“Risk profile of Qatari women treated for infertility, 2018”

Background: female infertility is a multifactorial condition constituting a worldwide public health problem. Although many potential risk factors of female infertility can be preventable, there is no much attention directed toward preconception care. Aim: to explore the risk profile of infertility among Qatari women and compare risk factors distribution among primary vs. secondary infertility. Methodology: A hospital-based case control study was conducted from September 17th, 2017-February 10th, 2018. Cases (n=136) were enrolled from infertility clinic and controls (pregnant women, n=272), were enrolled from antenatal clinic, Women Hospital, Hamad Medical Corporation (HMC). Interview questionnaire was utilized to collect data about sociodemographic, 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. Logistic regression was used to identify the associated factors to infertility. Statistical significance was set at 0.05. Results: 43 primary and 93 secondary infertility cases were included. Risk factors were age>35 years (OR=3.7), second-hand smoking (OR=2.44), steady weight gain (OR=4.65), recent weight gain (OR=4.87), menstrual cycle irregularities (OR=4.20), fallopian tube blockage (OR=5.45), and symptoms suggestive of sexually transmitted infections (STIs) including chronic lower abdominal/pelvic pain (OR=3.46), abnormal vaginal discharge (OR=3.32) and dyspareunia (OR=7.04). Predictive factors for secondary infertility were; This study attempts to explore the risk factors of female infertility to provide guidance for prevention and early management. We have interviewed infertile females (136) and fertile pregnant females (272) using questionnaires individually. We have classified infertility as primary (women with no previous conception) or secondary (women with previous conception). antenatal clinic systematic random sampling women HMC, Qatar. Cases with male or combined infertility were excluded and controls with prior history of infertility or previously managed to treat infertility and those with the current pregnancy being a product of infertility management were excluded. A sample size of 408 (136 cases, 272 controls) was calculated using a case-control equation, according to the prevalence of common risk factors of female infertility in Qatar. A ratio of 2:1 was utilized for controls to cases, according to the rate of patients per month. Data were collected using predesigned interview questionnaire composed 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 dilatation & curettage, appendectomy, pelvic or abdominal birth control


INTRODUCTION
Infertility is a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. (1,2) Primary infertility is defined as the inability to conceive after one year of unprotected sexual intercourse, with no previous conceptions, while secondary infertility is referred to couples who are unable to conceive after one year of unprotected intercourse following a previous pregnancy. (3,4) About one-third or more of all infertility cases are related to women's causes, another third due to male causes, the remaining are caused by mixed or by unknown factors. (5) Globally, every year, 60 -80 million new couples suffer from infertility. (6) A systematic analysis published by the World Health Organization (WHO) in 2012, revealed that one in every four couples in developing countries are affected with infertility. (2) Infertility affects between 8 and 12% of reproductive-aged couples worldwide. (6,7) However, in some regions, the rates are much higher, reaching up to 30% in some populations such as Middle East and North Africa (MENA) region . (7)(8)(9) Infertility is a cause of instability in the lives of couples, particularly women, raising chances of divorce, lowering chances of entering into marriage and increasing the chances that her husband will marry another wife, in religions where polygyny is permitted, as in the Islamic Arab world. (10) Treatment of infertility can be medically invasive, associated with adverse health problems and my cause psychological stress, anxiety or depression. (11) Female infertility risk factors ranges from non-modifiable such as older age, ethnic background, congenital anomalies of reproductive organ, certain genetic conditions, family history, (12)(13)(14) and modifiable factors that include sociodemographic, STIs, post-abortal or postpartum infections leading to fallopian tube blockage, high risk sexual behaviour (e.g. early age at first sexual intercourse, multiple marriages/relations), environmental hazards (e.g. radiation exposure, chemotherapeutic and toxic agents), lifestyle factors (e.g. obesity, tobacco smoking, alcohol intake, emotional stress, etc.), some medical conditions (as menstrual cycle abnormalities, thyroid diseases, polycystic ovarian syndrome (PCOS)), and prior history of pelvic surgeries (e.g. caesarean section, appendectomy). (15)(16)(17)(18) According to the United Nation's (UN) "World Population Prospects": The 2015 Revision; total fertility rate in Qatar has dropped from 6.11 children per woman in 1965 -1980 to 2.1 in 2010 -2015. Projections show that total fertility will decline further to reach 1.76 in 2020 -2025, which is below the replacement level fertility. The most important factors they unveiled are as increased age at first marriage, increased educational level of Qatari women, and more women integrated in the labour force. (19) The aim of the present study was to explore infertility risk profile among Qatari females that will aid in planning preventive and management strategies to mitigate its burden, and consequently maternal and foetal morbidity, mortality and economic cost on families and on the healthcare system.

