BMJ Open...For peer review only 1 Periconception endogenous and exogenous sex steroid hormones and risk of asthma and allergy in the offspring: protocol for a systematic review and

For peer review only

Periconception endogenous and exogenous sex steroid

hormones and risk of asthma and allergy in the offspring: protocol for a systematic review and meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2016-014637

Article Type: Protocol

Date Submitted by the Author: 16-Oct-2016

Complete List of Authors: Talovic, Merhunisa; University of Edinburgh, Asthma UK Centre for Applied Research Sheikh, Aziz; University of Edinburgh, Division of Community Health Sciences McCleary, Nicola; University of Edinburgh, Asthma UK Centre for Applied Research Erkkola, Maijaliisa; University of Helsinki, Division of Nutrition Kaila, Minna; University of Helsinki, Department of Public Health Virtanen, Suvi; The National Institute for Health and Welfare, The Unit

of Nutrition; University of Tampere, School of Health Sciences Nwaru, Bright; The University Of Edinburgh, Allergy & Respiratory Research Group, Centre for Population Health Sciences

Primary Subject Heading:

Respiratory medicine

Secondary Subject Heading: Reproductive medicine

Keywords: Asthma < THORACIC MEDICINE, Allergy < THORACIC MEDICINE, children, hormonal contraceptives, pregnancy, systematic review

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Periconception endogenous and exogenous sex steroid hormones and risk of asthma and allergy in the offspring: protocol for a systematic review and meta-analysis Merhunisa Talovic,1 Aziz Sheikh,1 Nicola McCleary,1 Maijaliisa Erkkola,2 Minna Kaila,3 Suvi M Virtanen,4-7 Bright I Nwaru,1,4 1Asthma UK Centre for Applied Research, Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK 2Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland 3Public Health Medicine, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki AND Department of Pediatrics, Tampere University Hospital 4School of Health Sciences, University of Tampere, Tampere, Finland

5Nutrition Unit, Department of Lifestyle and Participation, National Institute for Health and Welfare, Helsinki, Finland 6Tampere Centre for Child Health Research, Tampere University Hospital, Tampere, Finland 7Science Centre of Pirkanmaa Hospital District, Tampere University Hospital and University of Tampere, Finland Correspondence to: Merhunisa Talovic Asthma UK Centre for Applied Research Centre for Medical Informatics Usher Institute of Population Health Sciences and Informatics The University of Edinburgh, Edinburgh UK Email: [email protected] Keywords asthma, allergy, children, oestrogen, hormonal contraceptives, pregnancy, progesterone, sex hormones, systematic review, testosterone Running head: Periconception sex hormones and offspring asthma

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ABSTRACT Introduction Pregnancy is associated with several hormonal changes, which influence the developing fetus. Variations in maternal endogenous hormones and pre-pregnancy use of sex hormonal preparations have been linked to asthma and allergy in the offspring, but findings are inconsistent. We plan to undertake a systematic review to synthesise the evidence on the association between endogenous and exogenous sex hormones and the risk of asthma and allergy in the offspring. Methods and analysis We will search MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Scopus, Google Scholar, AMED, Global Health, PsychINFO, CAB International, and WHO Global Health Library from inception until 2016 to identify relevant studies on the topic. Additional studies will be identified by searching databases of proceedings of international conferences, contacting international experts in the field, and searching the references cited in identified studies. We will include analytic epidemiological studies. Two researchers will independently screen identified studies, undertake data extraction, and assess risk of bias in eligible studies; a third reviewer will arbitrate any disagreement. We will use the Effective Public Health Practice Project to assess the risk of bias in the studies. We will perform a random-effects meta-analysis to synthesise the evidence. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the strength and quality of the overall evidence with respect to each outcome. Ethics and dissemination Level 1 ethics form from Edinburgh institutional review board was completed for this study, which indicated that no ethics approval is required since it is based only on the published literature. Our findings will be reported in a peer-reviewed scientific journal. Protocol Registration A detailed protocol for the review is registered with the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42016048324 and can be found at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016048324.

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Strengths

• Peer reviewed for all stages of the systematic review

• Data will be extracted onto a customized data extraction form

• The included studies will be assessed for bias using the EPHPP tool

• The studies will be assessed for meta-analysis and included when appropriate

Limitations

• Google Translate will be used as the translation tool

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INTRODUCTION Pregnancy is associated with numerous adjustments that occur in the endocrine system, which are normal and necessary adaptations to make adequate accommodation for the fetus.1-5 These adjustments, amongst others, include hormonal changes: oestrogen and progesterone levels steadily increase and are essential in suppressing the hypothalamic axis and the menstrual cycle.1-5 Human chorionic gonadotropin (HCG) also increases and helps to sustain the production of progesterone by the corpus luteum.4,5 Other changes include an increase in prolactin levels as a result of the maternal pituitary gland; an increase in parathyroid hormones, leading to increases in uptake of calcium in the gut and reabsorption in the kidney; and an increase in the levels of adrenal hormones such as cortisol and aldosterone.1-5 Oestrogen, primarily produced by the placenta, is known to play a role in the well-being and development of the fetus.4,5 Increases in the levels of progesterone production help to relax bronchiolar smooth muscle and are associated with an increase in minute ventilation, which can rise up to 50% greater than non-pregnant levels.4,5 Both oestrogen and progesterone are thought to act as immunosteroids, although the effect of this on the direction of shift in the T cells is not entirely clear.4,5 However, it has been suggested that the observed changes in levels of maternal endogenous sex steroid hormones, including oestrogen, progesterone, and testosterone, during pregnancy may influence subsequent risk of asthma and allergy in the offspring.6-9

