Use of both smoked and smokeless forms of tobacco is a major cause of preventable morbidity and mortality. It kills half of all its lifetime users ( WHO, 2011) and more than 8 million people each year, out of which, 1.2 million die due to second hand smoke ( WHO, 2019). Toxic and carcinogenic chemicals in tobacco along with other ingredients that are added to them are known to be causally associated with several non-communicable diseases (NCDs) including cancer, especially oral cancer which is the leading cancer among men and the third most common cancer among women in India ( Bhisey, 2012).

Smokeless tobacco (SLT) is “consumed without combustion at the time of use” ( WHO, 2015). It is generally used orally (sucked, chewed, dipped or held in the mouth, used as dentifrice or toothpaste) or nasally resulting in nicotine absorption across the mucous membrane, along with other chemicals. Majority of SLT users, approximately 286 million people, live in low and middle-income countries in South-East Asia region. Three countries, namely India, Bangladesh, and Myanmar, host around 86% of the global users ( NCI &CDC, 2014). As per Global Adult Tobacco survey 2016-17, women accounted for 2% among around 99.5 million adults current smokers. In contrast, 12.8% of women used SLT out of 199.4 million adults ( GATS, 2017).

SLT use is addictive; it leads to oral health problems and plays a contributory role in the development of cardiovascular disorders, fatal ischemic heart disease, stroke, peripheral vascular diseases, peptic ulcers, type 2 diabetes, chronic rhinitis, foetal morbidity and mortality ( WHO, 2015; Inamdar et al., 2015; Suliankatchi and Sinha, 2016; Hossain et al., 2017). The leading health consequences related to SLT use in Southeast Asia include cancers of numerous sites along with poor reproductive outcomes ( World Health Organization. News release 11 ^th Sept 2013).

Tobacco use in India is majorly considered a male-dominant behavior. However, over the past decade, the use of SLT products by Indian women is substantial and increasing, with adverse consequences for oral ( Niaz et al., 2017; Singh et al., 2020) and perinatal health ( Inamdar et al., 2015; Suliankatchi and Sinha, 2016; Nair et al., 2015). Women who use SLT are at risk of oral ( Singh et al., 2020) and pharyngeal cancers ( Niaz et al., 2017; Datta et al., 2014; Sinha et al., 2016; Awan and Patil, 2016), esophageal cancer ( Niaz et al., 2017; Datta et al., 2014; Sinha et al., 2016; Awan and Patil, 2016), cervical cancer, ischemic heart disease (IHD) ( Sinha et al., 2018) and osteoporosis ( Ayo-Yusuf and Olutola, 2014). Compounds in SLT products such as nicotine act as neuro-teratogens as they can cross the placental barrier ( Liao et al., 2012) affecting the fetal development along with other pregnancy complications like pre-term delivery, low-birth weight ( Inamdar et al., 2015; Suliankatchi and Sinha, 2016) increased stillbirth risk ( Hossain et al., 2017) and risk of cancers in the developing fetus ( Rogers et al., 2009). However, there is little evidence that explores the association between SLT use and reproductive health of women. Therefore, we planned to systematically conduct a review on smokeless tobacco (SLT) use and reproductive health among women.

The protocol was registered on PROSPERO on 2 ^nd October 2020 (CRD42020207176). This paper is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( Radhika, 2021).

We did an extensive literature search that described the association between SLT use and selected reproductive outcomes in women. For this, we selected three common reproductive outcomes, namely infertility, menstrual disorders and pelvic inflammatory disease. The search terms revolved around P (population): women, E (exposure): exposure to SLT, C (control): women who were not exposed to SLT, O (outcome): reproductive outcomes in women that included infertility, menstrual disorders, and pelvic inflammatory disorder (PID). The reference period was from 01 January 1990 to 31 ^st October 2020.

