Environmental & occupational exposure & female reproductive dysfunction.

All individuals are exposed to certain chemical, physical, biological, environmental as well as occupational factors. The data pertaining to role of these factors on female reproduction are scanty as compared to male. The available data suggest the adverse effects of certain toxicants, viz., metals such as lead, cadmium and mercury, pesticides such as bis(4-chlorophenyl)-1,1,1-trichloroethane and organic solvent such as benzene, toluene and ionizing radiation on the female reproductive system affecting directly the organ system or impacting in directly through hormonal impairments, molecular alterations, oxidative stress and DNA methylation impairing fertility as well as pregnancy and its outcomes. Thus, there is a need for awareness and prevention programme about the adverse effects of these factors and deterioration of female reproductive health, pregnancy outcome and offspring development as some of these chemicals might affect the developing foetus at very low doses by endocrine disruptive mechanism.

Introduction

With the advent of industrialization, participation of women in work sectors is increasing, and many of them are in reproductive age. Thus, women are exposed to a variety of chemical, physical, biological and psychosocial factors. Effects of occupational exposure of these factors on the female reproductive system may become apparent in the form of alteration in sex hormone levels, diminished sexual desire and potency, menstrual disorders, early menopause, delayed menarche, ovarian dysfunction, declined fertility and adverse pregnancy outcome. Maternal exposure during pregnancy may interrupt foetal development. Exposure to toxic substances may lead to many wide-ranging effects, e.g., intrauterine growth retardation, foetal and postnatal death, birth defect, preterm birth (PTB), disorders in cognitive development and immunological function.

Environmental deterioration can lead to the elevated risk of human exposure to heavy metals and consequently leading to reproductive disorders1. Higher prevalence of birth deficiencies in offspring may be attributed to paternal occupations such as mathematical, physical and computer scientists, photographers and photoprocessors, artists, food service workers, landscapers and groundskeepers, cosmetologists and hairdressers, office and administrative support workers, sawmill workers, chemical workers, petroleum and gas workers, printers, material moving equipment operators and vehicle operators2. Slama and Cordier3 reviewed the data of chemical and physical factors with respect to pregnancy and its outcome. The highest magnitude of effects was observed due to passive smoking on foetal growth followed by lead on pregnancy-induced hypertension and foetal growth and polychlorinated biphenyls (PCBs) on foetal growth. Effect of atmospheric pollutants on foetal growth and preterm delivery was found to be at a lesser magnitude. They also reported that except for air pollutants, the data on non-persistent compounds are little conclusive. The present review provides information on the effects of environmental and occupational factors on female reproduction and outcome.

Metals and female reproduction

Mercury (Hg)

Mercury is a naturally occurring element and a man-made contaminant of the environment. Olfert4 reported a significant relationship between exposure to nitrous oxide and spontaneous abortion, reduced fertility among dental personnel. El-Badry et al5 reported that dental staff faced higher odds of spontaneous abortion, pre-eclampsia and infants small for gestational age (SGA), and this might be linked to mercury-induced oxidative stress. Vejrup et al6 found that women in the highest quintile of mercury exposure delivered offspring with 34 g lower birth weight (LBW), risk of SGA offspring as compared to the lowest quintile exposed women. Elemental mercury exposure might be related with a higher prevalence of irregular menstrual cycles but not with miscarriage7. Another study reported that the prevalence of abdominal pain and dysmenorrhoea was significantly higher among the mercury exposed workers8 (Table I).

