Khat chewing in pregnant women associated with prelabor rupture of membranes, evidence from eastern Ethiopia

Introduction Prelabor rupture of membranes (PROM) is a major factor that affects pregnancy outcome. Results from previous studies have suggested that there is an association between pregnant women, khat chewing and preterm birth, but evidence of association with PROM is sparse. This study therefore aims at identifying association between khat chewing in pregnancy and premature rupture of membranes in eastern Ethiopia. Methods A health facility-based cross-sectional study was conducted among 1688 pregnant women who came for delivery service in Harar town, Eastern Ethiopia between June to October in 2016. Data were collected using a pre-tested structured questionnaire and checklist to extract data from the medical record. The association between khat and PROM was examined using logistic regression analysis. A statistical significance was declared at p-value < 0.05. Results Of the 1688 pregnant women who participated in the study, 397 had prelabor rupture of the membranes, representing a proportion of 23.5% [(95% CI: (21.5, 25.6%)]. Of these 397 prelabor rupture of the membranes 198 (31.53%) were from Khat chewing mothers and, 199(18.77%) were from non-khat chewing mothers. After controlling for potential confounders, the multivariable logistic regression analysis revealed the odds of PROM was 1.51 times higher among khat chewed pregnant women [AOR = 1.51; 95% CI; (1.11, 2.07)] were had no khat chewing. Conclusion This study found a significant association between khat chewing in pregnancy and PROM. Efforts to reduce PROM need to consider prevention of khat chewing in pregnancy. A specific strategy need to protect pregnant women from khat chewing.


Introduction
Prelabor rupture of membranes (PROM) is rupture of membranes that occurs before the onset of labor. Membranes rupture before labor and before 37 weeks of gestation is referred to as preterm PROM. Term Prelabor Rupture of Membranes (term PROM) is defined as rupture of the membranes prior to the onset of labor at or beyond 37 weeks gestation [1]. Prelabor rupture of membranes complicates approximately 8% of pregnancies. Prelabor rupture of membranes has been shown to increase the risk of cord prolapse, cord compression and placental abruption, maternal chorioamnionitis, infectious endometritis, neonatal sepsis, and perinatal death. Preterm PROM is responsible for 1 of every 3 preterm births and is associated with signi?cant morbidity for both women and neonate [2][3][4][5][6][7]. Widespread khat chewing in pregnancy, in east African countries, including Ethiopia is recognized as an important public health concern [8,9].
Khat is chewed for its central nervous system stimulant properties.
The major pharmacologically active constituent of the fresh khat leaf is cathinone which is extracted by mastication [10]. Khat chewing in pregnancy women were at risk for preterm labor, labor induction and fetal distress, intra uterine fetal death (IUFD), lower mean hemoglobin concentration at delivery, low birth weight, higher perinatal mortality and congenital malformations [11]. During khat chewing, the leaves are simply kept in the side of the cheek to masticate over time.
Prolonged mastication of khat affects oral hygiene status of chewers.
The incidence of gingival bleeding, inflammation, ulcers on the oral mucosa, and gingival recession was significantly higher in khatchewers [12]. Khat use increase the risk of esophageal cancer [13].
Periodontal disease is associated with PROM [14,15]. Exposure to contaminated sources during khat chewing was reported to cause bacteremia and meningitis [16]. Khat chewing grown with chemical pesticides may cause considerable adverse health effects in khat users [17]. Khat may be a contributing factor in the pathological diseases found among khat users like liver disease, coronary problems, cancers of the digestive tract and incidents of domestic violence [18,19]. Despite impact of khat on adverse pregnancy outcome, pregnant women in the study area were khat chewing. This may be due to lack of information on the health impact of khat during pregnancy. The aim of this study was to perform an investigation on the association of khat chewing in pregnancy and PROM among pregnant women. Data collection: data were collected using a pretested and structured questionnaire. In addition, a checklist was used to extract data from the medical record. The data collection tools were developed by reviewing various previous related data collection instruments and articles [1, [21][22][23]. The questionnaire included sociodemographic characteristics of the participant like (age of mothers, residence of mothers, educational status, and khat chewing in pregnancy), obstetric and gynecologic history (history of abortion, history of preterm, history of PROM,), current pregnancy obstetric and gynecologic situation (ANC, parity and anemia). The original questionnaire was prepared in English language and later translated into the local languages (Amharic and Afan Oromo) for data collection.