Furthermore, pre-pregnancy use of oral contraceptive pills, which include combined pills and progestin-only pills, has been postulated to modulate the risk of asthma and allergy in the offspring through possible disruption of the immunologic balance.10-16 Wjst and Dold were the first to postulate that the use of contraceptive pills before pregnancy may influence subsequent offspring risk of asthma and allergy.10 According to their hypothesis, the effect of contraceptive pills may last for several years even after discontinuation; however, the dosage, frequency, and timing of use of oral contraceptive pills sufficient to instigate the immune effect that can result in increased offspring asthma and allergy risk are unclear.10 Although several studies have now investigated the role of both endogenous and exogenous sex steroid hormones during pregnancy in the development of asthma and allergy in the offspring, findings are inconsistent. To clarify the underlying evidence base, we plan to undertake a systematic review to identify, critically appraise, and synthesise studies on the role of changes in endogenous sex steroid hormones during pregnancy and the use of exogenous steroid hormones before pregnancy in the development of asthma and allergy in the offspring. METHODS This protocol is reported following the recommendations of the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) checklist.17 Eligibility criteria Types of studies All analytic observational epidemiologic studies (cohort studies; case control studies; and cross-sectional studies) on the topic are eligible for inclusion. Reviews, case studies and case series, and animal studies will be excluded. Participants

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We are interested in the role of changes in endogenous sex hormones and use of exogenous sex hormones in the year before pregnancy and during pregnancy. We will therefore include women during preconception and pregnancy and their offspring of any age. Years considered We will include studies published from the inception of each database searched until the end of 2016. Language We will have no language restrictions and we will endeavour to translate literature published in languages other than English whenever this is possible. Information sources Database searches and other sources to identify studies To identify relevant studies, we will search MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Scopus, Google Scholar, AMED, Global Health, PsychINFO, CAB International, and WHO Global Health Library. Additional references will be identified by searching the references cited in eligible studies; by searching databases of the proceedings of international conferences, such as ISI Conference Proceedings Citation Index via Web of Knowledge, ZETOC (British Library); and by contacting a panel of international experts and authors who have published in the field. We will search trial registries, such as Current Controlled Trials (http://www.controlled-trials.com), ClinicalTrials.gov (http://www.clinicaltrials.gov), Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au) to identify ongoing studies. Search strategy We have prepared a search strategy using the Ovid interface for MEDLINE (Appendix 1) to identify and retrieve relevant studies. We will adapt this search strategy in searching the other databases. Study records Data management We will use Endnote Library for managing the references identified from the databases. All records will be exported to Endnote Library for onward study screening, de-duplication, and overall management of the retrieved records. Selection process Two reviewers (MT and NM) will independently screen the titles and/or abstracts and full texts of potentially eligible studies. A third reviewer (BN) will arbitrate any disagreements. Data extraction Two reviewers will independently extract relevant study data from eligible studies onto a customized data extraction form; a third reviewer will arbitrate any discrepancies. The data extraction form will be piloted using a select sample of the eligible studies prior to use in extracting data from all studies. Data items We will produce descriptive summary tables to summarise eligible studies. All relevant study data will be tabulated and as a minimum the tables will include the following: study author;

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country of study; year of publication; study design; size of study population; source of study population; type of exposure studied (endogenous vs exogenous sex hormones and the specific types) and method of assessment; time before pregnancy and trimester during pregnancy exposure was ascertained; length of follow-up in studies (for follow-up studies); confounding factors considered; study outcomes and methods of assessment; analysis methods; and key results. The PRISMA checklist will guide the reporting of the systematic review.18 Data sharing This original research article does not have additional unpublished data from the study available anywhere or to anyone. Types of exposures We will include studies that have investigated the role of all relevant endogenous sex steroid hormones (including oestrogen, progesterone, testosterone) and exogenous sex hormones (including oestogen-only, progesterone-only, and combined oral contraceptives).

Outcomes and prioritisation Our primary outcomes will include: objectively-measured or self-reported asthma, atopic

dermatitis/eczema, allergic rhinitis, anaphylaxis, urticaria, angioedema, and food allergy. The

secondary outcomes will include: atopic sensitization as defined either by skin prick test or

raised antigen specific immunoglobulin E; objective and subjective measures of disease severity

and impact on quality of life, including asthma exacerbations, use of asthma medications,

hospitalisation for asthma, wheeze as defined by self-report or objective diagnosis; indicators of

airway function including (peak expiratory flow, forced expiratory volume in 1 second, forced vital

capacity, forced expiratory flow rate or alternative age appropriate pulmonary function tests

[oscillometry or exhaled nitric oxide analysis]); and measures of patient-reported health-related

quality of life related to asthma or allergy. We will also assess the impact of sex hormones on

any allergic or respiratory outcome.

Risk of bias in individual studies Two reviewers (MT and NM) will independently evaluate the risk of bias in eligible studies and consensus will be reached through discussion; a third reviewer (BN) will arbitrate any discrepancies. We will employ the Effective Public Health Practice Project tool (EPHPP) (www.ephpp.ca) in appraising the risk of bias in studies. The EPHPP tool allows the grading of key components of the studies, including: suitability of the study design for the research question; risk of selection bias; exposure measurement; outcome assessment; and generalisability of findings. From these component-specific grading, we will derive an overall grading for each study. Data synthesis We will synthesise the data both narratively and quantitatively. For quantitative synthesis, we will perform random-effects meta-analysis to combine the estimates from studies judged to be clinically, methodologically, and statistically homogeneous. Heterogeneity between studies will be quantified using the I2 statistic. Subgroup analyses will be performed by: age of offspring at onset/diagnosis of outcomes (where possible using the following age groups: 12 years); sex; trimester of assessment of sex hormones; and parity. Using the grading derived from the quality appraisal of eligible studies, we will perform sensitivity analyses to evaluate the robustness of our findings and whether these are influenced by the risk of bias in studies. The meta-analyses will be performed using the statistical package Stata 14.

