Reproduction, immunity, metabolism and behavior are all influenced by the natural and man-made chemicals that intervene in the endocrine system(1). Endocrine disruptors (EDCs) can be identified in everyday products such as plastic bottles, even those for babies, food containers, detergents, flame retardants, toys and cosmetic, as well as in pesticides and various metals(2). Among EDCs, Bisphenol A (BPA) may contribute to weight gain, insulin resistance and pancreatic-cell dysfunction in pregnancy, disturbing the hormonal signaling pathways by binging on estrogen receptors(7), being an instrument for pregnancy complications such as high glucose and high cholesterol(3), preterm birth(4), fetal growth restriction(5), recurrent miscarriages(6) and developmental effects of fetuses(8).
For this reason, the goal of this paper is to review the recent findings on fetal-maternal exposure to BPA and to refresh what we know about the exposure during pregnancy.
What is indeed BPA?
BPA is a chemical mix achieved from a reaction of condensation between phenol and acetone(3). It does not include the phenanthrene nucleus and still it is presumed to be the first synthetic estrogen(9). BPA is widely used by the chemical industry to produce plastic polymers since 1960, because it is considered a linker between chemicals(3).
Being exposed to BPA is very simple. Since 2011, EU prohibited the use of BPA in baby bottles, but yet it is replaced by its structural analogs Bisphenol S (BPS) and Bisphenol F (BPF) in many other consumers goods. It has a negative impact, similar to BPA, like cytotoxicity, genotoxicity, reproductive toxicity, dioxin-like effects and neurotoxicity. In addition, BPS and BPF reveal estrogenic and/or anti-androgenic activities similar or even higher than BPA(10,11). BPA is assimilated by the organism by skin through direct contact and by the digestive system, being metabolized by the intestinal microbiota and by the liver, resulting in BPA monoglucuronide (BPA-G) and BPA sulphate (BPA-S), which is the main metabolite in human(12). The enzymes responsible for BPA glucuronidation did not detect enzyme activity or low activity during the prenatal period(13). Still, the fetus is susceptible to high BPA concentration, since BPA-G and BPA-S are deconjugated and converted back to BPA in the placenta(14).
BPA-G did not show estrogen receptor mediated estrogenic affinity(15), but it conducted proinflammatory effects via the competitive inhibition of PPAR-signaling(16).
BPA and fetal growth restriction
In five fetal growth studies examining the first and second trimester exposure, BPA was measured in biological samples collected during the first or second trimester.
Other group with BPA measuring in the early second trimester in maternal plasma and amniotic fluid of 52 non-smoking women found no relationship between BPA levels in plasma (median: 8.69 ng/mL) or either in amniotic fluid (median: 1.03 ng/mL); it was also shown that while BPA levels in plasma were not correlated with birth weight, the BPA permeability factor (a ratio of fetal-to-maternal BPA concentration) was negatively associated with this growth indicator (R=-0.54; p<0.001)(17).
Another team, using as a biological sample second-trimester amniotic fluid of mothers with singleton-term pregnancies, demonstrated that concentrations between 0.40 and 2 ng/mL resulted in markedly lower birth weight (-241.8 g, p=0.049), concluding that BPA has a non-monotonic effect and that low-level exposure can reduce birth weight(18).
No difference in BPA concentration (mean concentration: 0.5 ng/mL) in maternal serum at 15-16 weeks of pregnancy was found in a case-referent study of 69 cases and 69 referent pools of full-term singleton pregnancies below the 10th percentile of estimated weight for gestational age and neonates(19).
In two of these studies, it was found a contrary association between BPA and lower birth weight. But it is still a question if the composition of fetal plasma is good enough in order to be used in the early second trimester to draw an association.
In the fetal growth studies examining third-trimester exposure, the conclusion was that there is a positive association of BPA in maternal urine with birth weight, particularly in male fetuses, a positive association with ponderal index values in particular in female fetuses, and a decreased third-trimester femoral length in both sexes in two studies(20,21).
In the studies that measured BPA at delivery, some failed to show any correlation between BPA and cord blood(22), while other found that there was a negative association of BPA in maternal and umbilical cord blood with birth weight and an increased risk for low birth weight and small for gestational age, especially in male neonates(23).
In 620 women from China, when BPA was measured in the maternal urine, there was found decreased birth weight and decreased risk for gestational diabetes mellitus, a result that was borderline and not statistically significant – each unit increase in natural log-transformed BPA reduced birth weight by 25.70 g (95% CI; -54.48, 3.07) and ponder index by 0.02 (95% CI; -0.03, 0.00)(24).
In conclusion, no mother how the BPA level was measured, the results are contradictory in all three trimesters, and further investigations are needed in order to make light whether there is an association between the BPA and the restricted fetal growth. Anyhow, nine studies obviously showed a statistically negative association between BPA and fetal growth restriction, in contradiction with others, but taking into account the fact that BPA has a short half-life, this can conduct to measurement errors(5).
