Comparison of Baseline Characteristics, Sociodemographics, and Gynecological Risk Factors Associated with Secondary Infertility of Females in Pakistan

Introduction: Secondary infertility is characterized by the inability to conceive for a period of 1 year, after having previously conceived at least once. Objectives: To explore the risk factors of secondary infertility and compare sociodemographics and anthropometric variables of each studied group. Methods: Study was conducted at University Institute of Public Health, Faculty of Allied Health Sciences, The University of Lahore, collecting data from Gilani Ultrasound Center in 18 months after approval of synopsis. Total 690 females (345 cases and 345 controls) were enrolled. Participants were included in case group if they were 20–45 years of age, having any parity, and confirmed diagnosis of secondary infertility. Results: The mean age of cases and controls was 33.08 ± 4.17 years and 31.37 ± 4.36 years, respectively. The mean body mass index (BMI) in cases was 27.61 ± 4.27 kg/m2, and in controls the mean BMI was 25.52 ± 4.30 kg/m2. There was not a significant difference among religion that shows no association (p = 0.73) with secondary infertility as profession has association with it (p = 0.01). History of polycystic ovary syndrome, pelvic inflammatory disease, endometriosis, uterine fibroids, menorrhagia, intermenstrual bleeding, and history of abortion are associated with secondary infertility. Conclusions: While several sociodemographic features and medical disorders have been associated to secondary infertility, it is vital to stress that not all of these factors are controllable by medical therapy. Factors like age and certain medical issues may be unaffected by intervention. However, for controllable variables like BMI and certain medical diseases, focused therapies and lifestyle changes may reduce the chance of subsequent infertility.


Introduction
Human infertility is a major health problem worldwide having its impact on the social, psychological, economical, and sexual life of a couple.The common definition of infertility is the inability of a couple to conceive following 12-24 months of unprotected intercourse.Infertility can be primary where a couple has never been able to conceive and secondary following a pregnancy. 1Approximately 10%-15% of couples suffer from infertility all over the world. 2 Female factor is responsible in 35% and male factor in 45% of cases, while the rest of the couples either have combination of factors or unexplained infertility. 3,4Infertility is divided into primary and secondary infertility. 4It is recently reported that globally, infertility is a major health issue.Around 40 million couples actively sought treatment for infertility in 2010, of whom 34 million were in developing nations.There were *48.5 million infertile couples worldwide. 5The highest rate of infertility is said to be in females. 6Tubal factor infertility accounts for a large portion of female factor infertility.The most prevalent cause of tubal factor infertility is pelvic inflammatory disease (PID) and acute salpingitis.The incidence of tubal damage after one episode of pelvic infection is *12%, 23% after two episodes, and 54% after three episodes. 7However, the causes of infertility may be different in different geographic parts. 8An infertility evaluation is usually initiated after 1 year of regular unprotected intercourse in women under age 35 and after 6 months of unprotected intercourse in women age 35 years and older.However, the evaluation may be initiated sooner in women with irregular menstrual cycles or known risk factors for infertility, such as endometriosis, a history of PID, or reproductive tract malformations. 9Infertility in women can be diagnosed using various methods. 10Different risk factors are associated to secondary infertility like lifestyle related factors, such as obesity, diet, smoking, alcohol consumption, and chemical environments, and secondary factors related to human infertility such as unsafe methods of childbirth and postpartum period, as well as symptoms of sexually transmitted diseases. 11he other common factors responsible for infertility in females are anovulatory disorder, tubal factors, polycystic ovarian syndrome, peri-tubo-ovarian adhesions, endometriosis, uterine and cervical factors, etc. 12,13 Traditional methods of statistical analysis are to determine a precise reason behind infertility and to provide effective predictors of treatment. 12The relationship between the analyzed factor and treatment outcome can be determined by univariate analysis.Secondary infertility in developing countries is mostly attributable to modifiable risk factors. 14here is a dearth of information on the prevalence and causes of secondary infertility from Pakistan.To date, literature is lacking on local population to explore the determinants of secondary infertility for comparison of multiple logistic regression and Artificial Neural Networks identification, and prediction of secondary infertility is limited in Pakistan and generally around the world.Therefore, this study is designed to explore sociodemographics and risk factors for secondary infertility in local population.After early determination of these risk factors through better modeling technique, we may highlight the issue to stakeholders and health care providers so that they could act for awareness of females and motivate them for modification of possible risk factors.

Methods
A Case-control study was designed by nonprobability consecutive sampling.This study was conducted at University Institute of Public health by taking data from Gilani Ultrasound Center during time of 18 months after approval of synopsis.This study was approved by the Ethics Committee of Gilani Ultrasound Center and The University of Lahore also.A total of 690 females (345 cases and 345 controls) were taken.Inclusion criteria for cases were females with age of 20-45 years, having any parity, and diagnosed as secondary infertility (as per operational definition).Inclusion criteria for control group were females not diagnosed with secondary infertility, couples who were living together for at least 12 months, couples with male factor infertility, and with age of 20-45 years.Exclusion criteria for cases and controls were couples who had not lived together for at least 12 months, couples with male factor infertility, and infertile female with H/O Tuberculosis.The rules and regulations set by the Ethics Committee of University of Lahore were followed while conducting the research, and the rights of the research participants were respected.Written informed consent (attached) was taken from all the participants.A STROBE flow diagram represents how many patients were excluded from study on exclusion criteria (Fig. 1).All information and data collection were kept confidential.Demographic information, that is, age, years since marriage, and duration of infertility, was collected.Complete history and examination were done and recorded.All information was recorded on question answer sheet and analyzed.
All data were entered and analyzed using Stata program.In descriptive analysis, for quantitative data meanstandard deviation and medianinterquartile range were used.Independent sample t-test (where data were normal) and Mann-Whitney U test were applied (where data were not normal).For categorical data frequency (%) was used and Chi-square test was applied to see association between cases and controls and other factors.p-Value £0.05 was considered as significant.

