Table 1. Overview of the included studies per outcome.
Outcome | Phthalates and/or bisphenols | Sample size | Time of exposure | Associations | Outcome | Strenghts (S)/Weaknesses (W) |
---|---|---|---|---|---|---|
MATERNAL PREGNANCY OUTCOMES | ||||||
Time to Pregnancy[47 -48] | Phthalates | 2001[47] 501[48] | First trimester[47] Preconceptional inclusion[48] | Positive / negative / null | One pregnancy cohort found no association between first trimester phthalates and recalled time to pregnancy.[47] A preconceptional cohort found several phthalates to be associated with longer time to pregnancy in males, while other phthalates were associated with shorter time to pregnancy in females.[48] | S: 1 preconceptional cohort study, couples with infertility/sterility excluded, urinary samples adjusted for urinary dilution, the preconceptional study explored both males and females W: 1 retrospective analysis in a cohort study based on recalled data. |
BPA | 2001[47] 501[48] | First trimester[47] Preconceptional inclusion[48] | Null | One pregnancy cohort found no association between first trimester BPA and recalled time to pregnancy.[47] A preconceptional cohort found no associations between BPA and time to pregnancy.[48] |
S: 1 preconceptional cohort study, couples with infertility/sterility excluded, urinary samples adjusted for urinary dilution, the preconceptional study explored both males and females W: 1 retrospective analysis in a cohort study based on recalled data |
|
Miscarriage risk[49-50] | BPA | 115[49] 50[50] | First trimester[49-50] | Positive | Both studies found a positive association between the level of BPA and (recurrent) aneuploidy and euploid miscarriages.[49,50] | S: 1 cohort study, only unknown etiology of miscarriages included W: 1 case-control study, blood samples instead of urinary samples |
Maternal blood glucose, triglycerides and fatty acid levels[51-53] | Phthalates | 72[52] 318[53] | First trimester[52] Second trimester[53] | Negative | Women in the highest tertile of urinary MiBP and MBzP had lower blood glucose levels at time of routine GMD screening compared to women in the lowest tertile.[52] Maternal serum MEHP concentrations were associated with lower triglyceride and fatty acid levels during pregnancy.[53] | S: 2 cohort studies, quite accurate about the time of sampling W: Only one sample, 1 study with blood samples, regarding triglycerides and fatty acids only DEHP and MEHP measured |
BPA | 94[51] | Third trimester[51] | Null | No association between BPA and gestational diabetes mellitus was found.[51] | S: Accurate about time of sampling W: Case-control study, only one urinary sample |
|
Preeclampsia [54] | BPA | 58 | Before delivery and umbilical cord blood | Positive | Preeclamptic women have significantly higher concentrations of BPA in placental tissue compared to normotensive pregnant women, while concentrations in serum and cord blood did not differ significantly.[54] | S: Placental biopsies W: Case-control study, blood samples instead of urinary samples, only BPA measured |
FETAL OUTCOMES | ||||||
Gestational age at birth[55-65] | Phthalates | 283[55] 404[56] 86[57] 207[58] 482[59] 482[60] 84[61] 60[62] 72[63] | First trimester[55] Third trimester[56,62] Shortly postpartum or cord blood[57,58,61] Four samples over pregnancy[59-60] Term not specified[63] | Mainly negative | Six studies found a significant association between phthalate exposure and gestational age reduction or preterm delivery.[58-63] One study found no association [58] and two studies found a positive correlation between phthalate exposure and gestational age at delivery.[55, 56] | S: All (subsets from) cohort studies, mainly urinary samples used all corrected for dilution, the majority of studies reported information on gestational age estimation W: Only 2 studies multiple sampling, sampling often taken over broad time, sampling time in one study not specified, various outcome measures used |