BPA and preterm birth
In order to talk about how BPA influences preterm birth, we have to know what exactly preterm means. It is specified as a childbirth that takes place before 37 weeks of gestation and, as we know it, this is a vital issue for the public system in all countries, causing many difficulties at older ages and high mortality and morbidity among children below 5 years old(27,28).
We know that, since 2012, Hunag et al. and Patel et al. tried to demonstrate that there is a link between preterm birth and higher maternal urinary BPA, but others, like Cantonwine et al. and Aker et al. (2019), proved the contrary(29-32). It might be the heterogeneity in biological specimens for BPA exposure evaluation, level and time of exposure, the trimester of exposure and the adjustments that can cause discrepancy in outcomes(33).
The latest studies, a meta-analysis conducted in 2021 by Namat et al., concluded that a significant correlation was found between preterm birth and higher BPA exposure among the populations who had concentrations higher than 2.16 ng/ml (OR 1.92; 95% CI; 1.38, 2.47). In the subgroup analyses by maternal urinary BPA exposure evaluated in different trimesters, a significant association of preterm birth was simply noted when BPA was assessed in the third trimester (OR 1.62; 95% CI; 1.15, 2.09). BPA exposure in the latest trimester may be a vital period for preterm birth, but we don’t know yet if for the all of the compounds of BPA might be the same(33).
BPA and recurrent miscarriages
Recurrent miscarriage and BPA have been studied since 2005, when Osgawara et al. noticed that, in women with recurrent miscarriage, BPA levels were higher compared to the control group (2.59±5.23 versus 0.77±0.38; p=0.024)(25).
After this study, there were a few others that discovered the same thing, and the latest study, by Ao et al., published in the Environmental Research, concluded that environmental exposure to bisphenol analogues is associated with an increased risk of unexplained recurrent miscarriages. Women over 30 years old may be more susceptible to this. They conducted a hospital-based, case-control study with 1180 cases of unexplained recurrent miscarriages and 571 controls in China, from 2014 to 2016, measuring the concentrations of six bisphenol analogues (BPA, BPAF, BPAP, BPB, BPP and BPS) in the urine samples collected at median intervals of 7.6 months after the last miscarriage (interquartile ranges: 4.8-14.7 months). Significantly higher levels of all urinary bisphenols were observed in the cases than the controls(26).
How to reduce exposure to BPA?
The major origin of BPA in our dietary exposure is found in canned foods and beverages, as well as in cosmetics, bottle tops, contact lenses and, as mentioned before, in all polycarbonate plastics(3). Buyers might be exposed to the residual monomer that migrates from the packing of food and drinks or the product that results from the polymer hydrolysis(35).
The National Institute of Health(35) made some practical arrangements for food selection, cooking and storage on how to limit exposure to EDC, which was revised by Rolfo et al.(1,34-36,37) and might be useful for women who want to have a healthy future pregnancy or for those who are already pregnant.
1. It is recommended fresh seasonal food, especially fish, fruits and vegetables.
2. To reduce the consumption of canned fish or frozen seafood to one per week.
3. Use glass jars for tomato sauce and legumes.
4. Drink tap water if possible or buy glass bottles of water.
5. Dodge ready-made food as “heat-and-go” cups or instant soups.
6. Fresh pizza or sandwich without boxes or wrappers.
7. Don’t use popcorn bags for microwave cooking, choose stovetop alternatives.
8. Better use a French press or ceramic drip.
9. Prefer loose tea, better than plastic tea bags.
10. Eliminate burned parts (i.e., meat or pizza) of partially charred/burned foods.
11. Eat maximum one smoked food per month.
12. Try to avoid heat and use only intact containers to heat food and beverages and only for the uses specified by the manufacturer.
13. Do not put polycarbonate plastics in the microwave. Use glass, porcelain or stainless-steel containers for hot foods and liquids in place of plastic containers.
14. Remove the fatty portion of meat before cooking – reduce barbecuing or grilling, especially those over charcoal, preferring other cooking methods.
15. When you cook, make sure you have a proper ventilation in the room and use an appropriate kitchen range hood.
16. Don’t put plastic containers in the dishwasher that are not suitable for high temperatures.
17. Do not recycle worn out plastic containers for food and beverages.
18. Food and beverages should be cool before pouring in plastic containers not suitable for high temperatures.
19. Follow the manufacturer’s instructions for the use of grease-proof paper or film for food packaging (e.g., cling film).
20. Choose for home only BPA-and phthalates-free products.
Regardless of the measurements of BPA levels in the samples of pregnant women, the results were that there is an association between BPA and restricted fetal growth, BPA and preterm birth and between BPA and recurrent miscarriages. Pregnancy is a vital period for the development of the baby regarding cardiovascular, neurological, endocrine, reproductive systems and behaviorally, and it should not be invaded in any way by any endocrine outsider. New limits may be needed for the levels of BPA and for its analogues that were not studied enough since inserted in market and, due to these, new studies must be performed.
Conflict of interests: The authors declare no conflict of interests.