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Publication bias We will evaluate the potential for publication bias by using funnel plots and Begg and Egger tests19,20

Protocol registration A detailed protocol for the review is registered with PROSPERO. The registration number is CRD42016048324 and can be found at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016048324. Ethics and dissemination Level 1 ethics form from Edinburgh institutional review board was completed for this study, which indicated that no ethics approval is required since it is based only on the published literature. Our findings will be reported in a peer-reviewed scientific journal. Confidence in the cumulative estimate We will evaluate and grade the strength and quality of the overall evidence emanating from the review using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.21 CONCLUSION Clearer understanding of the impact of changes in endogenous sex hormones during pregnancy on the development of asthma and allergy in offspring may provide key targets for monitoring and potentially regulating thresholds of oestrogen, progesterone, testosterone levels to a level that will not adversely affect the risk of atopic disorders in the offspring. Similarly, synthesising the evidence on the role of use of hormonal contraceptives prior to pregnancy in the development of asthma and allergy in offspring will help to identify potential lifestyle changes regarding the use of hormonal contraceptives before pregnancy. COMPETING INTERESTS The authors declare no competing interest related to this work. AUTHORS’ CONTRIBUTIONS BN conceived the idea for this work and is the guarantor. AS contributed subject expertise to the development of the protocol. The protocol was drafted by MT and BN and was then revised after several rounds of critical comments from AS and additional feedback from MK, ME, SV and NM. All authors will be involved in the systematic review process. FUNDING MT undertakes this work as part of the requirement for her dissertation for the award of a Master’s in Public Health at The University of Edinburgh. The work received no specific funding. BN was supported by the Institute for Advanced Social Research Fellowship, University of Tampere, Finland; School of Health Sciences, University of Tampere, Finland. Additional support was received from the Farr Institute and Asthma UK Centre for Applied Research. The views presented here are those of the authors and not necessarily those of the Universities of Tampere and Edinburgh.

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5. Newbern D, Freemark M. Placental hormones and the control of maternal metabolism

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6. Pincus M, Keil T, Rücke M, et al. Fetal origin of atopic dermatitis. J Allergy Clin Immunol

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7. Xu B, Pekkanen J, Husman T, et al. Maternal sex hormones in early pregnancy and

asthma among offspring: a case-control study. J Allergy Clin Immunol 2003; 112: 1101-

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8. Shaheen SO, Hines M, Newson RB, et al. Maternal testosterone in pregnancy and atopic

outcomes in childhood. Allergy 2007; 62: 25-32.

9. Hartwig IR, Bruenahl CA, Ramisch K, et al. Reduced levels of maternal progesterone

during pregnancy increase the risk for allergic airway disease in females only. J Mole

Med 2014; 92: 1093-1104.

10. Wjst M, Dold S. Is asthma an endocrine disease? Pediatr Allergy Immunol 1997; 8: 200-

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11. Yamamoto-Hanada K, Fuamura M, Yang L, et al. Preconceptional exposure to oral

contraceptive pills and the risk of wheeze, asthma and rinitis in children. Allergol Int. in

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12. Brooks K, Samms-Vaughan, Karmaus W. Are oral contraceptive use and pregnancy

complications risk factors for atopic disorders among offspring? Pediatr Allergy Immunol

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13. Frye C, Mueller JE, Niedermeier K, Wjst M, et al. Maternal oral contraceptive use and

atopic diseases in the offspring. Allergy 2003; 58: 229-232.

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respiratory outcomes in early childhood. Pediatr Allergy Immunol 2011; 22: 528-536.

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maternal use of contraceptive pills and allergic disease among offpring. Allergy 2006; 61:

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16. Xu B, Järvelin M, Pekkanen J. Prenatal factors and occurence of rhinitis and eczema

among offspring. Allergy 1999; 54: 829-836.

17. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review

and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ

2015;349:g7647.

18. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred

Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.

PLoS Med 6: e1000097.

19. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088-101.

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20. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple.

Graphical test. BMJ 1997; 315: 629-34.

21. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann

HJ for the GRADE Working Group. GRADE: an emerging consensus on rating quality of

evidence and strength of recommendations. BMJ 2008; 336: 924.

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Appendix 1: MEDLINE search strategy 1. exp hormones/ 2. hormon*.mp. 3. exp gonadal steroid hormones/ 4. sex hormon*.mp. 5. exp estrogens/ 6. estrogen?.mp. 7. exp progesterone/ 8. progesterone?.mp. 9. exp testosterone/ 10. testosterone?.mp. 11. exp contraceptive agents/ 12. exp contraceptive agents, female/ 13. exp contraception/ 14. contracep*.mp. 15. exp contraceptives, oral/ 16. oral contraceptive?.mp. 17. exp contraceptives, oral combined/ 18. combined oral contraceptive?.mp. 19. exp contraceptives, oral, hormonal/ 20. hormonal contraceptives.mp. 21. exp medroxyprogesterone acetate/ 22. exp ethinyl estradiol/ 23. or/1-22 24. exp pregnancy/ 25. exp pregnant women/ 26. pregnan*.mp. 27. pre pregnan*.mp. 28. preconception*.mp. 29. before pregnan*.mp. 30. periconception*.mp. 31. antenatal*.mp. 32. prenatal*.mp. 33. or/24-32 34. exp adolescent/ 35. exp child, preschool/ 36. exp child/ 37. child.mp. 38. children.mp. 39. exp Infant/ 40. exp infant, newborn/ 41. infan*.mp. 42. toddler.mp. 43. offspring.mp. 44. or/34-43 45. exp asthma/ 46. asthma.mp. 47. exp wheezing/ 48. wheez*.mp. 49. exp bronchial hyperreactivity/ 50. airway function.mp.

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51. exp forced expiratory volume/ 52. forced expiratory volume 1 second.mp. 53. exp peak expiratory flow rate/ 54. peak expiratory flow.mp. 55. exp vital capacity/ 56. forced vital capacity.mp. 57. forced expiratory flow.mp. 58. lung function.mp. 59. exp hypersensitivity/ 60. hypersensitivit*.mp. 61. allerg*.mp. 62. exp allergic rhinitis/ 63. allergic rhinitis.mp. 64. exp atopic dermatitis/ 65. atopic dermatitis.mp. 66. exp eczema/ 67. eczema*.mp. 68. exp urticaria/ 69. urticaria.mp. 70. exp anaphylaxis/ 71. anaphylaxis.mp. 72. angioedema/ 73. exp food hypersensitivity/ 74. food hypersensitivit*.mp. 75. food allergy.mp. 76. allergy, food.mp. 77. milk hypersensitivity/ 78. milk/ 79. exp milk proteins/ 80. milk, human/ 81. cattle/ 82. cow*.mp. 83. cow* milk.mp. 84. wheat hypersensitivity/ 85. triticum/ 86. wheat.mp. 87. nut hypersensitivity/ 88. nuts/ 89. juglans/ 90. walnut*.mp. 91. corylus/ 92. hazelnut*.mp. 93. bertholletia/ 94. brazil nut*.mp. 95. anacardium/ 96. cashew*.mp. 97. sesamum/ 98. sesame.mp. 99. pistacia/ 100. pistachio*.mp. 101. prunus dulcis/