Table I

Metals exposure and female reproduction and pregnancy outcome

Exposure	Effects
Mercury (Hg)
Dental personnel exposed to Hg	Limited evidence of SAb, reduced fertility, congenital abnormalities4
Maternal exposure to Hg in pregnancy	Offspring with 34 g LBW and increased risk of SGA6
Dental staff exposed to Hg	SAb, preeclampsia and SGA babies, and this might be due to Hg-induced oxidative stress5
Elemental Hg exposure	Higher prevalence of irregular menstrual cycles7
Hg exposure	Abdominal pain, dysmenorrhoea and abnormal menstruation8
Lead (Pb)
Men occupationally exposed to Pb	Increased risk of infertility and pregnancy delay in wives of men occupationally exposed to Pb9
Girls exposed to environmental Pb	Delay in pubertal development and growth of girls10
Prenatal higher blood Pb level	Preterm delivery, lower head circumference and crown-heel length11
Higher blood and cord Pb level	LBW offsprings of mothers with higher blood Pb and a negative association between cord Pb levels and birth length12
Pregnant women with blood Pb level ≥10 µg/dl	Three-fold higher risk PTB and four-fold of SGA birth13
Pb exposure to women	Risk of SAb but blood Pb (<5 μg/dl) not a risk factor for SAb14
Low to moderate Pb exposure	Risk of SAb15
Cadmium (Cd)
Women living in Cd polluted area	Abnormal menstrual cycle, dysmenorrhoea in unmarried women and sterility in married women16
Cd exposure	Associated with preeclampsia17
Maternal Cd exposure	High-risk of early delivery and LBW18
Low level Cd exposure	Interferes steroid hormones and disrupts steroidogenesis leading to alter sex differentiation and gametogenesis19
Arsenic (As)
As-contaminated drinking water	Negative effect on menarcheal age20 SAb, stillbirth and PTB21 Non-significant risk of PTB and LBW22
As exposure during pregnancy	Decreasing gestational age and lower maternal weight gain23 Six-fold risk of stillbirth, no relation with infant mortality or SAb24 Increases oxidative stress and inflammation in the placenta25
Zinc (Zn)
Role of Zn	Normal growth, development, cellular integrity, protein synthesis, nucleic acid metabolism. Beneficial to infant’s neurobehavioural development26
Maternal Zn deficiency	Infertility and embryo/foetal death, intrauterine growth retardation and teratogenesis27
Mangnese (Mn)
Maternal Mn level	High concentration related with LBW28
Maternal and cord blood Mn	Birth weight elevated with Mn upto 4.18 μg/dl and reducted at higher levels29
Mn exposure	Birth weight increased with Mn upto 3.1 μg/l and reducted at higher levels30
Chromium (Cr)
Female workers exposed to occupational Cr	Increased risk of SAb and threatened abortion31
Female exposed to Cr during pregnancy	Higher risk of PTB (particularly male offsprings)33 and LBW (mainly female offsprings)32
Vanadium (V)
Vanadium exposure through food, water and polluted air	Positive relationship between LBW and maternal urinary V34

SAb, spontaneous abortion; LBW, lower birth weight; SGA, small gestational age; PTB, preterm birth

Lead (Pb)

Occupational and environmental lead exposure has been linked to various health issues such as alterations in growth, endocrine function, organ system and effects on reproduction and outcome. Sallmén et al9 reported increased risk of infertility and pregnancy delay among the wives of men occupationally exposed to lead. There are reports on maternal lead exposure and adverse pregnancy outcomes such as delay in pubertal development and growth among the girls who were exposed to environmental lead10, three-fold higher PTB and four-fold risk of SGA birth among pregnant women with blood lead level ≥10 μg/dl13. LBW offsprings of mothers with higher blood lead level, and a negative relationship between cord blood lead levels and birth length12. Increased blood lead was shown to be significantly associated with reductions in birth weight, head circumference and crown-heel length11. Ahamed et al35 elucidated the possible free radical-mediated mechanism behind PTB due to lead exposure, and lead-induced elevated oxidative stress might be one of the reasons for PTB. Vigeh et al14 found that higher lead level increased the risk of spontaneous abortion. However, low blood lead levels (<5 μg/dl) in early pregnancy may not be a risk factor for spontaneous abortion. Low to moderate lead exposures may elevate the risk of spontaneous abortion which may be dose dependent15.

Cadmium (Cd)

Human are exposed to cadmium by consuming cadmium-contaminated food, inhaling cigarette smoke and during industrial processes such as smelting and electroplating. In cadmium polluted areas significantly higher prevalence of irregular menstrual cycle and dysmenorrhoea in unmarried and sterility in married women have been observed16. Rates of queasiness, spontaneous abortion and stillbirth were significantly higher in married women of polluted area during the first two pregnancies. Mothers exposed to cadmium have a high-risk of early delivery, LBW and traces of cadmium are transferred to the next generation through breast milk18. Kippler et al36 found sex difference between maternal cadmium exposure and birth size that was apparent in girls. A correlation has been found between cadmium and preeclampsia in exposed women17. Low-level exposure to cadmium interferes with the activity of steroid hormones in reproductive organs of both sex and cadmium disrupts steroidogenesis by meddling with the biosynthesis of androgens, oestrogens and progesterone both in vivo and in vitro, thus, leading to disturbed sex differentiation and altered gametogenesis19.

