A retrospective cohort study was designed and conducted, accessing records from the General Practice Research Database (GPRD). The GPRD provides anonymised access to electronic primary care medical records and prescription data for a representative 6% of the UK population , and has been extensively validated as a reliable source of GORD information . Diagnoses were identified using Read codes and prescriptions using Prescription Pricing Authority (PPA) codes; all codes for GORD symptoms, outcomes, medications and covariates are available on request. Data were accessed under the Medical Research Council licence for academic groups (protocol reference 07109).
Menopausal symptoms were defined using a wide range of diagnostic and referral codes indicating menopause or menopausal symptoms such as “menopause” and “syndrome menopausal”. Gastro-oesophageal outcomes were categorised in two ways firstly using diagnostic codes specific to GORD (ICD 10 category K21), for example “gastro-oesophageal reflux”, and secondly including Barrett’s Oesophagus and more general codes indicative of symptoms of GORD such as ‘reflux oesophagitis’ and ‘waterbrash’. In recognition of the reported lack of standardisation of GORD recording  in general practice; we also investigated the association between proton-pump inhibitor (PPI) and hormone use.
The original GPRD cohort contained complete records for 102,602 women with a recorded diagnosis of menopause aged between 40–70 at menopause diagnosis (T0). Diagnosis occurred within the cohort window of 01/01/1995 – 31/12/2004 (largely avoiding the subsequent reduction in HRT following reports of increased cancer and cardiovascular risk). Patients with less than 24 months of continuous GP registration were excluded, as were patients with malignancy or pregnancy recorded within the study window. The study window for identifying the cohort was defined as two years from menopause diagnosis (T0 +/− 24 months). Patients who commenced HRT more than 2 years before or after the first record of menopause were excluded, thus a cohort of N = 51,182 women with a record of menopause were within the study window. A sub-cohort of hormone users were matched, according to calendar year, age at menopause, socio-economic status of GP practice, and date closest to menopause, with one user for every two non-users.
In addition to GORD, records were evaluated for hysterectomy, osteoarthritis, non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates and calcium supplement use at menopause diagnosis. Limited by variable reporting within the GPRD, smoking and alcohol status were crudely categorized by “non-user”, “user” or “ex-user” at menopause. Mean BMI was calculated using all BMI readings (kg/m2) within the study window and categorized as underweight (<18.5), normal (18.5 to 24.9), overweight (25 to 29.9), obese (30 to 39.9), morbidly obese (≥40). GP practices were allocated a quintile score for socioeconomic status based in the Index of Multiple Deprivation (IMD) .
Drug exposure definitions
Hormone use incorporated the following proprietary and generic classifications: Combined hormone (conjugated oestrogen with progestogen; estradiol with progestogen); oestrogen-only (oestradiol only; oestradiol, oestriol and oestrone; oestriol only; oestropipate only; conjugated oestrogens only); tibolone; and progestogen (other than for contraception; dydrogesterone; medroxyprogesterone; norethisterone; progesterone). For analytic purposes, the term ‘All hormone (AH)’ incorporates all of the above categories; sensitivity analysis reports on the differences between categories.
Bisphosphonates incorporated bisphosphonates and other drugs affecting bone metabolism including alendronic acid. Calcium supplements comprised calcium gluconate, calcium lactate, and calcium carbonate preparations. Non-steroidal anti-inflammatory drugs comprised all NSAIDs. Exposure to these drugs was defined as at least one prescription record in the time window of 2 years prior to or at menopause diagnosis. Proton pump inhibitors (PPIs) comprised esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole sodium. Use of PPI (categorised as yes/no) was identified both before and after hormone exposure.
The relative risk of GORD or PPI use was estimated as an odds ratio (OR) for hormone use compared to non use. Models were subsequently adjusted for demographic, comorbidity and drug exposures variables. Data management and manipulation was performed using Stata/IC 10. Binomial logistic regression analyses used SPSS v15; the response variable was the presence or absence of GORD or PPI use, and independent variables were either categorical, ordinal or continuous as appropriate. The analysis fitted odds ratios for each of the independent variables with 95% confidence intervals (CIs). The Wald statistic was used to indicate the statistical significance of each fitted logit coefficient (different from zero) corresponding to each independent variable.
Simple regression examined the unadjusted strength of association between each different form of HRT and GORD. Cases and controls were then matched according to calendar year, age at menopause, socio-economic status of GP practice, and date closest to menopause, and simple matched analysis was conducted. The matched dataset was then used to conduct multiple regression analysis taking into account smoking (never/ever/ex), alcohol (never/ever/ex), BMI (subdivided as <18.5, 18.5–24.9, 25–29.9, 30–39.9) and current drug use (NSAID use, calcium supplements and bisphosphonate, duration subdivided into <30 days, and ≥30 days). After extensive exploration, five models for PPI-use and for GORD response were chosen for further detailed analysis on the basis that they allowed for full exploration of the relative effects of risk factors. Model A featured simple regression (unadjusted estimates). Models B to E featured multiple regression (adjusted estimates). Model B incorporated NSAID use (never/ever) calcium use (never/ever), bisphosphonate use (never/ever), BMI, alcohol, and smoking; Model C incorporated NSAID use (never/ever), calcium use (never/ever), bisphosphonates (never/ever); Model D incorporated Model B but exchanged never/ever drug use for drug duration (<30 days, and ≥30 days) plus BMI, alcohol and smoking; Model E incorporated Model D minus BMI, alcohol and smoking. All subgroup analyses were prospectively planned, informed by previous research and clinical expertise. Smoking, alcohol, and BMI had high proportions of missing or unreliable (out of range) data; the final models reported did not include these variables.