Predictors of Miscarriage in the West of Iran: A Case-Control Study

Abstract
Background: Since the risk factors for miscarriage vary in different societies, the present study was conducted to investigate the effect of the related factors on miscarriage in the west of Iran (Zanjan city). We aimed to determine the modifiable and non-modifiable predictors of miscarriage.
Methods: In this case-control study, 219 cases and 420 controls were selected among those living in the Zanjan (a city located in western Iran) in 2019. Data were collected by a 25-item checklist of medical records available in the comprehensive urban health service center. For assessing the effects of explanatory variables on miscarriage, the multiple logistic regression model was used at a 95% confidence interval. All analysis was conducted by Stata 14 software. 
Results: Short birth interval (less than 36 months) (OR=2.4, p<0.001) and ectopic pregnancy (OR=3.5, p<0.011) increase the odds of miscarriage. In other words, high education reduced the odds of miscarriage (OR:0.07,p<0.001).
Conclusion: In the present study, increasing age, low education level, history of previous coagulation, previous spontaneous abortion, history of previous ectopic pregnancy and short birth intervals (less than 36 month) were associated directly with miscarriage.  
Keywords: Abortion, Case-control study, Iran, Spontaneous

Introduction
Miscarriage means intentional or spontaneous loss of the fetus; it refers to the premature withdrawal of the pregnancy product (during the first 20 weeks of pregnancy) and before its development (1). The global risk of miscarriage rate has been reported to be 10% to 20% of pregnancies (2,3). Based on the latest report by the World Health Organization (WHO), miscarriage increases the risk of mental disorders in pregnant women by 2.5 times. According to WHO report, the most common complications following abortion are infections, hemorrhage, embolism, and physical problems (4). Previous studies showed that the risk of miscarriage is a function of factors like lifestyle, including diet, maternal smoking, alcohol consumption, and other factors such as obesity, maternal age of 35 years and above, previous history of miscarriage, history of extrauterine pregnancy, and paternal age (5-8).
Despite research on multiple known maternal-related factors, it is unknown in more than 50% of couples (9).
In Iran, the miscarriage rate is less available due to its legal limitations, but estimates indicate that more than 5% of maternal mortality is due to abortion and its complications (10). 
Previous studies have suggested that chromosomal abnormalities account for more than 50% of miscarriages. Other factors associated with abortion include aging, gynecological infections, diabetes, inadequate progesterone production, polycystic ovary syndrome, maternal factors such as phospholipid antibodies, a history of two or more miscarriages, obesity, smoking, alcohol, and caffeine consumption. Psychological stress is vitamin D deficiency and anti-epileptic drugs (1,11). Other studies have estimated that about 2-3% of miscarriages are related to hypothyroidism (12). The consequences of miscarriage are widespread, including bleeding, shock, and death. Other complications of abortion comprise emotional reactions such as depression, sleep disorders, anger, marital discord (11).
Several studies have been conducted in different countries to investigate the prevalence and risk factors of miscarriage. In Iran, few studies have been conducted on the causes of miscarriage. The risk factors for miscarriage vary in different societies. Thus, the study was conducted to investigate the role of the related factors on miscarriage in the west of Iran.

Materials and Methods
This case-control study was conducted in Zanjan city (Iran) from April 2019 to March 2019. The Research Council of Hamadan University of Medical Sciences approved the study. Zanjan city includes 36 urban health centers. 
Women refer to urban health centers for periodic checkups during pregnancy. Health data (such as medical history, physical examination, and routine laboratory tests during pregnancy) for these women was recorded. 
The participants of this case-control study were selected among those living in Zanjan (a city located in western Iran) in 2019. The women with miscarriage history were chosen randomly as the case and women with a successful pregnancy history in 2019 as the control. The cases and controls had a pregnancy record in comprehensive urban health service centers. The women with a history of miscarriage at last pregnancy were considered as the case group, and the women with successful pregnancy at later gestation were regarded as a control group. The exclusion criteria were women with a history of intentional abortion and legal abortion. Therefore, women whose health records were incomplete and those having a history of induced abortion or extramarital pregnancy were excluded from the study.
Data were collected by a checklist of contraceptive records available in comprehensive urban health service centers in Zanjan. The checklist had 25 items with demographic characteristics and risk factors for miscarriage. A stillbirth was defined as the birth of a baby with no signs of life at or after 20 weeks’ gestation. The birth weight of a live-born infant of less than 2,500 g, regardless of gestational age, was defined as the Low Birth Weight (LBW) and more than 4,000 g as the High Birth Weight (HBW).
The relationship between each of the independent variables with miscarriage was statistically analyzed using a multiple logistic regression at a 95% confidence level. The backward technique was used for selecting variables. Only those variables whose p-value was≤ 0.20 (in the univariate model) remained in the final model. Analysis was performed using Stata version 11 (StataCorp, College Station, TX, USA). Informed consent was obtained from the subjects to participate in the study. The ethics committee of the Hamadan University of Medical Sciences approved the study protocol.

Table 1. Characteristics of the study population

Table 2. The role of some risk factors on miscarriage according to multivariable logistic regression

* UTI: urinary tract infection, IBP:  interval between pregnancies.