Arsenic (As)

Arsenic has a semi-metallic property and is the naturally occurring element in the earth's crust and highly toxic in its inorganic trivalent form. Human are exposed to arsenic generally through drinking contaminated water and food. Arsenic exposure might have a negative impact on menarche age20, and spontaneous abortion, stillbirth and PTB were significantly higher in the arsenic exposed group21. Yang et al22 found that arsenic exposure was associated non-significantly with the risk of PTB and LBW in area with high arsenic contaminated water. Exposure to arsenic (≥200 μg/l) during pregnancy was linked to six-fold risk of stillbirth, but no relationship was found with infant mortality or spontaneous abortion24. Kwok et al37 found a small but significant relationship between arsenic exposure and birth defects, whereas other outcomes (stillbirth, LBW, childhood stunting and childhood underweight) were not related. Ahmed et al25 have reported that arsenic can deteriorate immune function which might also be responsible for impairment of foetal and infant health, and maternal exposure to arsenic during pregnancy increases oxidative stress and inflammation in the placenta.

Trace elements

It is established that certain metals in trace amounts are essential for the normal growth, development, reproduction and physiological processes. Zinc is an essential element which plays an important role in growth, development, cellular integrity and various biological functions, including nucleic acid metabolism and protein synthesis26. Zinc is also involved in cell division, foetal growth and development. The pilot human studies showed the beneficial effect of prenatal zinc supplementation on infant's neurobehavioural development. Uriu-Adams and Keen27 reported many adverse effects extending from infertility, embryo/foetal death, to intrauterine growth retardation and teratogenesis due to maternal zinc deficiency. About 10 per cent of the human proteome is reported to contain zinc-binding sites38. Copper is another important trace element which is necessary for normal biological functions. It plays a role in maintaining normal foetus development in mammals39. However, at higher level, it may be a reproductive toxicant.

Manganese is also an essential trace element and important for growth, development and cellular functioning. However, at higher dose, it may have toxic effects on reproductive functions. Eum et al28 mentioned that higher concentration of maternal manganese was linked with LBW. An inverted U-shaped association has been reported between maternal blood manganese level and birth weight29. The birth weight was observed to be elevated with manganese levels upto 4.18 μg/dl, whereas a slight reduction occurred at higher manganese levels. Zota et al30 found a non-linear relationship between maternal manganese exposure and birth weight. The birth weight was elevated with manganese levels up to 3.1 μg/l, and then, a small decline was found at higher levels. Xia et al40 observed higher risk of LBW in lowest tertile (≤0.30 μg/g creatinine) as well as highest tertile (≥1.16 μg/g creatinine) manganese level groups. The data suggested that manganese may affect foetal growth by obstructing weight gain.

The data on female reproduction on chromium exposure are scanty as compared to male. The data closely resemble with those reported in experimental studies with respect to Cr(VI) exposure on pregnancy and outcome41. Yang et al31 reported increased risk of spontaneous as well as threatened abortion in female workers who were exposed to high-dose of chromium. Mothers who were exposed to higher chromium levels during pregnancy might have higher risk of delivering LBW infants mainly for female offsprings32 and PTB particularly linked with male infants33. Vanadium exposure in human arises through intake of food, water and polluted air, and an association was found between a vanadium exposure and decrease in birth weight34. A significant positive trend was found between odds of LBW and vanadium level in maternal urine34.

Solvents

Hooiveld et al42 assessed the risks of reproductive disorders and birth defects in offspring of male painters exposed to organic solvents. Increased risk of congenital malformations was observed in painter's offspring in comparison with carpenter's offspring. The risk of LBW children was slightly higher while other outcomes [TTP (time to pregnancy), spontaneous abortion and PTB] did not show higher risks among painters. Hannigan and Bowen43 reported that the children whose mothers were exposed to high concentrations of organic solvents during pregnancy had higher risk of pregnancy complications, developmental delays and neurobehavioural difficulties. These implications were found to be more among toluene abusers. Chen et al44 assessed association between birth weight and exposure to benzene and work stress. They found that birth weight was negatively associated with exposure to benzene and work stress (Table II). Protano et al46 found an association between maternal exposure to benzene or early exposure to aromatic solvents and risk of PTB or a decrease in biparietal diameter growth, while no inferences could be drawn with other pregnancy outcomes.