METHODOLOGY
This was a case-control study 17 th September 2017-10 th February 2018. Cases were 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, by convenient sampling and controls were pregnant women recruited from antenatal clinic using systematic random sampling technique, at women Hospital, HMC, Qatar. Cases with male or combined infertility were excluded and controls with prior history of infertility or previously managed to treat infertility and those with the current pregnancy being a product of infertility management were excluded. A sample size of 408 (136 cases, 272 controls) was calculated using a case-control equation, according to the prevalence of common risk factors of female infertility in Qatar. A ratio of 2:1 was utilized for controls to cases, according to the rate of patients per month. Data were collected using predesigned interview questionnaire composed 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, postpartum/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 questionnaire was PHQ -2. Medical review was performed as well as anthropometric measurement of weight, height and body mass index (BMI). A pilot study was done on 20 women to test the pre-designed questionnaire and modifications were done accordingly. These cases were not included in the study. The completed questionnaires were reviewed on daily basis and revised for data completion, consistency and coding. 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 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. Approvals were obtained from Research Ethics Committee of Women Hospital, Medical Research Center, and Institutional Review Board of Hamad Medical Corporation. Verbal informed consent was obtained after explaining the aim, objectives and possible benefits from the study. Participation was voluntarily and confidentiality of the information was strictly adhered to by assuring the women that no details about their status will be released and data will be used only for research purpose.

PATIENT AND PUBLIC INVOLVMEMENT
Patients were involved in identifying research priorities. They were interviewed during rotations at infertility clinic to identify the most important and relevant outcome measures. Patients worked with us in formulating the research questions, however it was difficult to involve patients in other areas of the study design due to data protection restriction and ethical considerations. Dissemination strategies will include raising awareness of preventive risk factors of female infertility among Qatari through media such as television programmes, newspaper and social media. Moreover, leaflets will be designed for Primary Health Care Centers to be available at premarital clinics, post-natal clinic and well-women clinic, as well as infertility clinics related to Hamad Medical Corporation.

RESULTS
It was found that 68.4% of infertile participants were suffering from secondary infertility (n = 93), while 31.6% are primary (n = 43) as seen in Figure (1).

Table (1)
shows the distribution of cases and controls according to their sociodemographic characteristics. The mean age of cases and controls was 32.5 + 6.6 years and 30.2 + 5.5 years, subsequently. Regarding the educational level, majority of participants in both groups have completed secondary and/or university education or higher. More than half of cases and more than three quarter of controls had their average monthly income in the high category (> 25.000 Qatari Riyals). Occupation showed no statistical difference between the two groups. Regarding the age at first marriage, 11.7% of infertile women got married at an age of 30 year or above as compared to only 5.1% of controls (p=0.024). In respect to husband's absence, only 14.7% of control reported their husbands being absent from home, compared to as high as 31.6% of infertile participants, the difference was statistically significant (p = 0.001). However, consanguinity, recurrent marriage and duration of menstrual cycle had no statistical significance between groups. Table (2) shows the distribution of study participants according to their lifestyle history. Only 2.2% of cases are currently cigarette smokers, compared to none of their fertile counterparts, who reported never being smokers either currently or previously. Similarly, nine cases (6.6%) are currently or previously smoked water pipe tobacco, while only 1.5% of controls have similar exposure, the difference was statistically significant (p = 0.006). Around 58.1% of cases reported exposure to second hand smoke, the figure was significantly higher than their controls (p = 0.014). None of the study participants reported alcohol consumption. Infertile participants reported practicing vigorous exercise (as swimming, fixed cycling and jugging) more commonly that their controls, 8.8% and 3.3% respectively (p = 0.017). Around one fourth of cases had history of childhood obesity, while the majority of them reported steady weight gain since the start of marriage and/or recently during the last 6 months. On the other hand, controls significantly showed much lower figures. Table (3) demonstrates the distribution of study participants according to gynaecological history. Majority of the cases and controls had normal age of menarche. Cases were more likely to report history of mensural cycle irregularity of duration more than 6 months, as well as history of menorrhagia, intermenstrual bleeding, dysmenorrhea and secondary amenorrhea, with statistical significance differences. Symptoms suggestive of STIs (chronic pelvic pain, abnormal vaginal discharge, painful urination, dyspareunia) were highly significant among cases as compared to controls. Gynaecological related-fever had no statistical significance difference.

