Rosas-Bermúdez A, Kafury-Goeta AC. Birth spacing and riskof adverse perinatal outcomes: a meta-analysis. JAMA. 2006;295(15):1809–23.9. Zhu BP, Rolfs RT, Nangle BE, Horan JM. Effect of the interval betweenpregnancies on perinatal outcomes. N Engl J Med. 1999;340(8):589–94.10. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.Preferred reporting items for systematic review and meta-analysis protocols(PRISMA-P) 2015 statement. Syst Rev. 2015;4:4053–4-1.11. The World Bank. Country and lending groups. 2016. http://data.worldbank.org/about/country-and-lending-groups. Accessed 8 Feb 2016.12. ProQuest. RefWorks and RefShare - Citation Management Software. https://www.refworks.com/refworks2/.13. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. TheCochrane Collaboration’s tool for assessing risk of bias in randomised trials.BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928.14. Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, et al. TheNewcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomisedstudies in meta-analyses. 1999. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 8 Feb 2016.15. BMJ Clinical Evidence: What is GRADE? 2012. http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665072.html. Accessed 13 Dec 2017.16. Higgins JPT, Green S. Cochrane handbook for systematic reviews ofinterventions Version 5.1.0 [updated March 2011]. The CochraneCollaboration. 2011. http://handbook.cochrane.org/front_page.htm.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Asgharpour et al. Systematic Reviews  (2017) 6:75 Page 4 of 4

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