Results
The mean age of cases (females with secondary infertility) and controls was 33.08 -4.17 years and 31.37 -4.36 years, respectively.The median age was statistically higher in cases (34.0 -6 years) than control (30.0 -7 years), p-value <0.05.The mean age at marriage of cases was 24.33 -4.76 years and of control was 24.59 -2.96 years.The median age at marriage was statistically insignificant in cases and controls, that is, 25.0 -6 years and 25.0 -5 years, p-value >0.05.The mean body mass index (BMI) in cases was 27.61 -4.27 kg/m 2 and in controls the mean BMI was 25.52 -4.30 kg/m 2 .The median BMI was statistically higher in cases than controls, that is, 27.64 -7.56 than 24.77 -6.73, p-value <0.05.The mean education of females in cases and control groups was 11.61 -5.72 years and 11.47 -5.43 years.The median education was statistically insignificant in cases and controls, that is, 14.0 -6 and 12.0 -5, respectively, p-value >0.05.The average monthly income was 64.05 -84.20 in cases and was 72.52 -106.85 in control group.The me-dian monthly income was statistically same in cases and control groups, that is, 45.0 -30 and 32.0 -50, p-value >0.05 (Table 1).

Discussion
After 12-24 months of consistent unprotected intercourse, couples who are unable to conceive are said to be infertile.Infertility varies by individuals.In both men and women, the fertility process is complex.Around 10%-15% of all couples experience infertility. 15The single most significant factor affecting both spontaneous and treatment-related conception is female age.The threshold for advanced reproductive age lacks a universally agreed-upon definition; however, it is generally acknowledged that 35 years marks a significant point in terms of fertility. 16In this study patients presenting with secondary infertility were of age, that is, 33.08 -4.17 years.A study was conducted in 2010 by Nosheen, 17 reported mean age in secondary infertility was 32, while Talib reported 29.4 years of mean age in secondary infertility. 18The healthy development of female reproductive functions depends on adipose tissue.The numerous reproductive issues seen in infertile women are caused by an association between fat and hyperinsulinemia, hyperandrogenism, and abnormal hormone production, including leptin. 19,20Factors related to nutrition and lifestyle that impact fertility encompass conditions such as anemia, weight imbalances, and smoking.The American Society for Reproductive Medicine emphasizes that 12% of infertility instances arise from being either underweight or overweight. 21According to current study,  women with obesity had 1.45 times higher chances of secondary infertility.A study found BMI significantly higher in females with secondary infertility. 22Yet, research in China has indicated that the highest incidence of infertility in women is observed among those who are underweight. 23In this study females with PID had higher chances of secondary infertility, that is, 3.77 times, same results have been reported by a study in Peshawar 24 followed by PCOS, that is, 2.03 times, endometriosis, that is, 1.78 times, and uterine fibroids, that is, 1.56 times.By comparing our results with other studies, PCOS, endometriosis, and uterine fibroids are also found to be the cause of secondary infertility. 17,23Sultana and her team documented parallel results in a local study, noting occurrences of ovulation failure in 60% of cases, polycystic ovarian disease in 32%, bilateral tubal occlusion in 8%, and pelvic adhesions in 24%. 25 Another interesting finding in our study was the significant association of abortion with secondary infertility with 5.24 times more chances.A study was conducted in Nigeria in which induced abortion and postabortion sepsis were the most important risk factors for secondary infertility. 26Another study found association between abortion and secondary infertility. 27ur study highlights several significant factors associated with secondary infertility.Female age, particularly after 35 years, emerges as a crucial determinant of fertility.Lifestyle-related factors, such as obesity and diabetes, also play a notable role.In addition, conditions like polycystic ovarian syndrome, endometriosis, and uterine fibroids contribute to secondary infertility.Moreover, tubal disease, often linked to PID, stands out as a major cause of secondary infertility.Importantly, abortion related complications were found to significantly increase the risk of secondary infertility.
Several limitations should be considered when analyzing this secondary infertility research.The small age range of participants may limit the findings' applicability.The cross-sectional research design makes causal linkages and temporal dynamics between risk variables and secondary infertility difficult to establish.Recall bias may affect lifestyle characteristics and medical histories indicated by self-reported data.Finally, a single-center research may not reflect different health care contexts and procedures.Addressing these limitations in future research may strengthen and apply the study's findings.

Conclusion
The purpose of this study was to identify social and demographic factors among females in both case and control groups, such as age, BMI, profession, monthly income, and medical histories such as PCOS, PID, endometriosis, uterine fibroids, menorrhagia, intermenstrual bleeding, and abortion history.While some sociodemographic characteristics and medical illnesses have been linked to secondary infertility, it is important to highlight that not all of these factors are changeable via medical treatment.Age and certain medical issues may be unaffected by intervention.However,  for controllable variables like BMI and certain medical diseases, focused therapies and lifestyle changes may reduce the chance of subsequent infertility.It is critical to grasp the subtle nature of these linkages and to evaluate the constraints of trying to adjust nonmodifiable elements.

Table 1 .
Comparison of Baseline Characteristics of Participants a Results by the z test were considered statistically significant if Z test score is below À1.960 or above +1.960.b Highly significant.c Significant; Mann-Whitney U test was applied.BMI, body mass index; IQR, interquartile range.

Table 2 .
Comparison of Sociodemographic Variables in Both Study Groups