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102. almond*.mp. 103. peanut hypersensitivity/ 104. arachis/ 105. peanut*.mp. 106. egg hypersensitivity/ 107. exp eggs/ 108. hen* egg.mp. 109. chickens/ 110. chicken*.mp. 111. shellfish hypersensitivity/ 112. exp fishes/ 113. exp fish proteins/ 114. parvalbumins/ 115. fish allergen*.mp. 116. exp carps/ 117. carp.mp. 118. penaeidae/ 119. shrimp*.mp. 120. exp gadiformes/ 121. cod.mp. 122. or/45-76 123. 77 or 84 or 87 or 103 or 106 or 111 or 115 124. 78 or 79 or 80 or 81 or 82 or 83 or 85 or 86 or 88 or 89 or 90 or 91 or 92 or 93 or 94 or 95 or 96 or 97 or 98 or 99 or 100 or 101 or 102 or 104 or 105 or 107 or 108 or 109 or 110 or 112 or 113 or 114 or 116 or 117 or 118 or 119 or 120 or 121 125. or/59-76 126. 122 or 123 or (124 and 125) 127. 23 and 33 and 44 and 126

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PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to

address in a systematic review protocol*

Section and topic Item No Checklist item

ADMINISTRATIVE INFORMATION

Title:

Identification 1a Identify the report as a protocol of a systematic review p. 1

Update 1b If the protocol is for an update of a previous systematic review, identify as such

Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number p. 2, 7

7Authors:

Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of

corresponding author p. 1

Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review p. 7

Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes;

otherwise, state plan for documenting important protocol amendments

Support:

Sources 5a Indicate sources of financial or other support for the review p. 7

Sponsor 5b Provide name for the review funder and/or sponsor

Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol

INTRODUCTION

Rationale 6 Describe the rationale for the review in the context of what is already known p. 4

Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions,

comparators, and outcomes (PICO) p. 4

METHODS

Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years

considered, language, publication status) to be used as criteria for eligibility for the review p. 4-6

Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other

grey literature sources) with planned dates of coverage p. 5

Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be

repeated p. 10-12

Study records:

Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review p. 5

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Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the

review (that is, screening, eligibility and inclusion in meta-analysis) p. 5

Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any

processes for obtaining and confirming data from investigators p. 5

Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data

assumptions and simplifications p. 5-6

Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with

rationale p. 6

Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the

outcome or study level, or both; state how this information will be used in data synthesis p. 6

Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised p. 6

15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and

methods of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ) p. 6

15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression)

15d If quantitative synthesis is not appropriate, describe the type of summary planned p. 6

Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies)

p. 6-7

Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE) p. 7

* It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important

clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the

PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.

From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and

meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

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Merhunisa Talovic Usher Institute of Population Health Sciences and Informatics

The University of Edinburgh UK

7h October 2016

Trish Groves

Editor-in-Chief

BMJ Open

Dear Dr. Groves,

Re: Periconception endogenous and exogenous sex steroid hormones and risk of asthma and allergy in the offspring: protocol for a systematic review and meta-analysis We are submitting the above named protocol for a systematic review and meta-analysis for

consideration for publication in BMJ Open.

Although several studies have now investigated the role of both endogenous and exogenous sex steroid hormones and risk of asthma and allergy in the offspring, the findings are inconsistent. In order to provide the most comprehensive and unbiased estimate on this topic, we plan to undertake a systematic review to identify, critically appraise, and synthesize studies on the role of changes in endogenous sex steroid hormones during pregnancy and the use of exogenous sex steroid hormones before pregnancy in the development of asthma and allergy in the offspring. We believe that this topic will be of interest to the international readership of BMJ Open and hope that you will find the protocol suitable for publication in the journal. The submitted material is original research, has not been previously published, and has not been submitted for publication elsewhere while under consideration at BMJ Open. All study authors declare no competing interest and have commented and approved the final version being submitted. Sincerely, Merhunisa Talovic, Aziz Sheikh, Nicola McCleary, Maijaliisa Erkkola, Minna Kaila, Suvi M Virtanen, Bright I Nwaru

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Periconception endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in the

offspring: protocol for a systematic review and meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2016-014637.R1


Date Submitted by the Author: 05-Apr-2017

Complete List of Authors: Talovic, Merhunisa; University of Edinburgh, Asthma UK Centre for Applied Research Sheikh, Aziz; University of Edinburgh, Division of Community Health Sciences McCleary, Nicola; University of Edinburgh, Asthma UK Centre for Applied Research Erkkola, Maijaliisa; University of Helsinki, Division of Nutrition Kaila, Minna; University of Helsinki, Department of Public Health Virtanen, Suvi; The National Institute for Health and Welfare, The Unit of Nutrition; University of Tampere, School of Health Sciences

Nwaru, Bright; The University Of Edinburgh, Allergy & Respiratory Research Group, Centre for Population Health Sciences








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Periconception endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in the offspring: protocol for a systematic review and meta-analysis Merhunisa Talovic,1 Aziz Sheikh,1 Nicola McCleary,1 Maijaliisa Erkkola,2 Minna Kaila,3 Suvi M Virtanen,4-7 Bright I Nwaru,1,4 1Asthma UK Centre for Applied Research, Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK 2Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland 3Public Health Medicine, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki AND Department of Pediatrics, Tampere University Hospital 4School of Health Sciences, University of Tampere, Tampere, Finland


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ABSTRACT Introduction Pregnancy is associated with several hormonal changes which influence the developing fetus. Variations in maternal endogenous hormones and pre-pregnancy use of hormonal preparations have been linked to asthma and allergy in the offspring, but findings are inconsistent. We plan to undertake a systematic review to synthesise the evidence on the association between endogenous and exogenous maternal sex hormones and the risk of asthma and allergy in the offspring. Methods and analysis We will search MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Scopus, Google Scholar, AMED, Global Health, PsycINFO, CAB International, and WHO Global Health Library from inception until 2016 to identify relevant studies on the topic. Additional studies will be identified by searching databases of proceedings of international conferences, contacting international experts in the field, and searching the references cited in identified studies. We will include analytic epidemiological studies. Two researchers will independently screen identified studies, undertake data extraction, and assess risk of bias in eligible studies, while a third reviewer will arbitrate any disagreement. We will use the Effective Public Health Practice Project tool to assess the risk of bias in the studies. We will perform a random-effects meta-analysis to synthesise the evidence. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the strength and quality of the overall evidence with respect to each outcome. Ethics and dissemination Ethical approval is not required since the study is a systematic review of published literature. Our findings will be reported in a peer-reviewed scientific journal. Protocol Registration A detailed protocol for the review is registered with the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42016048324 and can be found at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016048324.

