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Tylenol associated with both low vitamin D and Autism

Bauer chart - 2013
Image

Note: CYP450 is encoded by CYP27A1 gene


Apparently: Tylenol ==> liver damage ==> decreased vitamin D activation

See also Vitamin D Life

Dr. Cannell on Tylenol, oxidative stress and autism Feb 2014

(commenting on his letter to the editor below)

  • “There are three main antioxidant systems in the body, superoxide dismutase, glutathione reductase, and glutathione peroxidase.”
  • “Activities of all 3 of these antioxidants are strongly associated with serum vitamin D levels”
  • “In a randomized controlled trial of 48 pregnant women, vitamin D supplementation increased total plasma antioxidant capacity (P.0.002)”

Paracetamol, oxidative stress, vitamin D and autism spectrum disorders.– 2014

Cannell JJ1.
Int J Epidemiol. 2014 Jun;43(3):974-5. doi: 10.1093/ije/dyu004. Epub 2014 Feb 11.
1Vitamin D Council, 1411 Marsh Street, Suite 203, San Luis Obispo, CA 93401, USA. E-mail: jjcannell at vitamindcouncil.org.
Comment in: Authors' Response: More research on paracetamol is required. Int J Epidemiol. 2014
Comment on: Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study.

PMID: 24518930

Brandlistuen et al. recently documented the detrimental role that gestational paracetamol exposure has on childhood neurodevelopment, putatively due to oxidative stress.1 Although the authors did not use the words ‘autism spectrum disorder’ (ASD), clearly some of the adverse neurodevelopmental effects they demonstrated are consistent with ASD.

This is not the first time that paracetamol has been implicated in ASD. In an ecological analysis, Bauer and Kriebel found a strong correlation between use of paracetamol and prevalence of ASD.2 If paracetamol causes ASD, and if oxidative stress is the mechanism, then the antioxidant capability of the mother and child would be key to explaining why some exposed children develop ASD and some do not.

Activities of superoxide dismutase, glutathione reductase and glutathione peroxidase are all strongly associated with serum vitamin D levels.3 Asemi et al. found, in a randomized controlled trial of 48 pregnant women, that vitamin D supplementation increased total plasma antioxidant capacity (P-interaction = 0.002), and total glutathione concentrations (P-interaction = 0.02) compared with controls.4 Another randomized controlled trial of vitamin D3 found that it increased human antioxidant capabilities.5 Thus, the fetuses of vitamin D-deficient mothers would be less able to bear the oxidative stress caused by gestational paracetamol exposure.

A recent review concluded that vitamin D deficiency may be a major risk factor for ASD, in part due to lack of the antioxidant properties of vitamin D.6 Three recent studies, using community controls, have found that vitamin D levels are significantly lower in children with ASD.7,8,9 Two of the studies (Mostafa et al. and Gong et al.) also found that ASD severity, as rated on standard ASD rating scales, is inversely correlated with vitamin D levels. Mostafa et al. found an R value of -.86 for the association of serum vitamin D with ASD severity on rating scales.

This model (oxidative stress triggering ASD in vitamin D-deficient pregnant women and young children) is one of the theories of ASD with significant support.10 Other insults that increase oxidative stress are implicated in ASD, such as infections, toxins, fever and inflammation. It may be that paracetamol exposure is one of several oxidative stressors that trigger ASD development in vitamin D-deficient pregnant women and young children.

Potential conflict of interest: J.J.C. is executive director of the non-profit Vitamin D Council and receives remuneration from Purity Products.

© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
References
? Brandlistuen RE, Ystrom E, Nulman I, et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013;42:1702–13., Abstract/FREE Full Text
? Bauer AZ, Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health 2013;12:41., CrossRefMedlineGoogle Scholar
? Saedisomeolia A, Taheri E, Djalali M, et al. Vitamin D status and its association with antioxidant profiles in diabetic patients: A cross-sectional study in Iran. Indian J Med Sci 2013;67:29–37., CrossRefMedlineGoogle Scholar
? Asemi Z, Hashemi T, Karamali M, Samimi M, Esmaillzadeh A. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr 2013;143:1432–38., Abstract/FREE Full Text
? Nikooyeh B, Nyestani TR, Tayebinejad W, et al. Daily intake of vitamin D- or calcium-vitamin D-fortified Persian yogurt drink (doogh) attenuates diabetes-induced oxidative stress: evidence for antioxidative properties of vitamin D. J Hum Nutr Diet 2013. doi: 10.1111/jhn.1242., Google Scholar
? Kocovská E, Fernell E, Billstedt E, Minnis H, Gillberg C. Vitamin D and autism: clinical review. Res Dev Disabil 2012;33:1541–50., CrossRefMedlineGoogle Scholar
? Gong ZL, Luo CM, Wang L, et al. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport 2013;25:23–27., Web of ScienceGoogle Scholar
? Meguid NA, Hashish AF, Anwar M, Sidhom G. Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism. J Altern Complement Med 2010;16:641–45., CrossRefMedlineGoogle Scholar
? Mostafa GA, Al-Ayadhi LY. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation 2012;9:201., CrossRefMedlineGoogle Scholar
? Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses 2013;81:26–35., CrossRefMedlineWeb of ScienceGoogle Scholar

Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms - June 2016

Int J Epidemiol. 2016 Jun 28. pii: dyw115. [Epub ahead of print]
Avella-Garcia CB1, Julvez J2, Fortuny J3, Rebordosa C3, García-Esteban R4, Galán IR5, Tardón A6, Rodríguez-Bernal CL7, Iñiguez C7, Andiarena A8, Santa-Marina L9, Sunyer J10.
1Center for Research in Environmental Epidemiology (CREAL) Unitat Docent de Medicina Preventiva i Salut Publica H. Mar-UPF-ASPB IMIM (Hospital del Mar Medical Research Institute) Universitat Pompeu Fabra (UPF) Universitat Autònoma de Barcelona, Barcelona, Spain.
2Center for Research in Environmental Epidemiology (CREAL) IMIM (Hospital del Mar Medical Research Institute) CIBER Epidemiología y Salud Pública (CIBERESP), Spain jjulvez at creal.cat.
3RTI Health Solutions, Barcelona, Spain.
4Center for Research in Environmental Epidemiology (CREAL) IMIM (Hospital del Mar Medical Research Institute) CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
5Servicio de Pediatria, Hospital San Agustin, Aviles Asturias, Spain.
6CIBER Epidemiología y Salud Pública (CIBERESP), Spain Public Health Department, University of Oviedo, Oviedo, Spain.
7Environment and Health Area, CSISP-FISABIO-REDISSEC, Valencia, Spain.
8Basic Psychological Processes and Development Department, Faculty of Psychology, University of the Basque Country, Gipuzkoa Health Research Institute, Biodonostia, San Sebastián, Spain.
9CIBER Epidemiología y Salud Pública (CIBERESP), Spain Health Research Institute, Biodonostia, San Sebastián, Spain Public Health Division of Gipuzkoa, Gipuzkoa, Basque Government, Spain.
10Center for Research in Environmental Epidemiology (CREAL) IMIM (Hospital del Mar Medical Research Institute) Universitat Pompeu Fabra (UPF) Universitat Autònoma de Barcelona, Barcelona, Spain.