Results
During the study period, 219 miscarriages were diagnosed. Controls were selected randomly. The mean (standard deviation) age of the cases and controls were 32.28 (6.45) and 31.26 (5.67) (p=0.020) years, respectively. The characteristics of the study population are given in detail (Table 1).
The mean difference was analyzed by independent t-test and the difference in ratios by Chi-square test. 
Results from the logistic regression analysis of several binary and continuous predictors of miscarriage are given in table 2. According to the results, there was a direct association between.
There was an inverse association between miscarriage and educational level (OR=0.65,95%CI:0.54,0.77). The OR of miscarriage was 5.80 (95%CI:1.0-33.7) for those women with a history of previous coagulation disease and 3.64 (95%CI:1.39-9.55) for those with a history of previous ectopic pregnancy. Finally, pregnancy interval less than three years was associated with miscarriage (OR=2.5,95%CI: 1.7,3.7). These four associations were statistically significant.
Previous stillbirth (OR=1.28,p=0.635), previous spontaneous abortion (OR=1.09,p=0.697), prior anemia (OR=1.66,p=0.130), previous Urinary Tract Infection (UTI) (OR=1.18,p=0.557), and high blood pressure (OR=1.89,p=0.225) during pregnancy were related to miscarriage, but the associations were not statistically significant.

Discussion 
Miscarriage, also known as spontaneous abortion and pregnancy loss, is a multifactorial complication affected by several risk factors that may vary across communities. The present study revealed the crude and adjusted effect of several predictors that may play a role in miscarriage.
According to the results, miscarriage is directly associated with short birth intervals (less than 36 months). Concerning the role of the gap between pregnancies, it is noteworthy that consecutive pregnancies with short intervals increase the risk of anemia in women and thus disrupt the maternal anemia, oxygen delivery, nutrition, and health of the fetus (13). Rodrigues et al (14) reported that short inter-pregnancy intervals increased the risk of miscarriage and fetal death; also, for women of all ages, short intervals between pregnancies were associated with a higher risk for preterm birth and having infants small for their gestational age (15,16). Furthermore, Nonyane et al (17) showed that the short inter-outcome intervals after stillbirth, neonatal death and spontaneous abortion were associated with a high risk of a similar outcome in the next pregnancy.
The effect of education was significant in the multivariate logistic regression model. Therefore, with an increase in education, unintentional abortion was reduced by 35%. Higher education is usually connected with a higher economic and social status. In this respect, the women with higher socioeconomic status have higher chances of having lower risk factors than other women, including a better lifestyle, awareness of the need for prenatal care and distance, and proper placement between pregnancies. This result was confirmed by Poorolajal et al (18). Also, Vaisanen et al demonstrated that women with basic education had a higher likelihood of abortion than women with academic education (19). Miscarriages usually occur in young women under 20 and in low-income countries. Women in developing countries are more likely to be at risk than other women, including low age at delivery, high and short-term pregnancies, premature birth, low income, inappropriate sexual partner, abortion in unsafe conditions, dropping out of school, and improper use of contraceptives (20).  
Another influential factor was the history of previous ectopic pregnancy, which was related directly to miscarriage (statistically significant). Ectopic pregnancy is a considerable health problem accounting for about 10% of maternal mortality. Women with a history of Recurrent Spontaneous Abortion (RSA) have a higher frequency of ectopic pregnancy than the general population (21,22).
We found a direct association (with a significant statistically) between previous coagulation disease and miscarriage. Previous studies indicated recurrent miscarriage syndrome caused by blood protein or platelet defects as disorders associated with a hemorrhagic tendency or as defects related to a thrombotic tendency (23,24). 
In this study, all the miscarriage cases (which were registered in the comprehensive urban health service centers) during 2020 were included. Thus, the selection bias was minimized. 
We indicated that miscarriage was directly associated with several factors, such as previous stillbirth, previous spontaneous abortion, previous anemia, previous UTI, and high blood pressure during pregnancy. This may be attributed to the rarity of these predictors in both cases and controls, and in fact, many previous investigations have shown that miscarriage is associated with most of these factors. In this case-control study, none of the case and control groups of women had a history of smoking and alcohol use. Hence, the analysis of this variable was impossible.
The present study suffered from several critical limitations. Firstly, we used data recorded in health centers, so the quality and accuracy of the results depend on the quality of the recorded data. This might result in information bias. Secondly, due to the nature of case-control studies, the observed effect may not necessarily be causal; thus, overall, a major longitudinal study with appropriate power and more accurate laboratory study is strongly recommended. In this study, the effect of other factors such as diabetes, social class, and income was not studied as a separate factor, so their survey in future studies is recommended.

Conclusion
In the present study, increasing age, low education level, history of previous coagulation, previous spontaneous abortion, history of previous ectopic pregnancy and short birth intervals (less than 36 month), were associated directly with miscarriage. 
 
Ethics approval and consent to participate 
This case-control study (Code: IR.UMSHA.REC.1399.386) was approved by the research committee of the Hamadan University of Medical Sciences (UMSHA), Hamadan, Iran.

Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of Interest
The authors declare that there is no conflict of interest. 

Funding
This study (code: 9809056534) was funded by the Vice-Chancellor of Research and Technology of Hamadan University of Medical Sciences. The funders had no role in the study design, data collection, and analysis, decision to publish, or manuscript preparation.

Acknowledgements
In this study (ethics code: IR.UMSHA.REC.1398.706), we appreciate the cooperation of experts from comprehensive urban health service centers in data collection. Moreover, all the participants of the study are appreciated for their responsiveness.