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Strengths and Limitations

• This is the first systematic review examining the role of endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in the offspring and thus will contribute to knowledge on the foetal origin of allergy and asthma.

• We will identify studies from major healthcare databases without using geographical or language limitations, as well as including an extensive review on all of the current literature, ongoing and unpublished studies, and will employ replicable methods. • Existing studies may be heterogeneous, thus making it difficult to derive pooled estimates from included studies.

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INTRODUCTION Pregnancy is associated with numerous adjustments that occur in the endocrine system, which are normal and necessary adaptations that adequately accommodate the fetus.1-5 These adjustments include oestrogen and progesterone hormonal changes, which see steady levels of increase and are essential in suppressing the hypothalamic axis and the menstrual cycle.1-5

Human chorionic gonadotropin (HCG) also increases and helps to sustain the production of progesterone by the corpus luteum.4,5 Prolactin levels increase as a result of the maternal pituitary gland. Adrenal hormones such as cortisol and aldosterone increase, as do parathyroid hormones, which leads to greater uptake of calcium in the gut and reabsorption in the kidney.1-5 Oestrogen plays a key role in the well-being and development of the fetus.4,5 Increases in the levels of progesterone production help to relax bronchiolar smooth muscle and are associated with an increase in minute ventilation, which can rise to up to 50% greater than pre-pregnancy levels.4,5 Both oestrogen and progesterone are thought to act as immunosteroids, although the effect on the direction of shift in the T cells is not entirely clear.4,5 However, it has been suggested that the observed changes in levels of maternal endogenous sex steroid hormones, including oestrogen, progesterone, and testosterone, during pregnancy may influence subsequent risk of asthma and allergy in the offspring.6-9

Pre-pregnancy use of oral contraceptive pills, including combined pills and progestin-only pills, has been postulated to modulate the risk of asthma and allergy in the offspring through possible disruption of the immunologic balance.10-16 Wjst and Dold were the first to postulate that the use of contraceptive pills before pregnancy may influence subsequent risk of asthma and allergy in the offspring.10 According to their hypothesis, the effect of contraceptive pills may last for several years even after discontinuation; however, the dosage, frequency, and timing of use of oral contraceptive pills which may instigate the immune effect that can result in increased offspring asthma and allergy risks are unclear.10 Although several studies have now investigated the role of both endogenous and exogenous sex steroid hormones during pregnancy in the development of asthma and allergy in the offspring, findings are inconsistent. To clarify the underlying evidence base, we plan to undertake a systematic review to identify, critically appraise, and synthesise studies on the role of changes in endogenous sex steroid hormones during pregnancy and the role of exogenous steroid hormone use before pregnancy in the development of asthma and allergy in the offspring. METHODS This protocol is reported following the recommendations of the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) checklist.17 Eligibility criteria Types of studies All analytic observational epidemiologic studies: cohort studies, case control studies, and cross-sectional studies on the topic are eligible for inclusion. Animal studies, case series, case studies, and reviews will be excluded. Participants

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We are interested in the role of changes in endogenous sex hormones and in the use of exogenous sex hormones in the year before pregnancy and during pregnancy. We will therefore include women during preconception and pregnancy and their offspring of any age. Years considered We will include studies published from the inception of each database searched until the end of 2016. Language We will have no language restrictions and we will endeavour to translate literature published in languages other than English whenever this is possible. Information sources Database searches and other sources to identify studies To identify relevant studies, we will search MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Scopus, Google Scholar, AMED, Global Health, PsycINFO, CAB International, and WHO Global Health Library. Additional references will be identified by searching the references cited in eligible studies; by searching databases of the proceedings of international conferences, such as ISI Conference Proceedings Citation Index via Web of Science, ZETOC (British Library); and by contacting a panel of international experts and authors who have published in the field. We will search trial registries, such as Current Controlled Trials (http://www.controlled-trials.com), ClinicalTrials.gov (http://www.clinicaltrials.gov), Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au) to identify ongoing studies. Search strategy We have prepared a search strategy using the Ovid interface for MEDLINE (Appendix 1) to identify and retrieve relevant studies. We will adapt this search strategy when searching the other databases. Study records Data management We will use Endnote Library for managing the references identified from the databases. All records will be exported to Endnote Library for onward study screening, de-duplication, and overall management of the retrieved records. Selection process Two reviewers (MT and NM) will independently screen the titles and/or abstracts and full texts of potentially eligible studies. A third reviewer (BN) will arbitrate any disagreements. Data extraction Two reviewers will independently extract relevant study data from eligible studies onto a customized data extraction form, while a third reviewer will arbitrate any discrepancies. The data extraction form will be piloted using a select sample of the eligible studies prior to use in extracting data from all studies. Data items We will produce descriptive summary tables to summarise eligible studies. All relevant study data will be tabulated and as a minimum the tables will include the following: study author; country of study; year of publication; study design; size of study population; source of study