BPA | 404[56] 72[63] 567[64] 60[65] | Third trimester[56,65] Term not specified[63] Before delivery[64] | Mainly negative | Three studies found a significant association between BPA and gestational age reduction [63-65] of which in one this association only remained in male infants after stratification for gender.[63] One study found no associations.[56] | S: All cohort studies or subsets from cohort studies, mainly urinary samples used all corrected for dilution, the majority of studies reported information on gestational age estimation W: No multiple sampling, sample often taken over a broad period of time, sampling time in one study not specified, various outcome measures used |
|
Body size measures at birth[53,56-58,64,66-73] | Phthalates | 318[53] 404[56] 86[57] 207[58] 126[66] 119[67] 201[68] | Second trimester[53] Third trimester[56,66,67] Shortly postpartum or cord blood[57,58,68] | Mainly negative | Four studies found a negative effect of phthalates on body size measures at birth.[58,66-68] One study found no associations.[53] Two studies found positive associations between LMW phthalates and head circumference at birth.[56,57] | S: The majority of studies were cohort studies or subsets from cohort studies, based on urinary samples corrected for dilution W: No multiple sampling, sample often taken over a broad period of time |
BPA | 404[56] 567[64] 520[69] 550[70] 97[71] 219[72] 737[73] | Second trimester[69,70] Third trimester[56, 73] Before delivery[64, 71] Cord blood[71] Three samples over pregnancy[72] | Mainly null, study with repeated measurements negative | Four studies found no associations.[56,64,69,70] Two studies, including a study with up to 3 measurements during pregnancy, found a negative association between BPA exposure and body size measures at birth.[71,72] One study found a positive association between BPA and birth weight in male neonates and ponderal index in female neonates.[73] | S: The majority of studies were cohort studies or subsets from cohort studies, based on urinary samples corrected for dilution. One study collected up to three samples W: The majority of studies collected only one sample, which was often taken over a broad period of time. |
|
CHILDHOOD OUTCOMES | ||||||
Childhood growth, prenatal exposure[6,69, 74-78] | Phthalates | 89[74] 234[75] 391[76] | Cord blood[74] Third trimester[75] First & third trimester[76] | Boys: negative Girls: positive | All three studies found prenatal exposure to phthalates to be associated with reduced BMI in boys. Additionally, one of the studies found also a reduced fat mass and waist circumference in boys, not girls.[75] In one of the studies prenatal exposure to phthalates was associated with a higher BMI in girls.[76] | S: All studies were cohort studies, 1 study with repeated sampling, one of the studies collected additionally multiple childhood samples, urinary samples corrected for dilution W: Study with multiple urinary samples did not analyse the measurements separately but averaged the results, 1 smaller study with cord blood |
BPA | 402[6] 520[69] 402[77] 297[78] | First & second trimester[6] Second trimester[69,78] First & third trimester[77] | Positive / negative | Two studies showed that prenatal BPA exposure had a negative effect on BMI in girls, not boys.[6, 78] After stratification for puberty stage in one of these studies, only in prepubertal girls prenatal BPA exposure remained negatively associated with BMI and waist circumference.[6] Two studies, of which one consisted only of boys, reported a positive effect of prenatal BPA exposure on several growth parameters, including height adjusted weight (not significant), waist circumference and BMI.[69,77] | S: All studies were cohort studies with urinary samples, 3 studies collected two pregnancy samples, two of the studies collected additionally multiple childhood samples, all except for one study corrected for urinary dilution, one study performed sensitivity analyses for BPA measurements by trimester W: Studies with multiple urinary samples did not analyse the measurements separately but averaged the results |
|
