Study design
An analytical case-control study was conducted.
Study settings and duration
Cases were recruited from infertility clinics, Women Hospital-HMC, Doha. It is the main governmental hospital providing infertility counselling and management services in the State of Qatar, where most cases are served on the national level coverage. The clinic serves around 3500 patients annually, at an average rate of 300 patients per month. For the year 2017, the clinics covered 1486 new cases as well as 1973 follow up cases. Among those, 42% were Qatari women. Controls were recruited from the antenatal clinic, Women Hospital-HMC, Doha. Antenatal clinics at Women Hospital are the main provider of such service within secondary care level in Qatar, parallel to Primary Health Care Corporation (PHCC). The clinic serves around 60,000 patients annually, at an average rate of 5000 patients per month. For the year 2017, the clinics covered 10,657 new cases and 48,503 follow-up cases. Among those, 40% were Qatari women. The study was conducted during the period from 17th September 2017 to 10th February 2018.
Target population
Inclusion criteria
Cases
Defined as; any Qatari women within the reproductive age (15–49 years), who reports failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse, attending infertility clinic at Women’s Hospital - HMC. Controls: Defined as; any Qatari pregnant woman within the reproductive age (15–49 years), attending antenatal clinic at Women Hospital - HMC. Controls are supposed to be those seeking healthcare (antenatal care) at the same setting (Women’s Hospital) and mostly attributed to the same population pool where cases came from. A ratio of 2:1 was utilized for controls to cases.
Exclusion criteria
For cases
Those with clinical diagnosis of infertility due to male or combined causes.
For controls
Those with prior complain/history of infertility or previously managed to treat infertility and those with the current pregnancy being a product of infertility management.
Sample size calculation and sampling technique
Sample size of 408 (136 cases and 272 controls) was calculated using the following case-control study formula [20]:
n = \( \frac{\left(r+1\right)}{r}X\frac{\left(\ P\ \right)\ x\ \left(\ 1-P\ \right)\ x\ \left(\ Z\beta + Z\alpha\ \right)2}{\left(P1-P2\right)2.} \)
Where:
n: Minimum sample size required [for the cases group]
r: Ratio of control to cases [i.e. 2: 1] = 2
Zα: Standard normal variant for the selected significance level [i.e. 95%] = 1.96
Zβ: Standard normal variant for the desired 80% power = 0.84
OR: The assumed least Odds Ratio foreseen = 2
P: Average proportion exposed
P1: The assumed proportion exposed in the case group that is calculated as the following:
$$ P\; cases\;\mathit{\exp}o=\frac{OR\times P\; controls\kern0.17em expo}{p\; controls\kern0.17em expo\;\left( OR-1+1\right)} $$
P2: The assumed proportion exposed in the control group, where three different proposed risk factors of infertility were reviewed in literature to acquire their prevalence in the studied community. They were the following; Qatari women suffering chlamydial infection (5.3) [21], polycystic ovarian syndrome (18.33%) [22] and, obesity (36.4%) [23]
The average for the three was calculated to be 20%.
Sampling technique
Cases were recruited using a convenient non-probability sampling technique. Controls were selected from those pregnant women attending the antenatal clinic, using probability systematic random sampling technique. List of attendees at the daily appointment sheet was used as a sampling frame where participants were selected systematically each fourth listed, after selecting the first one randomly. The average Qatari women attending the clinic /month = 2000. The clinic runs AM/PM shifts 5 days a week. Average daily attendance AM shift = 50 (two stations each 25 cases/station/shift). The sampling interval (k) was calculated based on the following formula [k = N/n], where N is the population size = 2000/2 shits = 1000 divided by n = 272 = 3.67 rounded into 4.