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population; type of exposure studied (endogenous vs exogenous sex hormones and the specific types) and method of assessment; time before pregnancy and trimester during pregnancy exposure was ascertained; length of follow-up (for follow-up studies); confounding factors considered; study outcomes and methods of assessment; analysis methods; and key results. The PRISMA checklist will guide the reporting of the systematic review.18 Types of exposures We will include studies that have investigated the role of all relevant endogenous sex steroid hormones (including oestrogen, progesterone, testosterone) and exogenous sex hormones (including oestogen-only, progesterone-only, and combined oral contraceptives). Outcomes and prioritisation Our primary outcomes will include: objectively-measured or self-reported asthma, atopic dermatitis/eczema, allergic rhinitis, anaphylaxis, urticaria, angioedema, and food allergy. The secondary outcomes will include: atopic sensitization as defined either by skin prick test or raised antigen specific immunoglobulin E; objective and subjective measures of disease severity and impact on quality of life, including asthma exacerbations, use of asthma medications, hospitalisation for asthma, wheeze as defined by self-report or objective diagnosis; indicators of airway function including (peak expiratory flow, forced expiratory volume in 1 second, forced vital capacity, forced expiratory flow rate or alternative age appropriate pulmonary function tests [oscillometry or exhaled nitric oxide analysis]); and measures of patient-reported health-related quality of life related to asthma or allergy. We will also assess the impact of sex hormones on any allergic or respiratory outcome.

Risk of bias in individual studies Two reviewers (MT and NM) will independently evaluate the risk of bias in eligible studies and consensus will be reached through discussion; a third reviewer (BN) will arbitrate any discrepancies. We will use the Effective Public Health Practice Project tool (EPHPP) (www.ephpp.ca) to appraise the risk of bias in studies. The EPHPP tool allows for the grading of key components of the studies, including: suitability of the study design for the research question; risk of selection bias; exposure measurement; outcome assessment (giving a higher grade to objectively-defined outcomes than subjectively-defined outcomes); and generalisability of findings. From these component-specific gradings, we will derive an overall grading for each study. Data synthesis All analyses will be undertaken separately for studies on exogenous hormones and studies on endogenous hormones. We will synthesise the data both narratively and quantitatively. For quantitative synthesis, we will perform random-effects meta-analysis to combine the estimates from studies judged to be clinically, methodologically, and statistically homogeneous. Heterogeneity between studies will be quantified using the I2 statistic. For analyses investigating the role of endogenous sex hormones, data syntheses will be undertaken by pregnancy trimester. Subgroup analyses will be performed according to: age of offspring at onset/diagnosis of outcomes (where possible using the following age groups: 12 years); sex; parity; and, for analyses investigating the role of exogenous sex hormones, time of exposure before pregnancy (e.g. 6 months vs 12 months before pregnancy). Using the grading derived from the quality appraisal of eligible studies, we will perform sensitivity analyses to evaluate the robustness of our findings and whether they are influenced by the risk of bias in studies. The meta-analyses will be performed using the statistical package Stata 14. Publication bias

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We will evaluate the potential for publication bias by using funnel plots and Begg and Egger tests19,20

Protocol registration A detailed protocol for the review is registered with PROSPERO. The registration number is CRD42016048324 and can be found at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016048324. Confidence in the cumulative estimate We will evaluate and grade the strength and quality of the overall evidence emanating from the review using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.21 We do not envisage making clinical recommendations from this largely and exclusively epidemiological evidence-base. There may be no need to interfere with pregnancy hormones in otherwise healthy females. However, if prenatal endogenous hormones contribute to the risk of allergy and asthma in the offspring, understanding this role and the mechanisms through which these hormones operate is essential for the field, as this will contribute to knowledge of the fetal origin of allergy and asthma. Moreover, since studies have now reported such associations, with varying results, a synthesis of the underlying evidence is essential in clarifying any putative role of prenatal sex hormones in the development of asthma and allergy in the offspring. COMPETING INTERESTS The authors declare no competing interest related to this work. AUTHORS’ CONTRIBUTIONS BN conceived the idea for this work and is the guarantor. AS contributed subject expertise to the development of the protocol. The protocol was drafted by MT and BN and was then revised after several rounds of critical comments from AS and additional feedback from MK, ME, SV and NM. All authors will be involved in the systematic review process. FUNDING MT undertakes this work as part of the requirement for her dissertation for the award of a Master’s in Public Health at The University of Edinburgh. The work received no specific funding. BN was supported by the Institute for Advanced Social Research Fellowship, University of Tampere, Finland; School of Health Sciences, University of Tampere, Finland. Additional support was received from the Farr Institute and Asthma UK Centre for Applied Research. The views presented here are those of the authors and not necessarily those of the Universities of Tampere and Edinburgh.

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REFERENCES

1. Constantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol 2014; 5: 65. 2. Thornburg KL, Jacobson SL, Giraud GD, et al. Hemodynamic changes in pregnancy. Semin Perinat 2000; 24: 11-14. 3. Chesnutt AN. Physiology of normal pregnancy. Crit Care Clin 2004; 20: 609-615. 4. Schindler AE. First trimester endocrinology: consequences for diagnosis and treatment of pregnancy failure. Gynecol Endocrinol 2004; 18: 51-57. 5. Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabetes Obes 2011; 18: 409-416. 6. Pincus M, Keil T, Rücke M, et al. Fetal origin of atopic dermatitis. J Allergy Clin Immunol 2010; 125: 273-275. 7. Xu B, Pekkanen J, Husman T, et al. Maternal sex hormones in early pregnancy and asthma among offspring: a case-control study. J Allergy Clin Immunol 2003; 112: 1101-1104. 8. Shaheen SO, Hines M, Newson RB, et al. Maternal testosterone in pregnancy and atopic outcomes in childhood. Allergy 2007; 62: 25-32. 9. Hartwig IR, Bruenahl CA, Ramisch K, et al. Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway disease in females only. J Mole Med 2014; 92: 1093-1104. 10. Wjst M, Dold S. Is asthma an endocrine disease? Pediatr Allergy Immunol 1997; 8: 200-204. 11. Yamamoto-Hanada K, Fuamura M, Yang L, et al. Preconceptional exposure to oral contraceptive pills and the risk of wheeze, asthma and rinitis in children. Allergol Int. in press. 12. Brooks K, Samms-Vaughan, Karmaus W. Are oral contraceptive use and pregnancy complications risk factors for atopic disorders among offspring? Pediatr Allergy Immunol 2004; 15: 487-496. 13. Frye C, Mueller JE, Niedermeier K, Wjst M, et al. Maternal oral contraceptive use and atopic diseases in the offspring. Allergy 2003; 58: 229-232. 14. Hancock DB, Håberg SE, Furu K, et al. Oral contraceptive pill use before pregnancy and respiratory outcomes in early childhood. Pediatr Allergy Immunol 2011; 22: 528-536. 15. Keski-Nisula L, Pekkanen J, Xu B, et al. Does the pill make a difference? Previous maternal use of contraceptive pills and allergic disease among offpring. Allergy 2006; 61: 1467-1472. 16. Xu B, Järvelin M, Pekkanen J. Prenatal factors and occurence of rhinitis and eczema among offspring. Allergy 1999; 54: 829-836. 17. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015;349:g7647. 18. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6: e1000097. 19. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088-101. 20. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple. Graphical test. BMJ 1997; 315: 629-34.

