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Carl Heneghan, Elizabeth Spencer, Bennett Holman, Igho Onakpoya.

Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford, OX2 6GG.

Date stamp 23/10/2018

How to cite:
Hormone pregnancy test use in pregnancy and risk of abnormalities in the offspring: a systematic review protocol. Carl Heneghan, Elizabeth Spencer, Bennett Holman, Igho Onakpoya. March 25th 2019. CEBM https://www.cebm.ox.ac.uk/research/protocols/hpt-protocol

Background

Hormone pregnancy tests (HPTs) were used in several countries during the last century prior to the availability of urine pregnancy tests. HPTs contained norethisterone and ethinylestradiol (synthetic forms of progesterone and estrogen) and were used to detect pregnancy based on the principle was that menstruation would be induced in women who were not pregnant. Concerns about safety, in particular in relation to congenital abnormalities, were raised several decades ago, but a systematic assessment of all available data has been lacking. In this study we aimed to obtain all relevant data on hormone pregnancy tests and abnormalities in the offspring, and where possible perform meta-analysis to give a summary estimate of associations.

Objective

Systematic review of published and unpublished studies of hormone pregnancy tests in humans and abnormalities in the offspring.

Data sources

The full details of the literature search are in Appendix 1. We will search regulatory documents, including the UK Government’s ‘Report of the Commission on Human Medicines’ Expert Working Group on Hormone Pregnancy Tests’ (1), the electronic database MEDLINE, and reference lists of retrieved studies. We will use the following search terms in the PubMed search: (Primodos OR Duogynon OR  “hormone pregnancy test” OR “sex hormones” OR “hormone administration” OR “norethisterone” OR “ethinylestradiol”) AND pregnancy AND (congenital OR malformations OR anomalies OR abnormalities).

A number of comparable high dose HPTs were also available at the same time as Primodos and were cited in a 2015 MHRA call for evidence document (2). We will perform additional searches for evidence relating to these, shown in Appendix 2. There will be no date limits nor language restrictions.

Eligibility criteria

Studies will be eligible for inclusion if they include data for women who were or became pregnant during the study and were exposed to oral HPTs within the estimated first three months of pregnancy, and included a relevant control group of women. Case-control studies and cohort studies that included a control group will be eligible for inclusion.

For studies with more than one publication, the publication with the most comprehensive relevant data will be included. Where necessary, data on relevant outcomes will be extracted from supplementary publications.

Primary outcomes

Congenital abnormality in the offspring, recorded at any time during gestation or after birth.

Secondary outcomes

Congenital abnormality identified at any time, as categorised into the following major organ systems: congenital heart, gastrointestinal, musculoskeletal, neurological and urogenital defects. An additional secondary outcome was VACTERL syndrome (Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Esophageal atresia, Renal anomalies and Limb defects).

Data management and extraction

Two reviewers (CH and ES) will apply the inclusion and quality assessment criteria, compare results and resolve any conflicts of judgement. We will extract data on study type, and numbers of pregnancies exposed and not exposed to HPTs, and types and numbers of outcomes into a review template. Where available, data will be extracted about the women including ascertainment of cases, age, parity, setting, exposure to other medications and confounding variables. A woman could contribute more than one set of data if she had more than one pregnancy exposed to HPTs.

In case-control studies, if data are reported on more than one control group, we will extract data for the most matched controls (most closely matched to the cases).

We will assess study quality using the Newcastle–Ottawa Scale (NOS) for nonrandomized studies included in systematic reviews (3). The NOS assesses the selection of study groups, comparability of cases and controls and ascertainment of the outcome/exposure. Each positive criterion scores 1, with the exception of comparability which scores up to 2 points. The maximum NOS score is 9, and similar to previous reviews we will consider a score of 1 to 3 points to be at high risk of bias (4). We will also plot the relative risks against NOS scores to examine if a linear relationship between methodological quality and study results is present (5).

Data synthesis

Using the extracted data we will calculate study-specific risk ratios for outcomes, and associated confidence intervals. Where possible we will meta-analyse the data using a random effects model. We will assess heterogeneity across studies using the I2 statistic (6) and publication bias using Funnel plots and Egger’s test (7). Where appropriate we will perform a sensitivity analysis removing single studies to test for the stability of the effect and explore the impact on the heterogeneity of results, and we described any sources of variation. Where appropriate we will test robustness by removing studies of low quality from the analysis. We plan subgroup analyses for the timing of administration of HPT in relation to pregnancy and organogenesis, and study design (case-control versus cohort), if data are available. Where applicable and where there are sufficient studies, we will undertake meta-regression analysis for item 5 of the NOS scale, which records the comparability of cases and controls on the basis of the design or analysis least-matched (only matched for the most important factor) versus most matched (important additional factors) studies. We will use RevMan or STATA for the analysis where appropriate.

Reporting standards

We will follow the reporting guidelines of the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) (8).

Funding

CH, ES and IO receive funding from the NIHR SPCR Evidence Synthesis Working group. CH is also funded by the NIHR Oxford BRC and is an NIHR Senior Investigator.

Conflicts of interest

We have no conflict of interest to report.

Appendices

Appendix 1. Electronic database literature search strategy

1 Pregnancy Tests/
2 pregnancy test*.ti,ab.
3 1 or 2
4 Norethindrone/
5 Ethinyl Estradiol/
6 (norethindrone or norethisterone or ethinylnortestosterone or ethinyl estradiol or ethinylestradiol).ti,ab.
7 hormon*.ti.
8 4 or 5 or 6 or 7
9 3 and 8
10 (hormon* adj3 pregnancy test*).ti,ab.
11 (primodos or duogonyn).af.
12 9 or 10 or 11
13 exp animals/ not humans.sh.
14 12 not 13


Appendix 2.
List of HPTs included in evidence search.

Market name Manufacturer
Norlutin-A
Norlutin-A Paralut
Pregornot
Amenorone
Amenorone Forte
Disecron
Menstrogen
Norone
Norlestrin
Norlutin A
Orasecron
Paralut
Pregornot
Secrodyl
Gestest Squibb
Pro-Duosterone Roussel
Duphaston Will
Estro-Prodial Barlowe and Cote
Ethisterone Barlowe and Cote
Duogynon Schering AG

 

References

1 https://www.gov.uk/government/publications/report-of-the-commission-on-human-medicines-expert-working-group-on-hormone-pregnancy-tests (accessed 21 Feb 2018).

2 https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/424821/Primodos_public_call_for_evidence_-_April_2015.pdf (accessed 23 Feb 2018).

3     Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed 21 Feb 2018).

4     Lunny C, Knopp-Sihota JA, Fraser SN. Surgery and risk for multiple sclerosis: a systematic review and meta-analysis of case-control studies. BMC Neurol 2013;13:41.

5     Ernst E, Pittler MH. Re-analysis of previous meta-analysis of clinical trials of homeopathy. J Clin Epidemiol 2000;53:1188.

6     Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58.

7     Egger M, Smith GD. Bias in location and selection of studies. BMJ 1998;316:61–6.

8     Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008–12.