Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

BACKGROUND: Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. METHODS: The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. RESULTS: In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (ß = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. CONCLUSIONS: As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Sex difference of pre- and post-natal exposure to six developmental neurotoxicants on intellectual abilities: a systematic review and meta-analysis of human studies.

BACKGROUND: Early life exposure to lead, mercury, polychlorinated biphenyls (PCBs), polybromide diphenyl ethers (PBDEs), organophosphate pesticides (OPPs), and phthalates have been associated with lowered IQ in children. In some studies, these neurotoxicants impact males and females differently. We aimed to examine the sex-specific effects of exposure to developmental neurotoxicants on intelligence (IQ) in a systematic review and meta-analysis. METHOD: We screened abstracts published in PsychINFO and PubMed before December 31st, 2021, for empirical studies of six neurotoxicants (lead, mercury, PCBs, PBDEs, OPPs, and phthalates) that (1) used an individualized biomarker; (2) measured exposure during the prenatal period or before age six; and (3) provided effect estimates on general, nonverbal, and/or verbal IQ by sex. We assessed each study for risk of bias and evaluated the certainty of the evidence using Navigation Guide. We performed separate random effect meta-analyses by sex and timing of exposure with subgroup analyses by neurotoxicant. RESULTS: Fifty-one studies were included in the systematic review and 20 in the meta-analysis. Prenatal exposure to developmental neurotoxicants was associated with decreased general and nonverbal IQ in males, especially for lead. No significant effects were found for verbal IQ, or postnatal lead exposure and general IQ. Due to the limited number of studies, we were unable to analyze postnatal effects of any of the other neurotoxicants. CONCLUSION: During fetal development, males may be more vulnerable than females to general and nonverbal intellectual deficits from neurotoxic exposures, especially from lead. More research is needed to examine the nuanced sex-specific effects found for postnatal exposure to toxic chemicals.

Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort.

OBJECTIVE: Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride's developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6-12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort. METHODS: We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUFCRE). Children were administered the McCarthy Scales of Children's Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6-12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUFCRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUFCRE and child sex as well as for MUFCRE and time point on children's IQ. All models controlled for relevant available covariates. RESULTS: The mean/median MUFCRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64-1.11 mg/L). A 0.5 mg/L increase in MUFCRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUFCRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUFCRE and child sex or MUFCRE and time were observed. CONCLUSION: The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities.

Parenthood desire, childbearing plans and oocyte utilization among women who previously underwent planned oocyte cryopreservation.

RESEARCH QUESTION: To examine the motivations, life circumstances and parenthood aspirations of a cohort of women who underwent planned oocyte cryopreservation (POC) at a Canadian academic IVF centre. DESIGN: A single-site, cross-sectional, anonymous quantitative study using a study-specific questionnaire administrated via SurveyMonkey®. Of the 224 women who completed at least one POC cycle between 2012 and 2018, 198 were reached by email and invited to participate. RESULTS: Of the 98 (49.5%) questionnaires returned, 86 were fully completed and were analysed. Mean age at first POC cycle was 35.7 ± 2.4 (range 27-43) and at survey was 37.7 ± 2.5 years. At POC, 77% were single and 97.7% childless. At survey, 96% had not attempted to use their cryopreserved oocytes, yet 26 (30%) had tried natural conception or fertility treatments. Of these, three conceived naturally and two by assisted reproduction. Eighty-five per cent expressed a strong motherhood desire and 67.1% indicated that usage of their cryopreserved oocytes was mostly contingent on relationship status. Many expressed a desire for shared genetic parenthood within a committed relationship. Forty-seven per cent did not want to carry a pregnancy beyond the age of 46. CONCLUSION: The findings of this study confirm the central role of age and relationship status in influencing women's POC decisions and oocyte utilization plans. The late age at POC could be explained by women using it toward the end of their peak reproductive years to leverage their remaining chances of genetic motherhood. Surveying women at later points following POC would help to gain a more comprehensive picture of their oocyte utilization and disposition plans.

Assessing the quality of decision-making for planned oocyte cryopreservation.

PURPOSE: This survey study aims to examine the quality of planned oocyte cryopreservation (POC) decision-making in the domains of decision change, decision difficulty, decision regret and informed choice. METHODS: Of the 224 women who completed at least one POC cycle between 2012 and 2018 at a Canadian academic IVF centre, 198 were reachable by email for anonymous survey participation. RESULTS: Ninety-eight questionnaires were returned (response rate 49.5%). Of these, 86 fully completed questionnaires were analyzed for this study. Eighty-eight percent of respondents stated that it was a 'good decision' to cryopreserve oocytes, in retrospect. Despite this, 31% found the decision-making process to be 'difficult'. Three in five (61%) would have made 'exactly the same' decision without any change, yet slightly over a third (35%) would have made a 'similar' decision, but with option-related changes and process-related changes. A negative correlation between 'decision regret' and 'informed choice' was found (p < .005). Those who stated that they would have made exactly the 'same' POC decision were found to have a significantly higher 'informed choice' score compared to others who would have made a 'similar' or 'completely different' decision, in retrospect (p < .001). Respondents with lesser 'decision regret' were significantly more likely to appraise their decision as a well-informed choice (p < .001). CONCLUSIONS: Our findings show that high-quality POC decision-making is accompanied by the perception of being able to make an informed choice, which can be achieved by providing patients with adequate information and individualized counselling to help patients set realistic expectations of cycle outcomes.