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21. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ for the GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924.

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Appendix 1: MEDLINE search strategy 1. exp hormones/ 2. hormon*.mp. 3. exp gonadal steroid hormones/ 4. sex hormon*.mp. 5. exp estrogens/ 6. estrogen?.mp. 7. exp progesterone/ 8. progesterone?.mp. 9. exp testosterone/ 10. testosterone?.mp. 11. exp contraceptive agents/ 12. exp contraceptive agents, female/ 13. exp contraception/ 14. contracep*.mp. 15. exp contraceptives, oral/ 16. oral contraceptive?.mp. 17. exp contraceptives, oral combined/ 18. combined oral contraceptive?.mp. 19. exp contraceptives, oral, hormonal/ 20. hormonal contraceptives.mp. 21. exp medroxyprogesterone acetate/ 22. exp ethinyl estradiol/ 23. or/1-22 24. exp pregnancy/ 25. exp pregnant women/ 26. pregnan*.mp. 27. pre pregnan*.mp. 28. preconception*.mp. 29. before pregnan*.mp. 30. periconception*.mp. 31. antenatal*.mp. 32. prenatal*.mp. 33. or/24-32 34. exp adolescent/ 35. exp child, preschool/ 36. exp child/ 37. child.mp. 38. children.mp. 39. exp Infant/ 40. exp infant, newborn/ 41. infan*.mp. 42. toddler.mp. 43. offspring.mp. 44. or/34-43 45. exp asthma/ 46. asthma.mp. 47. exp wheezing/ 48. wheez*.mp. 49. exp bronchial hyperreactivity/ 50. airway function.mp.

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51. exp forced expiratory volume/ 52. forced expiratory volume 1 second.mp. 53. exp peak expiratory flow rate/ 54. peak expiratory flow.mp. 55. exp vital capacity/ 56. forced vital capacity.mp. 57. forced expiratory flow.mp. 58. lung function.mp. 59. exp hypersensitivity/ 60. hypersensitivit*.mp. 61. allerg*.mp. 62. exp allergic rhinitis/ 63. allergic rhinitis.mp. 64. exp atopic dermatitis/ 65. atopic dermatitis.mp. 66. exp eczema/ 67. eczema*.mp. 68. exp urticaria/ 69. urticaria.mp. 70. exp anaphylaxis/ 71. anaphylaxis.mp. 72. angioedema/ 73. exp food hypersensitivity/ 74. food hypersensitivit*.mp. 75. food allergy.mp. 76. allergy, food.mp. 77. milk hypersensitivity/ 78. milk/ 79. exp milk proteins/ 80. milk, human/ 81. cattle/ 82. cow*.mp. 83. cow* milk.mp. 84. wheat hypersensitivity/ 85. triticum/ 86. wheat.mp. 87. nut hypersensitivity/ 88. nuts/ 89. juglans/ 90. walnut*.mp. 91. corylus/ 92. hazelnut*.mp. 93. bertholletia/ 94. brazil nut*.mp. 95. anacardium/ 96. cashew*.mp. 97. sesamum/ 98. sesame.mp. 99. pistacia/ 100. pistachio*.mp. 101. prunus dulcis/

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102. almond*.mp. 103. peanut hypersensitivity/ 104. arachis/ 105. peanut*.mp. 106. egg hypersensitivity/ 107. exp eggs/ 108. hen* egg.mp. 109. chickens/ 110. chicken*.mp. 111. shellfish hypersensitivity/ 112. exp fishes/ 113. exp fish proteins/ 114. parvalbumins/ 115. fish allergen*.mp. 116. exp carps/ 117. carp.mp. 118. penaeidae/ 119. shrimp*.mp. 120. exp gadiformes/ 121. cod.mp. 122. or/45-76 123. 77 or 84 or 87 or 103 or 106 or 111 or 115 124. 78 or 79 or 80 or 81 or 82 or 83 or 85 or 86 or 88 or 89 or 90 or 91 or 92 or 93 or 94 or 95 or 96 or 97 or 98 or 99 or 100 or 101 or 102 or 104 or 105 or 107 or 108 or 109 or 110 or 112 or 113 or 114 or 116 or 117 or 118 or 119 or 120 or 121 125. or/59-76 126. 122 or 123 or (124 and 125) 127. 23 and 33 and 44 and 126

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PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to

address in a systematic review protocol*

Section and topic Item No Checklist item

ADMINISTRATIVE INFORMATION

Title:

Identification 1a Identify the report as a protocol of a systematic review p. 1

Update 1b If the protocol is for an update of a previous systematic review, identify as such

Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number p. 2, 7

7Authors:

Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of

corresponding author p. 1

Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review p. 7

Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes;

otherwise, state plan for documenting important protocol amendments

Support:

Sources 5a Indicate sources of financial or other support for the review p. 7

Sponsor 5b Provide name for the review funder and/or sponsor

Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol

INTRODUCTION

Rationale 6 Describe the rationale for the review in the context of what is already known p. 4

Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions,

comparators, and outcomes (PICO) p. 4

METHODS

Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years

considered, language, publication status) to be used as criteria for eligibility for the review p. 4-6

Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other

grey literature sources) with planned dates of coverage p. 5

Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be

repeated p. 10-12

Study records:

Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review p. 5

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Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the

review (that is, screening, eligibility and inclusion in meta-analysis) p. 5

Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any

processes for obtaining and confirming data from investigators p. 5

Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data

assumptions and simplifications p. 5-6

Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with

rationale p. 6

Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the

outcome or study level, or both; state how this information will be used in data synthesis p. 6

Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised p. 6

15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and

methods of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ) p. 6

15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression)

15d If quantitative synthesis is not appropriate, describe the type of summary planned p. 6

Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (such as publication bias across studies, selective reporting within studies)

p. 6-7

Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE) p. 7

* It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important

clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the

PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.