Table II

Solvent exposure and female reproduction and pregnancy outcome

Exposure	Effects
Exposure to organic solvents	(i) Risk of congenital malformations in offspring of male painters, risk of LBW42(ii) Pregnancy complications, developmental delays and neurobehavioural difficulties in children whose mother exposed to organic solvents43(iii) Reduced fertility (female workers in shoe manufacturing)45
Exposure to benzene and work stress	Decline birth weight44
Exposure to benzene or aromatic solvents during pregnancy	Higher risk of PTB or a decline in biparietal diameter growth, while no conclusion for other pregnancy outcomes46
Gasoline inhalation- petrol pump female workers	Increases menstrual disorders47
Women exposed to CS2	Menstrual disorders, early menopausal age and disturbances in neurohormonal system48
Paternal exposure to CS2	Risk of miscarriages49

CS2, carbon disulphide

Ekpenyong et al47 studied the effects of gasoline inhalation on menstrual and hormonal profile of female petrol pump workers. The menstrual complaints among the exposed and unexposed workers were 37.2 and 28.5 per cent, respectively, and duration of exposure was significantly associated with higher menstrual disorders. There were persistent low levels of serum oestradiol and inconsistent levels of other reproductive hormones. Sallmén et al45 investigated fertility potential of women exposed to organic solvents in shoe manufacturing industries. The organic solvents exposure was found to be hazardous for female reproduction, and association could be related to any of the solvents used in shoe manufacturing i.e., n-hexane and its isomers, ethyl acetate, methyl ethyl ketone, toluene, acetone and dichloromethane. Taskinen et al50 found significant delay in conception among formaldehyde-exposed female wood processing workers, whereas no association was observed between dusts, wood dusts, phenols, organic solvents exposure and TTP. Formaldehyde and organic solvents exposure has an increased risk of spontaneous abortion, endometriosis and adverse effect on fertility50.

Human are also exposed to carbon disulphide (CS2) at work place which is used in the viscose process. Patel et al49 assessed the incidence of miscarriages among wives of CS2-exposed male workers. The incidence of miscarriage was found to be 5.7 and 18.9 per cent among the spouses of workers who were exposed to 1.69 and 12.28 ppm CS2, respectively. Sieja et al48 concluded that reproductive disorders among women exposed to CS2 at the workplace were menstrual disorders, early menopausal age and disturbances in neurohormonal system.

Phthalates/plasticizers

Phthalates are chemicals used to soften and elevate the flexibility of plastic. Phthalates have detrimental effects on children's neurodevelopment and attention deficit hyperactivity disorder while the data are inconclusive related to negative effect of phthalates on gestational age and head circumference, but phthalates exposure affect the reproductive hormonal levels i.e., luteinizing hormone (LH), free testosterone, sex hormone-binding globulin and anogenital distance and thyroid function51. The phthalate levels in urine were significantly higher in pubertal gynecomastia individuals, girls with thelarche and precocious puberty. Colón et al52 found significantly higher levels of phthalates such as dimethyl, diethyl, dibutyl, and di-(2-ethylhexyl) and its major metabolite mono-(2-ethylhexyl) phthalate in 68 per cent thelarche patients while only one control was found with substantial levels of di-isooctyl phthalate indicating role of plasticizers in thelarche (Table III).

Table III

Phthalate exposure and female reproduction and pregnancy outcome

Exposure	Effects
Phthalates exposure on reproductive outcomes and children health	(i) Affect LH, free testosterone, sex hormone-binding globulin and anogenital distance and thyroid function.(ii) Urinery phthalates higher in pubertal gynecomastia individuals, girls with thelarche and precocious puberty51
Level of phthalates in thelarche and control individuals	High levels of phthalates (dimethyl, diethyl, dibutyl and DEH) and its metabolite mono-(2-ethylhexyl) phthalate in thelarche patients52
DEHP metabolite, MBP and MEP exposures during pregnancy	Linked with prenatal sex steroid hormone concentrations but sex steroid hormone levels not associated with infant reproductive outcome53
DEH and its metabolite, MEHP in endometriosis	Women with endometriosis had higher plasma level of DEHP, and 92.6% had detectable level of DEHP and MEHP in the peritoneal fluid54
Phthalate metabolites MBP, MBzP, mono (3-carboxylpropyl) phthalate and four metabolites of DEH phthalate urinary levels	Higher phthalates urinary concentrations of women who delivered PTB55

MEHP, monoethyl hexyl phthalate; DEHP, di-2-ethylhexyl phthalate; MBP, monobutyl phthalate; DEH, di-2-ethylhexyl; MBzP, monobenzyl phthalate; MEP, monoethyl phthalate; LH, luteinizing hormone