Research instruments
Data were collected using predesigned interview questionnaire consisting of the following components; Sociodemographic characteristics (age, education level, occupation, and income), marriage history (consanguinity, age at first marriage, recurrent marriage, duration of marriage, husband’s absence), lifestyle history (smoking, alcohol, vigorous exercise, weight gain), menstrual history (age of menarche, regularity of menstrual cycle, duration of menstrual cycle, number of menstrual flow days, menorrhagia, intermenstrual bleeding, dysmenorrhea, secondary amenorrhoea, obstetric history (previous and time of previous conception, stillbirth, miscarriage, ectopic pregnancy, antenatal care, post-partum/abortal infection, gynaecologic history (chronic pelvic pain, abnormal vaginal discharge, painful urination, dyspareunia, gynaecological related fever, pelvic inflammatory disease (PVD), tubal blockage, fibroid uterus, endometriosis or congenital anomaly of the reproductive organ, medical history (diabetes mellitus (DM), thyroid disease, hyperprolactinemia), medication history (cancer treatment, prolonged use of steroid, hormonal therapy, prolonged high dose of nonsteroidal anti-inflammatory drugs (NSAIDs), certain antihypertensive, anti-obesity, antidepressant/antipsychotic), surgical history (caesarean section, dilatation & curettage, appendectomy, pelvic or abdominal surgery), birth control history (contraception use and methods; oral contraceptive pills, intrauterine device, natural/barrier methods), family history (female infertility, menstrual cycle irregularity, early menopause, PCOS, fibroid uterus, DM, thyroid disease), sexual history (knowledge & loyalty to fertility window, coital frequency). The second component of the questionnaire was PHQ – 2 and any patients who scored positive were advised to get referral into a specialized care for further evaluation with the more explicit and specific PHQ-9. Medical review was performed as well as anthropometric measurement of weight, height and body mass index (BMI).
Study variables
Dependent (outcome)
Primary infertility
Women in the reproductive age group who are unable to conceive after 1 year of unprotected sexual intercourse with no previous conceptions.
Secondary infertility
Women in the reproductive age group who are unable to conceive after 1 year of unprotected intercourse following a previous pregnancy.
Independent
Included sociodemographic characteristics, history of marriage, lifestyle, menstrual, obstetric, gynaecological, medical, medication, surgical, birth-control, sexual and family, depression screening using patient health questionnaire (PHQ)-2 score, and anthropometric measurements. BMI was calculated and classified according to the World Health Organization (WHO).
Ethical considerations
Formal approvals were obtained prior to field work from the Arab Board of Medical Specialization, Research Ethics Committee of Women Hospital, Medical Research Center (MRC)-HMC and Institutional Review Board (IRB)-HMC. Informed consent was taken from the willing participants after explaining the aim, objectives and possible benefits from the study following the HMC-IRB standard template of informed consent. All eligible clients were participating totally voluntarily and given the chance to clarify any concerns. The study was conducted with no negative effect on the relationship between the clients and the healthcare provider. Clients were instructed that they could withdraw at any time without any adverse consequences. Confidentiality of the information and privacy have been assured throughout the study. Those screened as positive by the PHQ-2 were advised to go further with the PHQ-9 testing at specialized secondary care.
Quality control measures
Content and face validity of the constructed questionnaire were established by extensive literature review, consultation of experts in the fields of community medicine, maternal health, primary health care and consultants in obstetrics and gynaecology specializing in infertility. The principle investigator performed data collection with the assistance of an assigned data collector (physician). Adequate training of the data collector was done through explaining in details all sections of the questionnaire, as well as, interviewing few clients in front of the assigned physician. The researcher reviewed the questionnaires to ensure completion and consistency, together with extracting the pre-conception weight from electronic medical records to calculate BMI. Prior to data collection, the questionnaire was piloted using a convenient sample of 10 eligible cases and 10 controls to test for the clarity, understandability, feasibility and timeliness to complete the questionnaire. Those piloted participants were later omitted. The completed questionnaires were reviewed on daily basis and revised for data completion and consistency by the PI.
Data analysis
Data entry was done using Statistical Package of Social Science IBM-SPSS© version 22. Student t-test and chi square test were used to compare (mean + standard deviation) and (observed frequency) for numerical and categorical variables, consequently. Crude and adjusted odd ratios (OR) were calculated to examine the risk association between two variables. Variables having p-value equal or less than 0.05 at the bi-variable analysis were considered as statistically significant and were further included in the multivariate logistic regression. Two regression model using forward stepwise method were used; Model I was to obtain risk factors of primary and secondary infertility compared to controls, while Model II was to obtain risk factors of secondary infertility compared to controls with previous conception.