From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and

meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

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Periconception endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in

offspring: protocol for a systematic review and meta-analysis

Journal: BMJ Open

Manuscript ID bmjopen-2016-014637.R2


Date Submitted by the Author: 15-May-2017

Complete List of Authors: Talovic, Merhunisa; University of Edinburgh, Asthma UK Centre for Applied Research Sheikh, Aziz; University of Edinburgh, Division of Community Health Sciences McCleary, Nicola; University of Edinburgh, Asthma UK Centre for Applied Research Erkkola, Maijaliisa; University of Helsinki, Division of Nutrition Kaila, Minna; University of Helsinki, Department of Public Health Virtanen, Suvi; The National Institute for Health and Welfare, The Unit of Nutrition; University of Tampere, School of Health Sciences

Nwaru, Bright; The University Of Edinburgh, Allergy & Respiratory Research Group, Centre for Population Health Sciences








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Periconception endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in offspring: protocol for a systematic review and meta-analysis Merhunisa Talovic,1 Aziz Sheikh,1 Nicola McCleary,1 Maijaliisa Erkkola,2 Minna Kaila,3 Suvi M Virtanen,4-7 Bright I Nwaru,1,4 1Asthma UK Centre for Applied Research, Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK 2Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland 3Public Health Medicine, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki AND Department of Pediatrics, Tampere University Hospital 4School of Health Sciences, University of Tampere, Tampere, Finland


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ABSTRACT Introduction Pregnancy is associated with several hormonal changes which influence the developing fetus. Variations in maternal endogenous hormones and pre-pregnancy use of hormonal preparations have been linked to asthma and allergy in the offspring, but findings are inconsistent. We plan to undertake a systematic review to synthesise the evidence on the association between endogenous and exogenous maternal sex hormones and the risk of asthma and allergy in the offspring. Methods and analysis We will search MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Scopus, Google Scholar, AMED, Global Health, PsycINFO, CAB International, and WHO Global Health Library from inception until 2016 to identify relevant studies on the topic. Additional studies will be identified by searching databases of proceedings of international conferences, contacting international experts in the field, and searching the references cited in identified studies. We will include analytic epidemiological studies. Two researchers will independently screen identified studies, undertake data extraction, and assess risk of bias in eligible studies, while a third reviewer will arbitrate any disagreement. We will use the Effective Public Health Practice Project tool to assess the risk of bias in the studies. We will perform a random-effects meta-analysis to synthesise the evidence. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the strength and quality of the overall evidence with respect to each outcome. Ethics and dissemination Ethical approval is not required since the study is a systematic review of published literature. Our findings will be reported in a peer-reviewed scientific journal. Protocol Registration A detailed protocol for the review is registered with the International Prospective Register of Systematic Reviews (PROSPERO). The registration number is CRD42016048324 and can be found at http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016048324.

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Strengths and Limitations

• This is the first systematic review examining the role of endogenous and exogenous maternal sex steroid hormones and risk of asthma and allergy in the offspring and thus will contribute to knowledge on the foetal origin of allergy and asthma.

• We will identify studies from major healthcare databases without using geographical or language limitations, as well as including an extensive review on all of the current literature, ongoing and unpublished studies, and will employ replicable methods.

• Existing studies may be heterogeneous, thus making it difficult to derive pooled estimates from included studies.

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INTRODUCTION Pregnancy is associated with numerous adjustments that occur in the endocrine system, which are normal and necessary adaptations that adequately accommodate the fetus.1-5 These adjustments include oestrogen and progesterone hormonal changes, which see steady levels of increase and are essential in suppressing the hypothalamic axis and the menstrual cycle.1-5

Human chorionic gonadotropin (HCG) also increases and helps to sustain the production of progesterone by the corpus luteum.4,5 Prolactin levels increase as a result of the maternal pituitary gland. Adrenal hormones such as cortisol and aldosterone increase, as do parathyroid hormones, which leads to greater uptake of calcium in the gut and reabsorption in the kidney.1-5 Oestrogen plays a key role in the well-being and development of the fetus.4,5 Increases in the levels of progesterone production help to relax bronchiolar smooth muscle and are associated with an increase in minute ventilation, which can rise to up to 50% greater than pre-pregnancy levels.4,5 Both oestrogen and progesterone are thought to act as immunosteroids, although the effect on the direction of shift in the T cells is not entirely clear.4,5 However, it has been suggested that the observed changes in levels of maternal endogenous sex steroid hormones, including oestrogen, progesterone, and testosterone, during pregnancy may influence subsequent risk of asthma and allergy in the offspring.6-9

Pre-pregnancy use of oral contraceptive pills, including combined pills and progestin-only pills, has been postulated to modulate the risk of asthma and allergy in the offspring through possible disruption of the immunologic balance.10-16 Wjst and Dold were the first to postulate that the use of contraceptive pills before pregnancy may influence subsequent risk of asthma and allergy in the offspring.10 According to their hypothesis, the effect of contraceptive pills may last for several years even after discontinuation; however, the dosage, frequency, and timing of use of oral contraceptive pills which may instigate the immune effect that can result in increased offspring asthma and allergy risks are unclear.10 Although several studies have now investigated the role of both endogenous and exogenous sex steroid hormones during pregnancy in the development of asthma and allergy in the offspring, findings are inconsistent. To clarify the underlying evidence base, we plan to undertake a systematic review to identify, critically appraise, and synthesise studies on the role of changes in endogenous sex steroid hormones during pregnancy and the role of exogenous steroid hormone use before pregnancy in the de

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BMJ Open...For peer review only 1 Periconception endogenous and exogenous sex steroid hormones and risk of asthma and allergy in the offspring: protocol for a systematic review and