Childhood growth, childhood exposure [6,75,78-93] | Phthalates | 234[75] Not specified [79] 493[80] 259[81] 387[82] 2884[83] 845[84] 90[85] 76[86] | Toddlers till adolescence[86] Preschoolers[75] Preschool till mid childhood[84] Mid Childhood[80,82,85] Mid childhood till adolescence[79,81,83] | Mainly positive, most for boys | Five studies found a positive effect of childhood exposure to phthalates on childhood growth parameters, including BMI, subscapular skinfold thickness, hip-and waist circumference, predominantly found in boys.[79-83] Two studies found no associations.[85,86] Two studies found a negative association between childhood exposure to phthalates and mid-childhood growth, including, BMI, BSA, weight and height.[75,84] | S: All included studies collected urinary samples of which 1 study with multiple childhood samples, all samples were corrected for dilution |
BPA BPS | 402[6] 297[78] 90[85] 76[86] 39[87] 80[88] 259[89] 2838[90] 3370[91] 2200[92] 1326[93] | Toddlers till adolescence[86] Preschool till mid childhood[87,93] Mid childhood[85,88] Mid childhood till adolescence[89-92] | Mainly positive, not enough evidence to draw conclusions for BPS | Six studies found a positive effect of childhood exposure to BPA on childhood growth parameters measured from preschool till adolescence, including BMI, waist-to-height ratio and hip circumference.[6,89-93] One study found that early childhood exposure was associated with a lower BMI at the age of two, but BMI slopes increased more rapidly between 2 and 5 years of age.[78] No clear difference between the sexes. Two studies found no associations.[87,88] Two studies found a negative association between childhood exposure to BPA and BMI.[85,86] One of these studies also investigated BPS, but no associations were found.[86] | S: All included studies collected urinary samples of which 2 studies with multiple childhood samples, all samples were corrected for dilution, one study also included the newer bisphenol BPS | |
Cardiovascul ar risk, prenatal exposure, outcome measured during childhood[76] | Phthalates | 391[76] | First & third trimester | Negative | In girls the molar sum of both HMW and LMW phthalates were significantly associated with lower systolic blood pressure z-score. No studies have been performed on bisphenols. | S: Cohort study with two maternal urinary samples, reasonable follow-up, samples corrected for urinary dilution W: Urinary samples were averaged in the analysis, only phthalates measured, only blood pressure as a cardiovascular risk outcome |
Cardiovascul ar risk, childhood exposure and outcome[87,94-96] | Phthalates | 2838[94] 667[96] | Mid childhood till adolescence[94,96] | Positive | Both studies reported a positive link between phthalate exposure during childhood and adverse cardiovascular outcomes, including systolic blood pressure z-score and increased albuminuria.[94,96] | S: Childhood urinary samples corrected for urinary dilution, 1 study on blood pressure, 1 on albuminuria W: 2 cross-sectional studies, no studies with multiple sampling |
BPA | 39[87] 770[95] | Preschool till mid childhood[87] Mid childhood till adolescence[95] | Positive | Both studies showed also a positive association between childhood BPA exposure and adverse cardiovascular outcomes, including increased albuminuria and in boys an increased diastolic blood pressure.[87,95] | S: Childhood urinary samples corrected for urinary dilution, 1 study on blood pressure, 1 on albuminuria. W: 1 cross-sectional and one small case study, no studies with multiple sampling, one study measured also lipid levels but did not report on that outcome. |
|
Metabolic risk, childhood exposure and outcome[87-88,91,97-99] | Phthalates | 766[97] 356[98] | Adolescence[97,98] | Positive | Both studies found a positive association between childhood HMW phthalate exposure, mainly DEHP, and the newer DINP and insulin resistance.[97,98] | S: Both studies based on urinary samples corrected for urinary dilution W: No multiple sampling, both cross-sectional studies |
BPA | 39[87] 80[88] 3370[91] 188[99] | Preschool till mid childhood[87] Mid childhood[88,99] Mid childhood till adolescence[91] | Mainly null | One study showed a negative association between childhood BPA exposure and fasting insulin and insulin resistance, unfortunately not adjusted for urinary dilution.[87] Three studies did not find any associations between BPA and childhood metabolic outcomes.[88,91,99] | S: All studies collected urinary samples corrected for urinary dilution, except for one all studies used insulin resistance as an outcome measure W: No multiple sampling |