Sathyanarayana et al53 found an inverse association between di-2-ethylhexyl phthalate (DEHP) metabolite concentrations and lower total and free testosterone; this persists regardless of foetal sex. An inverse association between monobutyl phthalate (MBP) concentrations and total and free testosterone levels was also found in women carrying male foetuses. There was no significant relation between prenatal hormone concentrations with infant anogenital outcomes. Women with endometriosis had higher plasma level of DEHP, and 92.6 per cent had detectable level of DEHP and/ormono-ethylhexyl phthalate (MEHP) in the peritoneal fluid54. Phthalate metabolites MBP, monobenzyl phthalate (MBzP), mono (3-carboxylpropyl) phthalate and four metabolites of DEHP were found to be higher in urine of women who subsequently delivered PTB55. Thomsen et al56 reported that women exposed to MEP but not MBP, MBzP and MEHP were associated with longer TTP. The data suggest adverse effects of some of the phthalates and their metabolites on female reproduction and pregnancy outcome.

Stress

Women may face physical and mental stress which may affect reproduction. Hjollund et al57 determined the psychological stress during each menstrual cycle among couples who were first time attempting to concieve. No positive association was found between stress and serum concentration of follicle-stimulating hormone, LH, inhibin B, testosterone or estradiol. It has been reported that maternal mental health in pregnancy can impact on foetal development58. The imprinted genes, insulin-like growth factor 2 (IGF2) and H19, are involved in foetal growth, and both are regulated by DNA methylation. These findings suggest that maternal anxiety in pregnancy is related with decreased IGF2/H19 imprinting control region (ICR) DNA methylation in progeny at birth, mainly in female, LBW neonates. ICR DNA methylation may have association with poor maternal mental health and adverse birth outcomes. Earlier, Vrekoussis et al59 have reported that adverse prenatal stimuli, of either maternal or foetal origin, acting on the developing embryo in utero, can lead to the developmental disorders. These include PTB, LBW and the development of several adult diseases from the metabolic syndrome to several neurodevelopmental disorders. Women with depression are more likely to have caesarean delivery, preterm labour, anaemia, diabetes, preeclampsia or hypertension60. Maternal depression was also associated with adverse foetal outcomes such as foetal abnormalities, foetal growth restriction and foetal death. These studies suggest that maternal depression has adverse effect on mother and foetus.

Alcohol/caffeine use

Excess consumption of alcohol during pregnancy by women may be associated with offspring developmental delays and behavioural changes. Ornoy and Ergaz61 observed that the effect of alcohol on the developing foetus was dose dependent. They reported that after very high chronic doses of alcohol, there were 6-10 per cent chances of developing foetus to have foetal alcoholic syndrome (FAS) as revealed by prenatal and postnatal growth deficit, mental retardation, specific craniofacial dysmorphic features, behavioural changes etc. Lower chronic doses of alcohol also have a risk of ‘alcoholic effects’ demonstrated by slight intellectual impairment, behavioural changes and growth disturbances. Alcohol use during pregnancy is related with health complications that adversely affect the mother and foetus; no level of alcohol intake during pregnancy is reported to be safe62. There are inconsistent data on the foetal well-being due to dietary caffeine consumption during pregnancy, especially at levels of 300 mg/day or higher63. Although it is difficult to assess the threat of spontaneous abortion with caffeine use, most of the data do not support an elevated risk of adverse fertility, pregnancy or neurodevelopmental consequences with respect to 300 mg/day or less caffeine consumption. Gaskins et al64 investigated the relation between pre-pregnancy caffeine and caffeinated beverage consumption and risk of spontaneous abortion. They found that coffee consumption at levels ≥4 servings/day was associated with increased risk of spontaneous abortion. The data on caffeine use and female reproduction are inconclusive and needs more studies to confirm the reported findings.