Determinants of gestational surrogates' satisfaction in relation to the characteristics of surrogacy cases.

RESEARCH QUESTION: The study undertook an evaluation of the retrospective experiences of gestational surrogates within a Canadian context. DESIGN: Data were collected using an anonymous online survey from June 2016 to February 2017 with participants recruited from the Canadian surrogacy community and the internet. The characteristics of surrogacy arrangements carried out by the participants, factors influencing their surrogacy satisfaction, the impact of surrogacy on their family functioning, and their attitudes towards carrying a pregnancy for different types of intended parents were analysed. RESULTS: A total of 184 gestational surrogates (mean age at surrogacy 32 years, range 21-48 years) who were involved in 287 arrangements completed a study-specific survey. More than three-quarters of these cases involved an agency (225 cases, 78.4%). Most of the intended parents were heterosexual couples (158, 55.1%), followed by same-sex male couples (113, 39.4%). More than one-third of these cases were for non-residents from 15 different countries (n = 108, 37.6%). The two main determinants of surrogates' satisfaction were being a surrogate for domestic intended parents (P < 0.05) and having a viable pregnancy outcome (P < 0.005). Nine out of ten participants were comfortable with carrying a pregnancy for same-sex male couples (93.4%) and cancer survivors (89.6%), yet less than one-third (30.7%) were comfortable with being a surrogate for heterosexual couples at advanced ages of over 50 years. CONCLUSIONS: The findings suggest that many intended parents, including same-sex male couples and non-residents, used Canadian surrogacy services to build their families. A better understanding of the fundamentals contributing to positive experiences would help clinicians develop better practice models to care for the well-being of surrogates.

Prenatal fluoride exposure, offspring visual acuity and autonomic nervous system function in 6-month-old infants.

BACKGROUND: Prenatal fluoride exposure can have adverse effects on children's development; however, associations with visual and cardiac autonomic nervous system functioning are unknown. We examined associations between prenatal fluoride exposure and visual acuity and heart rate variability (HRV) in 6-month-old infants. METHODS: We used data from Canadian mother-infant pairs participating in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort. We estimated prenatal fluoride exposure using: i) fluoride concentration in drinking water (mg/L), ii) maternal urinary fluoride adjusted for specific gravity (MUFSG; mg/L) and averaged across pregnancy, and iii) maternal fluoride intake (µg/kg/day) from consumption of water, tea, and coffee, adjusted for maternal body weight (kg). We used multivariable linear regression to examine associations between each measure of fluoride exposure and Teller Acuity Card visual acuity scores (n = 435) and assessed HRV (n = 400) using two measures: root mean square of successive differences (RMSSD) and the standard deviation of N-N intervals (SDNN) measured at 6-months of age. RESULTS: Median (IQR) values for water fluoride, MUFSG, and daily fluoride intake were 0.20 (IQR: 0.13-0.56) mg/L; 0.44 (0.28-0.70) mg/L and 4.82 (2.58-10.83) µg/kg/day, respectively. After adjustment for confounding variables, water fluoride concentration was associated with poorer infant visual acuity (B = -1.51; 95 % CI: -2.14,-0.88) and HRV as indicated by lower RMSSD (B = -1.60; 95 % CI: -2.74,-0.46) but not SDNN. Maternal fluoride intake was also associated with poorer visual acuity (B = -0.82; 95 % CI: -1.35,-0.29) and lower RMSSD (B = -1.22; 95 % CI: -2.15,-0.30). No significant associations were observed between MUFSG and visual acuity or HRV. CONCLUSION: Fluoride in drinking water was associated with reduced visual acuity and alterations in cardiac autonomic function in infancy, adding to the growing body of evidence suggesting fluoride's developmental neurotoxicity.

Performance of the Social Responsiveness Scale-2 for the Assessment of Autistic Behaviors in a Sample of Canadian Preschool-Aged Children.