Table (4)
shows the distribution of secondary infertility participants and controls according to their obstetric history. Most of secondary infertile cases and controls had their previous pregnancy within last 5 years. Secondary infertile women were more likely to report history of stillbirth, recurrent miscarriage, post-partum/abortal infection, caesarean section, while history of ectopic pregnancy or dilatation & curettage were not found to be statistically significant. Around 15% of secondary infertile cases reported not having antenatal care in their previous pregnancies, compared to only 7.8% of controls, the difference reached statistical significance.

Table (5)
demonstrates the distribution of study participants according to medical/medication history. Hypothyroidism, hyperprolactinemia, depression were reported significantly higher among cases. More than half of the infertility cases were suffering from PCOS, versus 19.1% of their controls. Furthermore, around 17% of cases had fallopian tube blockage, compared to only 2.6% of their fertile controls. Secondary infertile women tended to have higher rate of fallopian tube blockage than women with primary infertility (20.4% vs. 9.3% respectively). Fibroid uterus was reported among 19.6% of cases compared to only 4.0% of controls. Endometrioses and reproductive congenital anomalies showed no statistical significance. More cases reported history of appendectomy compared to controls (8.3% vs. 3.3% respectively). Furthermore, the rate of surgical management of obesity (most commonly sleeve gastrectomy and/or liposuction) was significantly higher among cases compared to their controls (24.3% vs. 13.6% respectively). History of other pelvic surgeries was statistically more frequent amongst cases than controls (18.4% vs. 15.1% respectively). Cases were more likely to have history of prolonged use of steroid, hormonal therapy, prolonged high dose of NSAID, and anti-obesity. However, cancer treatment, anti-hypertensive and antidepressant showed no statistical significant difference.

Table (6)
shows the distribution of study participants according to their birth-control/sexual history. Among contraception users, hormonal control was the most commonly adopted method (71.7% and 50% among cases and controls subsequently), followed by natural/barrier method. However, the use of intrauterine devices as well as duration of birth control use, showed no statistical significant difference between the two groups. Controls were more likely to be aware and loyal to fertility window, while coital frequency showed no statistical significance difference.

Table (7)
demonstrates the distribution of study participants according to their family history. Family history of female infertility was observed in 41.9% of cases compared to 27.6% of controls. Moreover, family history of menstrual cycle irregularity, PCOS, fibroid, DM and thyroid disease were all more distributed among cases, with a significant statistical difference.

Table (8)
illustrates the distribution of study participants according to their WHO-BMI classification/ PHQ-2 results. The mean BMI values for cases was higher compared to their controls (mean+ standard deviation= 31.4 + 6.4 Kg/m 2 and 28.7 + 6.1 Kg/m 2 , respectively Infertile women were more likely to be obese as compared to controls with statistical significance difference. With regard PHQ-2 results, 14% of infertile women screened positive against depression compared to only 5.5% of their controls, with a statistical significant difference. Comparing the distribution of selected significant risk factors between primary and secondary infertility in bivariate analysis, it was found that husband's absence, older age, abnormal vaginal discharge, fallopian tube blockage, history of appendectomy and older age at first marriage, were more commonly found among secondary infertile women. Figure (2) Table (9) describes the result of multivariate logistic regression analysis. Among the forty two entered significant factors only nine were found to be predictors of infertility [Model I: X 2 (12) = 264, p<0.001] including; age>35 years, second hand smoking, steady weight since marriage, recent weight gain, menstrual cycle irregularity, chronic lower abdominal pain, abnormal vaginal discharge, dyspareunia and fallopian tube blockage. Furthermore, four variables were found to be predictors of secondary infertility (among those with history of previous conception) [Model II: X 2 (4) = 57.3, p<0.001], including duration of 5 years or more from previous conception, stillbirth, recurrent miscarriage and post-partum/abortal infection.