Search for infertility among women and SLT use resulted in 1093 results which were run through CADIMA for removal of the duplicate studies, which gave a final of 1062 results (9 from Pubmed; 44 from Wiley; 6 from Emerald; 11 from Cochrane and 992 from ProQuest). that for Menstrual disorders and SLT gave 1330 results. These results were run through CADIMA for removal of the duplicate studies, which gave a final of 1294 results (44 from Pubmed; 19 from Wiley; 25 from Cochrane and 1206 from ProQuest). For PID and SLT use, there were 3929 results. These results were run through CADIMA for removal of the duplicate studies, which gave a final of 3808 results (205 from pubmed; 27 from wiley; 46 from Cochrane and 3530 from proquest) ( Table 1).

The search revealed a total of two studies (prospective cohort, n = 501 and cross sectional, n = 192) addressing our research question related to infertility ( Figure 1, Table 2).

The prospective cohort study used population-based sampling with 501 couples who attempted pregnancy in Michigan and Texas, 2005–2009 (enrolled in the LIFE Study). Results showed that only 2% (n = 28) of men were SLT users and no women used smokeless tobacco. Smokers showed higher cadmium levels than SLT, adjusted for cadmium attenuated the cigarette–time-to-pregnancy (TTP) association, especially among women. Shorter TTP was observed among SLT users in comparison to smokers (FOR [fecundability odds ratio]: 2.86, 95% confidence interval [CI]: 1.47, 5.57). Compared with never users of tobacco, smoking by females (FOR: 0.53, 95% CI: 0.33, 0.85) was individually associated with longer TTP; for males, smoking remained significant (FOR: 0.46, 95% CI: 0.27, 0.79) when modeling partners together ( Sapra et al., 2016).

A cross sectional study carried out in India to evaluate the urinary cotinine levels in three common categories of gynecological complaints, among 192 women of reproductive age, who were not pregnant, and sought treatment from a Government Medical college. Results showed that mean urinary cotinine level in women exposed to secondhand smoking (SHS) was 23.82±12.67 ng/ml. PID was the most common gynecological complaint. Mean urinary cotinine levels in infertile women were 22.42±12.72 ng/ml. The limitations of this study were that the sample size was not enough, other confounding variables were not considered and none of the participants admitted to smoking or use of SLT ( Radhika et al., 2017).

The same study found that mean urinary cotinine levels in women with menstrual complaints was 19.32±10.29 ng/ml. Out of 1330 articles obtained on initial search, this was the only study selected in our review to study the association between SLT and menstrual problems ( Figure 2, Table 3). For the question related to PID, another study ( Simen-Kapeu et al., 2009) in addition to this study was selected ( Figure 3, Table 4). Women with PID had significantly higher urinary cotinine levels = 24.95 (±12.259) ng/ml (p = 0.0144) ( Radhika et al., 2017).

Another study ( Simen-Kapeu et al., 2009) compared the association between tobacco use (smoking and chewing) and the risk of multiple human papillomavirus (HPV) infections and cervical squamous intraepithelial lesions (SILs) in two populations with different exposure. For this, baseline data from 2144 women from Cote d'Ivoire, West Africa and 415 women from Finland, Northern Europe regarding cervical screening, HPV positivity and tobacco use (smoking and chewing habits) was re-analyzed to determine the association between tobacco chewing in Cote d'Ivoire and tobacco smoking in Finland and the age stratified risk of multiple HPV infections and cervical SIL. Results show that in Côte d'Ivoire tobacco chewing (2.6%) was more common than tobacco smoking (1.4%). In 236 cases (eligible women with SIL), mean age of the women was 28.4±6.6 years with low-grade SIL in 165 and high-grade SIL in 71. Tobacco users (smokers and chewers) showed an increased risk of LSIL. Tobacco chewers were at 5 times higher risk for HSIL in both younger age group (<30 years) with OR: 5.5, 95% CI: 1.2-26 and older age group (≥30 years of age) with OR: 5.5, 95% CI: 2.1-14) in comparison to non-chewers. Age-adjusted OR of cervical HSIL was significantly higher among tobacco chewers. Increased risk of LSIL and HSIL (not significant) was found in HPV positive women ≥ 30 years of age who were actively exposed to tobacco through smoking or chewing was seen.