BACKGROUND:
Acetaminophen is extensively used during pregnancy. But there is a lack of population-representative cohort studies evaluating its effects on a range of neuropsychological and behavioural endpoints. We aimed to assess whether prenatal exposure to acetaminophen is adversely associated with neurodevelopmental outcomes at 1 and 5 years of age.
METHODS:
This Spanish birth cohort study included 2644 mother-child pairs recruited during pregnancy. The proportion of liveborn participants evaluated at 1 and 5 years was 88.8% and 79.9%, respectively. Use of acetaminophen was evaluated prospectively in two structured interviews. Ever/never use and frequency of use (never, sporadic, persistent) were measured. Main neurodevelopment outcomes were assessed using Childhood Autism Spectrum Test (CAST), Conner's Kiddie Continuous Performance Test (K-CPT) and ADHD-DSM-IV form list. Regression models were adjusted for social determinants and co-morbidities.
RESULTS:
Over 40% of mothers reported using acetaminophen. Ever-exposed offspring had higher risks of presenting more hyperactivity/impulsivity symptoms [incidence rate ratio (IRR) = 1.41, 95% confidence interval (CI) 1.01-1.98), K-CPT commission errors (IRR = 1.10, 1.03-1.17), and lower detectability scores (coefficient β = -0.75, -0.13--0.02). CAST scores were increased in ever-exposed males (β = 0.63, 0.09-1.18). Increased effect sizes of risks by frequency of use were observed for hyperactivity/impulsivity symptoms (IRR = 2.01, 0.95-4.24) in all children, K-CPT commission errors (IRR = 1.32, 1.05-1.66) and detectability (β = -0.18, -0.36-0.00) in females, and CAST scores in males (β = 1.91, 0.44-3.38).
CONCLUSIONS:
Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders. These associations seem to be dependent on the frequency of exposure.

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Use of Acetaminophen (Paracetamol) During Pregnancy and the Risk of Autism Spectrum Disorder in the Offspring – 2016

J Clin Psychiatry 2016;77(2):e152–e154, dx.doi.org/10.4088/JCP.16f10637
Chittaranjan Andrade, MD

There are theoretical grounds to support the hypothesis that gestational exposure to acetaminophen (paracetamol) increases the risk of autism spectrum disorder (ASD), and there is support for this hypothesis from studies that compare trends in population-level use of acetaminophen with trends in the incidence/prevalence of ASD.
One large prospective observational study found that gestational exposure to acetaminophen was associated with risk of neurodevelopmental impairments at age 3 years; longer duration of gestational exposure was associated with worse neurodevelopmental outcomes. However, the impairments excluded social deficits that are the core features of ASD.
Another large prospective observational study found that gestational exposure to acetaminophen was associated with an increased risk of ASD, but only in cases with a comorbid hyperkinetic syndrome diagnosis.
Although the data are very limited, the data that do presently exist do not implicate acetaminophen exposure during pregnancy as an etiologic risk factor for the development of ASD.

Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%–65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention-deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring.
Introduction
The association between maternal antidepressant use during pregnancy and the risk of autism spectrum disorder (ASD) in the child has been the subject of considerable research; positive associations, when identified, have received much adverse media publicity even though causality remains unproven.1 In contrast, it is not commonly known that acetaminophen (paracetamol), a medication that is available over the counter in most countries and that is widely regarded as a safe drug for use during pregnancy,2,3 has also been associated with neuropsychiatric risks, with neurodevelopmental delay,4 ASD,5 and even attention-deficit/hyperactivity disorder (ADHD)6 described as possible consequences of prenatal use. This article examines the possible association between prenatal use of acetaminophen and ASD in the offspring. The subject is important because acetaminophen use is common in pregnancy, with exposures of 46%–65% reported.4,5,7 The subject is particularly important because if the oft-cited rising incidence of ASD is due to a genuine increase in the number of new cases as opposed to use of looser diagnostic criteria or increased ascertainment, then environmental factors that might be responsible need to be identified and addressed.
Background
Over a decade ago, Torres8 noted that autism is associated with maternal infection during pregnancy and, separately, that acetaminophen, used to treat fever associated with infection, interferes with cytokines that are important for brain development. Putting these 2 observations together, Torres8 proposed the intriguing hypothesis that prenatal use of antipyretics such as acetaminophen can interfere with normal immunologic development of the fetal brain, leading to neurodevelopmental disorders, such as autism, in children who have other genetic and immunologic predispositions. This hypothesis later received support from more detailed, theoretical discussions on inflammatory, immunologic, and genetic mechanisms that might lead to autism, and the possible contribution of acetaminophen thereto.9,10 Other hypotheses have also been advanced, such as acetaminophen-related oxidative stress11 and acetaminophen-related endocrine and cannabinoid receptor effects5 predisposing to ASD. However, as with other psychiatric disorders, the etiopathogenesis of ASD is incompletely understood, and so the mechanisms proposed by these authors8–11 must be recognized to be speculative.
An Ecological Link
Becker and Schultz9 drew attention to a possible ecological link between acetaminophen use and autism enrollment (by year of birth, 1960–1990) in California. The autism enrollment graph showed a steep rise from the late 1970s onward. There were 3 occasions, however, when the graph briefly leveled out, and 2 of these occasions were associated with a drop in acetaminophen sales because of public scares related to drug tampering. Prenatal use of acetaminophen has also been linked to an increased risk of asthma in the offspring,12 and Becker and Schultz9 suggested that there also seemed to be a leveling in the graph of asthma rates by year, corresponding to the periods of acetaminophen sales drop. A limitation of this study is that for both associations (with autism and asthma) the link was based on eyeball impressions, and perhaps not all readers would share those impressions.
Bauer and Kriebel10 compared country-level acetaminophen usage with population-weighted average autism prevalence rates. Using all available country-level data for 1984–2005 (8 countries), they found a high correlation (r = 0.8) between prenatal use of acetaminophen and autism/ASD prevalence. The regression analysis suggested that a 10% increase in population prenatal acetaminophen use would be associated with a 0.053% (95% CI, 0.13–0.93) increase in the autism population prevalence. Interestingly, there was an even higher, near perfect country-level correlation (r = 0.98) between the circumcision rates and the autism/ASD rate in males born after 1995 (9 countries); in this context, it must be noted that acetaminophen use in male children increased from 1995 when guidelines recommended its use for analgesia during circumcision, so circumcision rates were a proxy for acetaminophen use. A similar pattern was seen in an analysis of data from 14 US states and a comparison of the 3 main racial/ethnic groups in the United States.10
A limitation of Bauer and Kriebel’s10 interpretation of their data is that the pre-1995 country-level correlation between circumcision and autism rates was almost the same (r = 0.89) as the post-1995 value (0.98); this finding (r = 0.89) was obtained from an analysis of data from 12 countries. A limitation of the 2 ecological studies9,10 presented here is that acetaminophen use in the population may have merely been a marker for an unmeasured ASD risk factor.
Empirical Data: Effects on Neurodevelopment
Using data drawn from the prospective Norwegian Mother and Child Cohort Study, Brandlistuen et al4 examined child neurodevelopmental outcomes at age 3 years in relation to acetaminophen exposure identified through questionnaires administered around gestational weeks 17 and 30, as well as at 6 months postpartum. The sample comprised 48,631 children, including 2,919 same-sex sibling pairs; data from the latter were used to correct for familial and genetic factors. Analyses were adjusted for potential confounders, including maternal age, alcohol use, smoking, febrile illness, infections, and other medication use during pregnancy.