Methods
Forward and backward translations were performed by language experts. A six-day training was given to attending midwives and the supervisors who worked as data collectors. The training for data collectors and supervisors addressed issues related to data collection procedures and tools, interviewing techniques, medical record review procedures. A research manual was prepared to guide training, data collection and management. is defined as rupture of the membranes prior to the onset of labour at or beyond 37 weeks gestation [1]. Premature rupture of membranes was the dependent variable in this study and this information was obtained from medical records. It was labelled as "yes" and "no" with a code of 1 and 0, respectively. Khat chewing in pregnancy, age of mothers, residence of mothers, educational status, history of abortion, history of preterm, history of PROM, ANC, parity and anemia were independent variables. Khat chewing in pregnancy was collected based on maternal replay for the question "have you chewed khat during current pregnancy?", and labeled as "yes" and "no" and coded with 1 and 0, respectively. Age of the mother was documented based on maternal reply and later grouped as 15-19 and 20+ with code 1 and 2, respectively for analysis. Maternal education was grouped as "literate" for those who could read and write and all others as "illiterate" and was coded 0 and 1, respectively. Antenatal care visit was obtained from maternal reply and labeled as "yes" and "no" and coded with 1 and 0, respectively. Number of births (parity) were grouped as one primiparity (one delivery), multiparous (2-4 delivery) and grand multiparous (= 5 deliveries) and code with 1, 2 and 3, respectively [20]. History of abortion, history of preterm, and history of PROM was documented based on maternal reply and labeled as "yes" and "no" and coded with 1 and 0, respectively.

Statistical analysis: data were double entered and cleaned using
Epi-Data version 3.1 and analyzed using STATA version 14. Summary and proportions of the variables were computed against PROM. The logistic regression model was used to assess the association between independent and the outcome variable (PROM). Multicollinearity was tested using the Variance Inflation Factor (VIF) and the tolerance test.
Correlation matrix and covariate matrix were tested for the final model. The Hosmer-Lemeshow goodness-of-fit tests were used to test for model fitness [24]. Bivariate analysis was first made and the variables with a p-value less than 0.25 were considered for multivariable analysis, along with maternal age, important predictors of PROM, regardless of the cut-off point for p value. The association between khat chewing in pregnancy and the outcome variable (PROM) was analyzed by controlling for other potential confounding variables, a p value of less than 0.25 in bivariate analysis and maternal age.
Adjusted Odds Ratio (AOR) along with 95% confidence interval was estimated to assess the strength of the association. Statistical significance was declared at a p-value < 0.05.
Ethical approval and consent to participate: the study material Women experienced PROM was treated. Neonates with health problems were treated and immediate referral was also facilitated.

Results
Of the 1688 pregnant women who participated in the study, 397 had prelabor rupture of the membranes, representing a proportion of 23.5% [95% CI:(21.57,7 25.6%)7]. Of these 397 prelabor rupture of the membranes 198(31.53%) were from mother had khat chewing and, 199(18.77%) were from non-khat chewing (Table 1). Bivariable analysis revealed, khat, educational status, history of abortion, history of preterm, history of PROM, ANC, parity, and anemia were found to have a significant association with PROM (Table 1).
Multicollinearity test: multicollinearity was tested using the Variance Inflation Factor (VIF) and tolerance test. VIF for all variables was less than 10, and tolerance test was greater than 0.2. This indicate there was no multicollinearity problem [25] (  (Table 3).

Discussion
This study showed an association between PROM and khat chewing in pregnancy, after controlling for other potential confounders. Similar findings were reported from Yemen [11]. Khat is consumed by plucking off the leaves of the tree and rolling them into little balls that are pushed into the side of the cheek, where they form a large bolus (soft mass of leaves). The practice is usually referred to as khat chewing, but in fact the leaves are simply kept in the side of the cheek to masticate over time. Prolonged mastication of khat affects oral hygiene status of chewers. The incidence of ulcers on the oral mucosa, gingival bleeding, gingival recession is high [12]. Khat use increase the risk of esophageal cancer [13]. Periodontal disease is associated with PROM [14,15]. The link between periodontal disease and preterm delivery is a possible translocation of periopathogenic bacteria to the placenta and amniotic fluid as well as a systemic response to this chronic inflammatory disease [25,26]. Other studies have reported, khat chewing pregnant women were at risk for infection, due to exposure to contaminated sources during chewing [16].  [17]. At term, programmed cell death and activation of catabolic enzymes, such as collagenase and mechanical forces, result in ruptured membranes [8]. The aetiology of PROM has been shown to be multifactorial, and increasing evidence has regarded exposure to environmental pollutants as risk factors for PROM like lead exposure [9,27].
Experiencing anemia was one of the predictors´ of PROM. Similar findings were reported [11,28]. Khat chewing results in lowering mean hemoglobin concentration at delivery [11].  This study rises the discussion around the association between khat chewing in pregnancy and prelabor rupture of the membranes.

Competing interests
The authors declare no competing interests.

Authors' contributions
TA, GE, BS, and DM conceived and designed the paper, involved in data collection, performed the statistical analysis, interpreted the results, wrote and reviewed the manuscript.

Acknowledgments
The authors would like to thank Haramaya University for financial support, the study participants, data collectors, and supervisors for their kind cooperation.