DISCUSSION
The studied sample revealed that 68.4% had secondary infertility, while 31.6% had primary infertility. A systematic analysis (2) of national health surveys conducted among 190 countries by Mascarenhas MN et al. (2012) found that secondary infertility was more prevalent than primary (10.5% vs. 1.9% respectively). However, regionally, a study in Kuwait (20) conducted by Omu FE andOmu AE (2002-2007), revealed that among 268 women attending infertility clinic, the rate of primary and secondary infertility were 65.7% and 34.3%, respectively.

Risk factors for female infertility:
In the current study, It was found that age >35 years significantly increased the risk of infertility by around four times, (OR=3.72, 95% CI: 1.41 -9.83, p=0.008). It also revealed that with increasing age, the trend of infertility risk increases in a step manner. This is in consonance with a case-control study conducted in Lusaka, Zambia by Kalima- Munalula MN et al. (2017) who found a significant association between age and female infertility. There was an increasing trend of infertility risk, with increasing age, at age group 20 -29y, the OR was 2.39; and OR of 8.42 at 30 -39y. (21) This study found that second hand smoking (aOR=2.44, 95% CI= 1.26 -4.73, p=0.008) and water-pipe smoking were significantly associated with female infertility (OR=4.75, 95% CI= 1.44 -15.71, p=0.01). In agreement to our study, the association between second-hand smoking and infertility was assessed in a prospective cohort of postmenopausal women by Hyland A. et al. (1993Hyland A. et al. ( -1998. The study established that active-smokers were 1.14 (95% CI= 1.03 -1.26) times more likely to have infertility and 1.26 times (95% CI= 1.16 -1.35) more likely for earlier menopause than never-smoking women. (22) Moreover, the present study showed that obesity is a significant risk factors for female infertility. This was consistent with the results of a casecontrol study of 582 women, Algeria by MAÏ HA et al. (2015). It reported that women with BMI greater than 30 m 2 /kg were 3.26 times more likely to have infertility (OR=3.26, 95% CI= 1.62 -6.80, p=0.019). (23) Similarly, a study conducted in Saudi Arabia, King Fahad Medical City by Rafique M. et al. (2016), revealed that among 127 cases of female infertility, 33.2% were overweight and 48% were obese. In addition, PCOS was present in 30.8% of overweight and 38.7% of obese women. (24) In the current study, it was found that menstrual cycle irregularity is a significant risk of female infertility (aOR=4.20, 95% CI=1.14 -15.49, p=0.031) including oligomenorrhea, menorrhagia, dysmenorrhea and intermenstrual bleeding. Similarly, Shamila S et al. (2011) in their survey found that menstrual cycle irregularity was a common observation reported among infertile females in the three study areas (40%, 44.85% and 44.11% respectively) and was positively correlated with female infertility (p< 0.01). (25) Likewise, a case-control study in south-eastern Iran conducted by Ansari H et al. (2016), reported that women with irregular menstruation were nearly 4 times more likely to have secondary infertility, compared to their regular cycle counterparts (aOR=3.91, 95% CI= 1.5 -6.7, p<0.05). (26) A study conducted in Korea by Kwon SK et al. (2014), found that among the studied 1080 women suffering secondary amenorrhea, PCOS was the most common cause (48.4%). (27) It was also found in this study that PCOS increased the risk of female infertility by nearly 5 times and these results correlate with the studies concerning the percentage of women suffering infertility problems due to PCOS by Wendy A et al. (54.6%) (28) , Susan M. et al. (40%) (29) and Kristi P et al. (56%). (30) The present study found that symptoms suggestive of STIs were highly correlated with female infertility; dyspareunia (OR=7.04, 95% CI= 2.76 -17.95, p=0.001), while chronic lower abdominal pain or abnormal vaginal discharge increased the risk of infertility by more than three times. In Nigeria, Ogbu GI. et al. (2017) studied the relationship between Chlamydia trachomatis infection and tubal infertility found a statistically significant association between positive C. trachomatis antibody titre among cases with tubal factor infertility (75.0%) compared with controls (22.2%). They concluded that the clinical feature having the potential of identifying woman at high risk for Chlamydia infection were vaginal discharge (24.5%), followed by dysmenorrhea (24.5%) and lower abdominal pain (23.1%). (31) The present study also demonstrated that fallopian tube blockage is a risk factor for female infertility (OR=5.45, 95% CI= 1.75 -16.95, p=0.003). Fallopian tube blockage was much more common in secondary infertile females (20.4%) compared to only 9.3% of primary infertile. Tubal blockage is usually associated with chronic untreated STIs/PID, where screening could play a significant role.
In this study, hypothyroidism and hyperprolactinemia were found to be predictors for female infertility. This was also seen in a study by Hymavathi k et al. (2016), India to investigate the correlation of thyroid and prolactin hormones levels with female infertility. The study found that 27% of women with primary infertility were hypothyroid and 7% were hyperthyroid. Among those with secondary infertility the corresponding figures were 5% and 2% respectively. Additionally, hyperprolactinemia was detected in 37% of infertile cases, more commonly among primary infertile women (79.4%) as compared to 20.6% secondary infertile. In addition, history of appendectomy was found to be an independent risk factor for female infertility, in present study. On contrary, a meta-analysis by Elraiyah T et al. (2014) showed that previous appendectomy is not significantly associated with increased incidence of infertility in women, (OR= 1.03, 95% CI= 0.86 -1.24, p = 0.71). (32) Awareness and loyalty to fertility window were found in the current study to be protective against infertility. A cross-sectional study of fertility-awareness among women seeking fertility assistance in Australia by Hampton KD et al. (2013) found that 68.2% believed they had timed intercourse mainly within the fertile, but only 12.7% could accurately identify this window. Most infertile women were graded by the study as having either no fertility-awareness (11.8%) or poor fertility-awareness (52.5%). (33) Additionally, another study by Blake D et al. (1997), has investigated the fertility-awareness of infertile women seeking fertility assistance, they found that 74% of participants could not accurately identify the fertile window. (34)