Tobacco smoking/chewing

Shiverick and Salafia65 reviewed the effects of constituents of tobacco and smoking on ovarian, uterine and placental tissues. They reported an adverse effect of smoking on ovarian function which was dose dependent, whereas more reversible effects were seen in implantation and ongoing pregnancy. Smoking may alter fertility potential through effects on uterine-fallopian tube functions that mediate gamete and conceptus transport. The increased miscarriage rate among mothers who smoke may be related to direct effects of nicotine, cadmium and polycyclic aromatic hydrocarbons (PAHs) on trophoblastic invasion and proliferation65. Sapra et al66 reported that female smoking elevated TTP while links with male smoking were ambiguous. Detrimental effects of prenatal tobacco smoking on foetal growth and infant weight have been reported, and one of the mechanisms behind this association is variation in epigenetic programming67. Maternal smoking was observed to be inversely related with insulin-like growth factor II differentially methylated region (IGF2DMR) methylation in newborns, which might be one of the mechanisms through which smoking affect foetal growth. Salama et al68 evaluated the effects of environmental tobacco smoke exposure during pregnancy on neonates. The percentage of full-term babies in non-exposed women was 72 per cent as compared to 67 per cent in exposed group. The weight of newborn was significantly reduced, and neuron-specific enolase (NSE) and soluble E-cadherin (sE-cadherin) were significantly increased in exposed group. The increased morbidity in the neonates of the exposed group could be attributed to cessation of breast feeding and increased NSE.

England et al69 reported that mean birth weight was reduced by 39 and 190 g in snuff users and smokers, respectively. Further, snuff usage was related with elevated to the risk of PTB and preeclampsia. Baba et al70 suggested that snuff users and smokers in early pregnancy elevated risks of SGA births, and smoking cessation in early pregnancy was linked with a larger reduction in risk than smoking cessation at later in pregnancy (Table IV).

Table IV

Personnel habits and female reproduction and pregnancy outcome

Exposure	Effects
Prenatal very high doses of alcohol	6-10% of developing foetus have risk of FAS61
Alcohol during pregnancy	Adversely affect mother and foetus; women consume excess alcohol are at risk for a child with FAS62
Tobacco and smoking	Adverse effect on ovarian function and reversible effects on implantation and ongoing pregnancy. Modify fertility affecting uterine-fallopian tube functions. Miscarriage due to effects of nicotine, Cd and PAHs on trophoblast65
Female smoking	Elevates TTP while links with male smoking are ambiguous66
Prenatal tobacco smoking	Toxic effects of prenatal tobacco smoking on foetal growth and infant weight67
ETS exposure during pregnancy	Risk of SGA and LBW among neonates68
Snuff uses during pregnancy	Reduced birth weight 39 g in snuff users and risk of preterm delivery and preeclampsia69
Snuff uses during early pregnancy	Risks of SGA births70
Smokeless tobacco use in pregnancy	3-fold increased risk of stillbirth and 2-3 fold risk of LBW71
Prenatal smokeless tobacco use	Birth weight reduced 78 g while no association with PTB, hypertension or placental abruption of smokeless tobacco users72
Betel quid chewing during pregnancy	Adverse birth outcomes were five times higher73
Maternal areca nut chewing during pregnancy	Associated with birth weight loss, birth length reduction. Enhanced risk of LBW with simultaneous use of betel quid, cigarette and alcohol74

FAS, foetal alcoholic syndrome; TTP, time to pregnancy; ETS, environmental tobacco smoke; PAHs, polycyclic aromatic hydrocarbons

Consumption of smokeless tobacco in pregnant women showed three-fold higher risk of stillbirth and a two- to three-fold elevated risk in LBW babies71. England et al72 reported that using smokeless tobacco was not significantly related with PTB, hypertension or placental abruption while the mean weight of infants born to smokeless tobacco users was lesser by 78 g. Yang et al73 reported that maternal betel quid chewing and maternal age have adverse effect on birth outcomes. After adjusting for maternal age, adverse birth outcome was five times higher in betel quid-chewing women. They also reported that maternal areca nut chewing was significantly associated with birth weight loss and length reduction. The chances of male newborn rate were significantly lower among aboriginal women with a habit of betel quid chewing during pregnancy. Women using this substance showed 2.4-fold higher risk of LBW and 3.6-fold risk of full-term LBW74 (Table IV).