Having multiple HPV infections was common in HPV16 and/or HPV18 infected women (60.4% in Finland and 47.2% in Côte d'Ivoire). There was no increased risk of multiple HPV infections among tobacco consumers. It was found that women ≥ 30 years of age exposed to tobacco through smoking in Finland (OR: 2.2, 95% CI: 0.5-8.7) and chewing in Côte d'Ivoire (OR: 5.5, 95% CI: 2.1-14) had a moderately or highly increased risk of high-grade SIL, respectively. In the latter, the risk was statistically significant. Sampling bias was seen in the study as very few Ivorian women reported smoking evaluation, for this habit alone, and the regression analysis was restricted to Finnish women ( Simen-Kapeu et al., 2009).

The risk of bias assessed using appraisal tool for cross sectional studies (AXIS) for one and ROBIN E for observational studies. Risk of bias for cross sectional study was high due to the small sample size but the those for the prospective studies was low.

This systematically conducted rapid review to study association between SLT use and reproductive health of women yielded a total of three studies with findings from four different countries, namely India, USA, Finland and Cote d’Ivore and Finland. The differences in the study methodologies precluded us from combining the study findings.

Infertility was measured in terms of TTP and Urinary cotinine levels and both were seen to be higher in SLT users. Women with PID had highest mean urinary cotinine levels among the three, followed by infertility and menstrual complaints respectively ( Radhika et al., 2017). Another study showed longer TTP for cotinine levels more than 10ng/ml for SLT users ( Sapra et al., 2016). Another study comparing association between tobacco smoking and chewing with risk of PID in two populations with different exposures showed that SLT users were at a five times higher risk of SIL in comparison to non-chewers irrespective of age ( Simen-Kapeu et al., 2009). Results were however inconclusive regarding strong associations between SLT use and reproductive health in women.

Biologic fertility can be assessed using TTP. A study based in a community setting showed a remarkably comprehensible association between female smoking and sub-fecundity during the most recent waiting TTP ( Kassa and Kebede, 2018).

Cigarette smoking was also seen to be associated with an adverse effect on ovarian function and hence on fertility among women. Evidence suggests that there is an association between cigarette smoking and reduced fertility (risk of delayed conception), even at low doses ( Hatch et al., 2012; Gormack et al., 2015). Since the active metabolite is similar, it is natural to expect some effects on the reproductive outcomes i.e. menstrual function, infertility, PID and pregnancy outcomes with SLT use. However, there is a dearth of good quality studies to ascertain such an association.

Nicotine levels are found to be highest in bidis, followed by chewed tobacco and cigarettes ( Amith et al., 2018). Nevertheless, SLT products are more often abused than smoked tobacco products ( Sharma et al., 2015) and serum nicotine levels remain in significant amounts for a longer time period ( Mala et al., 2016). Like smoked form, SLT use causes alteration of the immune response to infections and has a damaging effect on majority of organ systems in the body including the reproductive system ( Willis et al., 2012). This justifies the biological plausibility between SLT and reproductive outcomes.

To conclude, the number of studies about an association between SLT use and reproductive health of women were very few despite the high prevalence of use in the South East Asia region. Impact of SLT on reproductive health of women requires more research. In this rapid review, we followed the principles of systematic review that offers strength to the study. We have considered the major reproductive outcomes comprehensively. However, we restricted our search to English papers that poses a limitation. In addition, our reference period was from 1990, though it possibly would not have made a difference even if we went beyond that timeline. Though our results show that there might be an association between the SLT and poor reproductive outcomes, we recommend more studies on this topic with robust study designs for conclusive results.

Figshare: PRISMA checklist for ‘Smokeless tobacco use and reproductive outcomes among women: a systematic review’. https://doi.org/10.6084/m9.figshare.16819102 ( Radhika, 2021).

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).