Secondary infertility risk factors:
The current study showed that recurrent miscarriages is significantly associated with secondary infertility and women with a history of stillbirth were 2.63 likely to be secondary infertile. History of post-partum / post-abortal infection and caesarean section were also found to be significant predictors of secondary infertility in this study. In agreement, Dhont N et al. (2009) in their study conducted in Rwanda, found that secondary infertile women were two times more likely to have history of an adverse pregnancy outcome (miscarriage / ectopic pregnancy), aOR =1.89, 95% CI= 1.17 -3.04), history of stillbirth (aOR= 7.52, 95% CI= 2.97 -19.01), history of postpartum infection (aOR= 11.49, 95% CI= 3.31 -39.89) or history of caesarean section (aOR= 11.49, 95% CI= 3.31 -39.89) compared to their controls. (35)

CONCLUSION
Infertility is a multifactorial complex disease that remains a significant burden for the individuals, families and communities. Several modifiable risk factors were found to be predictors of female infertility among Qatari females that maybe be considered for planning of better reproductive health care. Older age and delayed age at first marriage beyond 30 years were found to be independent risk factors for infertility. Lifestyle pattern including smoking whether water pipe of second hand, obesity, as well as symptoms suggestive of STIs can contribute significantly to infertile status. Furthermore, menstrual cycle abnormalities, PCOS, tubal blockage, fibroid, hyperthyroidism, hyperprolactinemia, appendectomy, post-partum infection, caesarean section, recurrent miscarriage, stillbirth, were all found to be risk factors of female infertility. Conversely, higher education/income and fertility window awareness were found to be protective against infertility. Therefore, primary prevention as well as screening and early management using cost-effective interventions targeting mainly modifiable risk factors are essential components of reproductive health care planning. Moreover, delivering integrated care through utilization of premarital, well women, antenatal, postnatal, and family planning clinics to raise awareness and screen for related risk factors. • Director of obstetrics and gynaecology department was informed and permission was obtained.

LIST OF ABBREVIATIONS
• Participation was voluntarily and clients were instructed that they could withdraw at any time without any adverse consequences.
• Confidentiality and privacy have been assured throughout the study.
• Participants scored positive in PHQ-2 were advised for further assessment and referral.
The following approvals were obtained: A. Women's Hospital-HMC. B. Medical Research Center-HMC. C. Institutional Review Board (IRB)-HMC