Behavioral traits of autism spectrum disorder (ASD) typically present in early childhood, underscoring the importance of screening tools for the early identification of ASD. The current study compared scores on the Social Responsiveness Scale-Second Edition (SRS-2) Preschool Form between the US standardization sample (n = 247) and a Canadian cohort of preschool-aged children (n = 595) recruited from the Maternal-Infant Research on Environmental Chemicals (MIREC) study. In the MIREC sample, we examined whether ASD-like traits are correlated with sociodemographic characteristics and child intellectual abilities, and how maternal ratings of social skills assessed by the SRS-2 are associated with maternal ratings of general problem behaviors. Mean total SRS-2 raw score was significantly lower in the MIREC sample (mean = 29.7, SD = 15.8) compared to the US standardization sample (mean = 41.9, SD = 26.0). Total raw score in the US standardization sample did not significantly differ between males (mean = 40.6, SD = 23.1) and females (mean = 42.8, SD = 28.7), whereas in the MIREC sample the total raw score was significantly higher among males (mean = 33.0, SD = 17.1) than females (mean = 26.6, SD = 13.9). A significantly larger proportion of the MIREC sample was White, younger in age, and had more educated parents compared to the US standardization sample. ASD-like traits were correlated with lower intellectual abilities, a less enriched home environment, more behavioral problems, and poorer adaptive skills. SRS-2 Preschool Form scores were significantly lower in the Canadian sample compared to the US standardization sample, which may reflect demographic differences between the two groups. Girls may be under-identified when SRS-2 Preschool Form norms are used for screening ASD.

Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort.

BACKGROUND: Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce. OBJECTIVE: To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex. METHODS: We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics. RESULTS: Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10-2.50), 4.97 (3.20-6.20) and 1.09 (0.67-1.60) µg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = -2.80, 95% CI: -4.92, -0.68; PFOS: B = -2.64, 95% CI: -4.77, -0.52; PFHxS: B = -2.92, 95% CI: -4.72, -1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = -3.16, 95% CI: -4.90, -1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: -0.99, 2.26). No significant associations were found for EF in either males or females. CONCLUSIONS: Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific.

Planned Oocyte Cryopreservation: Outcomes, Motivations, and Involvement of Primary Health Care Providers.

Background: With improvements in oocyte cryopreservation and widespread delays in childbearing, planned oocyte cryopreservation (POC) has become an increasingly attractive option. This study aimed to (1) review POC cycle outcomes at an academic in vitro fertilization (IVF) center and (2) examine POC users' motivations for pursuing POC, fertility knowledge, and the involvement of their primary health care providers (PHP). Materials and Methods: POC cycle outcomes were collected from IVF records of the 224 women who underwent ≥1 cycle from 2012 to 2018. The 198 who were reachable by e-mail were invited to complete an online survey. The study was approved by the University of Toronto Research Ethics Board (No. 32951). Results: Mean age of the 224 women at first cycle was 36.4 (range: 25-42), with a significant decrease in anti-Müllerian hormone level (p = 0.001) and mean number of oocytes retrieved (p = 0.006) and cryopreserved per cycle (p = 0.042) with increasing age. From those invited for survey participation, 98 (49.5%) questionnaires were returned, with 86 evaluable. Majority of respondents were Caucasian (66%), single (93%), and earned a gross annual income of >$70,000 (74%). Strongest motivation for pursuing POC was concern about age-related fertility decline in the absence of a partner. Respondents' annual income was positively correlated with the number of completed cycles (p = 0.032). Half the respondents correctly identified age of onset of marked fertility decline as ≥35 years. In only 19% of cases was the conversation PHP initiated, and 29% never discussed POC with their PHP. Conclusions: More than 50% of women underwent POC at an age when fertility has begun to markedly decline. It is important for PHPs to identify and discuss POC with appropriate patients and offer accurate preliminary information and timely referrals for those interested in exploring this option.

Iodine Status Modifies the Association between Fluoride Exposure in Pregnancy and Preschool Boys' Intelligence.

In animal studies, the combination of in utero fluoride exposure and low iodine has greater negative effects on offspring learning and memory than either alone, but this has not been studied in children. We evaluated whether the maternal urinary iodine concentration (MUIC) modifies the association between maternal urinary fluoride (MUF) and boys' and girls' intelligence. We used data from 366 mother-child dyads in the Maternal-Infant Research on Environmental Chemicals Study. We corrected trimester-specific MUF and MUIC for creatinine, and averaged them to yield our exposure variables (MUFCRE, mg/g; MUICCRE, µg/g). We assessed children's full-scale intelligence (FSIQ) at 3 to 4 years. Using multiple linear regression, we estimated a three-way interaction between MUFCRE, MUICCRE, and child sex on FSIQ, controlling for covariates. The MUICCRE by MUFCRE interaction was significant for boys (p = 0.042), but not girls (p = 0.190). For boys whose mothers had low iodine, a 0.5 mg/g increase in MUFCRE was associated with a 4.65-point lower FSIQ score (95% CI: -7.67, -1.62). For boys whose mothers had adequate iodine, a 0.5 mg/g increase in MUFCRE was associated with a 2.95-point lower FSIQ score (95% CI: -4.77, -1.13). These results suggest adequate iodine intake during pregnancy may minimize fluoride's neurotoxicity in boys.