Pesticides and agrochemicals

Some of the pesticides especially organochlorine have adverse effects on human health including reproduction which depend on the dose, duration and route of exposure. Heeren et al75 reported that infants with birth defects were seven times more likely to be born to mother exposed to chemicals used in gardens and fields and were nearly twice to be born to mothers who were involved in dipping livestock used to prevent ticks. They were 6.5 times more likely to be born to mother who were using plastic containers (formerly contained pesticides) for water (Table V). Thakur et al76 reported significantly higher adverse pregnancy outcomes such as spontaneous abortion (20.6/1000 live births) and premature births (6.7/1000 live births) were in the areas affected by heavy metal and pesticide pollution. Petrelli et al77 found the ratio of abortions/pregnancies for pesticide applicators to be 0.27 and 0.07 for food retailers. Odd ratio for spontaneous abortion after adjusting for the age of wife and smoking habit of parents was 3.8-fold higher in the multiple logistic regression model and 7.6-fold with interaction effects’ model than control (Table V). Certain pesticide exposure among men or women have higher risk of sperm abnormalities, decreased fertility, increased spontaneous abortion, deficit of male children, birth defects or foetal growth retardation78. Rogan and Chen79 mentioned that exposure to bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT) might cause PTB retracting the benefit of lowering infant mortality from malaria at the doses that would be needed in malaria control. Salazar-García et al80 also found an elevated risk of birth defects related with high occupational exposure to DDT. Bastos et al81 reported higher levels of a metabolite of DDT (p, p'-DDE) in 100 per cent infertile women. A relationship between the decreased fecundability ratio and pesticide exposure has also been reported82. Parental occupation in agriculture might escalate the risk of congenital malformations such as birthmarks in the form of haemangioma, orofacial cleft and nervous system impairment and musculoskeletal defects.

Table V

Pesticides and female reproduction and pregnancy outcome

Exposure	Effects
Exposure to agricultural chemicals	Birth defects seven times in offsprings of mother exposed to chemicals used in gardens and fields and twice to born to mothers involved in dipping livestock to prevent ticks and 6.5 times to born to mother using plastic containers (past used for pesticide) for water75
Water pollution due to heavy metals and high pesticide consumption	Spontaneous abortion (SAb), PTB and still births higher in area affected by heavy metal and pesticide pollution76
Pesticide applicators wives	SAb 3.8 times greater in multiple logistic regression model and 7.6 times with interaction effects’ model77
Men or women exposed to pesticides	Risk for sperm abnormalities, decreased fertility, deficit of male children, SAb, birth defects or foetal growth retardation78
Exposure to DDT	DDT quantities that needed in malaria control might cause PTB79 Risk of birth defects with paternal exposure to DDT80
DDT exposure	p,p’-DDE detected in 100% infertile women81
Employment in agriculture	Employment in agriculture on TTP unequivocal; most studies suggest a connection between decreased fecundability ratio and pesticide exposure82
High level of organochlorines	Menstrual disorders and SAbs, and prolonged TTP, reduced birth weight, skewed sex ratio, altered age of sexual development83
Fungicide applicators spouses	Risk for miscarriages, foetal loss in the spouses of applicators84

DDT, bis(4-chlorophenyl)-1,1,1-trichloroethane; DDE, dichlorodiphenyldichloroethylene

Organochlorines are predominant pollutants in humans and effects such as deterioration of semen quality, testicular cancer, menstrual cycle impairments, spontaneous abortions, and extended TTP, tilted sex ratio, reduced birth weight and altered age of sexual development are associated with higher concentrations of organochlorines83. Garry et al84 found a significant increase in the risk for miscarriages and/or foetal loss and lower number of male children born in the spouses of applicators who used fungicides. The overall data suggest a need for awareness programme among workers about potential adverse effect of some of the pesticides on fertility and pregnancy outcome.

Air pollutants

Exposure to indoor air pollution due to burning of biomass fuel is a common major source of domestic pollution in low- and middle-income countries. Tielsch et al85 assessed the health outcomes in early infancy due to exposure to biomass fuel and second-hand tobacco smoke (SHTS). Exposure to biomass fuel was found to be related with a 34 per cent increased incidence of respiratory illness, 49 per cent increased risk of LBW and 21 per cent increased risk of six-month infant mortality. Further, 45 and 30 per cent higher risks of underweight and stunting growth, respectively at six months among exposed infants were also reported. Ballester et al86 mentioned that the prenatal exposure to traffic-related air pollution might also be associated with declined foetal growth. Exposure to traffic-generated air pollution during pregnancy increases the risk of preeclampsia and PTB87. The exposure to air pollutants was found to be related with LBW and PTB and mechanisms of air pollutants affecting foetus health are not fully established88.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs)

Perfluoroalkyl substances have been reported to be associated with alterations in menstrual cycle and fecundity. Lum et al89 found an association between two perfluoroalkyl substances and variations in menstrual cycle length and diminished fecundity. Louis et al90 assessed polyfluoroalkyl substances (PFASs) and pregnancy loss. Seven PFASs were quantified, and no significantly elevated levels of PFASs were found suggesting no association with pregnancy loss.

Perfluorooctanoic acid (PFOA) has applications in several industrial and consumer products. Wu et al91 evaluated the exposure of women to PFOA and the potential hazards to neonates in an electronic waste recycling area. The PFOA concentration was higher in maternal serum from electronic waste recycling area. Maternal PFOA concentrations were significantly different between normal births and adverse birth outcomes i.e., premature delivery, term LBW and stillbirths. Kristensen et al92 reported that daughters exposed to greater levels of PFOA in utero had 5.3 months delay in age of menarche compared with reference group of lower PFOA.

Ionizing radiation

It is established that exposure to ionizing radiation may have adverse effects on human reproduction that depend on dose, duration, intensity and frequency of radiation exposure. Ogilvy-Stuart and Shalet93 reported that the response of the ovary to radiation exposure varied with age, dose and duration. An ovarian exposure to a dose of 4 Gy may cause 30 per cent of sterility in young women, but 100 per cent sterility occurs in women above 40 yr of age (Table VI). Based on experimental data, it has been suggested that ionizing radiation can induce DNA damage in the germ cells which can bring harmful effects in progeny, including miscarriage, LBW and congenital abnormalities94. However, no clear-cutproofs of such effects are seen in epidemiological studies.

Table VI

Radiations and female reproduction and pregnancy outcome

Exposure	Effects
Ionizing radiation	An ovarian exposure to 4 Gy may cause a 30% sterility in young women, 100% sterility in over 40 yr women93
Ionizing radiation	Induce DNA damage in germ cells, harmful effects in progeny, miscarriage, lower birth weight (LBW) and congenital abnormalities based on experimental data. No proofs of such effects in epidemiological studies94
High frequency electromagnetic radiation	Associated with LBW, but only for male newborns, other outcomes were statistically nonsignificant95
Women using visual display terminals in Ist trimester	No significant elevated risk for birth defects and positive findings might be due to unmeasured factors i.e., poor ergonomic conditions, job stress96
Exposure to shortwaves in women	Increased congenital malformations and LBW97

A few reports are also available with regard to non-ionizing radiation and female reproductive health with inconsistent findings. Larsen et al95 reported that high-frequency electromagnetic radiation was associated with LBW, but only for male newborns, and other outcomes were non-significant. Goldhaber et al96 evaluated the risk of miscarriage among women who were using visual display terminals during the first trimester and found no significant risk for birth defects. Positive findings might be due to unmeasured factors such as poor ergonomic conditions or job stress. Lerman et al97 found that exposure to short waves was associated with a significantly increased congenital malformations and LBW (Table VI). The available studies pointed out that ionizing radiation have harmful effect on reproduction, and more epidemiological studies are needed on non-ionizing radiation.

Shift and night work

Chau et al98 reviewed data on the impact of night work on women's reproductive health. A diverse relationship exists between circadian rhythms and reproductive hormones, and this in turn may affect the women reproductive health. However, the impact of night work on female reproduction is inconclusive. Night shift work may elevate menstrual cycle disorder and endometriosis, but evidence is preliminary99. Albert-Sabater et al100 found that nursing staff on the rotating shift did not demonstrate elevated risk of menstrual disorders. Night shift work led to a 50 per cent increase in risk of endometriosis and working more than half of shifts job at night doubled the risk101.

There are certain other occupations that may be accountable for the adverse effects on female reproduction. Bello et al102 reported the median TTP in administrative workers, domestic workers and teachers as 4, 12 and 3 months, respectively. After adjusting confounders, domestic workers had a significantly lower per-cycle probability of conception as compared to administrative workers. The effect of e-waste recycling exposure on birth outcomes has been studied103. Significantly elevated rates of stillbirth, LBW and lower APGAR (Appearance, Pulse, Grimace, Activity, Respiration) scores and birth weight were observed in exposed area births with higher cord blood lead level in neonates.

Conclusion

It is well established that certain chemical exposures during pregnancy may have a profound impact on reproductive health. Some organochlorine chemicals such as di-chloro-diphenyl trichloromethane; metals such as lead, mercury; industrial pollutants such as dioxin, organic solvents, radiations and lifestyle-associated factors i.e., tobacco smoking (active and passive) and excessive intake of alcohol had adverse effect on pregnancy and outcome104. The existing data support that working women have an elevated risk of undesirable reproductive outcomes, even though the data are inconclusive. Epidemiological studies are needed to find out the effects of those reproductive toxicants which have been proved to be toxic in animal models104. There is a need to educate the childbearing women to avoid exposure to the reproductive risk factors and increase the awareness among employers to take appropriate measures to reduce the workplace exposure.