In the sibling-control analysis, pairs discordant for gestational acetaminophen exposure were compared with concordant pairs. In this analysis, 28 or more days of gestational exposure to acetaminophen (discordant, n = 134; concordant, n = 1,346) was associated with impairments in motor milestones, gross motor development, communication, externalizing behavior, and internalizing behavior and with higher activity level. Shorter (1–27 day) acetaminophen exposure (discordant, n = 805; concordant, n = 1,980) was associated with impairments in motor milestones and gross motor outcomes, but the effects were smaller. Shorter exposure was also associated with impairment in fine motor outcomes. Emotionality, sociability, and shyness were not associated with either duration category of acetaminophen exposure. There was no trimester-of-exposure effect on outcomes.
In the exposed vs unexposed (n = 26,213) analyses, 1 to 27 days of gestational exposure to acetaminophen (n = 20,587) was associated with impairments in gross motor development, externalizing behavior, and emotionality; exposure for 28 days or more (n = 1,831) was associated with impairments in motor milestones, gross motor development, communication, externalizing behavior, and emotionality.
In contrast with exposure to acetaminophen, gestational exposure to ibuprofen was not associated with neurodevelopmental outcomes. This finding suggests that the outcomes with acetaminophen were not due to confounding by indication, but such a conclusion is limited by differences in the reasons why acetaminophen and ibuprofen may have been prescribed. Another concern is that the ibuprofen-exposed sample was small, raising the possibility of a type 2 error.
Brandlistuen et al4 estimated that 28 or more days of gestational exposure to acetaminophen increases the risk of adverse psychomotor and behavioral outcomes by almost 70% and doubles the risk of language problems at age 3 years. Their study, however, was not designed to provide information about risks associated with continuous vs intermittent use of acetaminophen during pregnancy, or dose-dependent risks. Although they did not explicitly say so, many of the neurodevelopmental impairments they recorded are common to those observed in ASD. However, they properly observed that the developmental impairments identified were not specific to ASD and that social impairments, which might be expected in ASD, were not associated with acetaminophen exposure.13 Readers interested in a conceptual and methodological critique of this article could consult a commentary14 and the response thereto.15
Empirical Data: Risk of Autism
Only 1 study appears to have specifically examined the risk of ASD in the context of maternal use of acetaminophen during pregnancy. In this study, Liew et al5 drew data from the Danish National Birth Cohort in which mothers with singleton livebirths (n = 64,322) were prospectively asked about acetaminophen use in computer-assisted telephone interviews at gestational weeks 12 and 30 and at 6 months postpartum. The children were followed up for 10.4–15.6 (mean, 12.7) years. Registry-linked data were used to identify ICD-10 diagnoses of ASD; this was previously shown to have high validity.
There were 1,027 (1.6%) children with ASD, of whom 345 (0.5%) were diagnosed with infantile autism, 306 (0.5%) with Asperger syndrome, and 518 (0.8%) with pervasive developmental disorder, not otherwise specified (PDD-NOS). Some cases received more than 1 ASD subtype diagnosis. Of note, 31% of the ASD cases and 26% of the infantile autism cases also received a hyperkinetic disorder diagnosis. Acetaminophen use during pregnancy was reported by 56.3% of the women.
Liew et al5 adjusted analyses for variables that might influence the ASD risk, including gender, birth year, maternal age, parity, socioeconomic status, maternal body mass index, maternal use of alcohol and tobacco, maternal medical and psychiatric illness, and maternal use of medications, including antidepressants. They found that, relative to no use of acetaminophen, prenatal use of acetaminophen at any time during gestation was associated with a small increase in the risk of ASD (hazard ratio HR, 1.19; 95% CI, 1.04–1.35); use during all 3 trimesters was associated with a higher risk (HR, 1.39; 95% CI, 1.14–1.70). No trimester-specific risk was evident, but the risk was dose-dependent, based on cumulative weeks of exposure during pregnancy.
ASD was comorbid with an ICD-10 hyperkinetic condition in 31% of cases; this figure was 26% for cases with a diagnosis of infantile autism. Despite the far smaller comorbidity sample sizes, acetaminophen use during pregnancy increased the risk of ASD only when ASD was comorbid with a hyperkinetic condition. Also, the risk was greater with greater cumulative weeks of exposure only when ASD was accompanied by a hyperkinetic disorder diagnosis. Similar findings were obtained in separate analyses for infantile autism, Asperger syndrome, and PDD-NOS. Importantly, the findings were similar when analyses were restricted to women who did not experience infection or fever during pregnancy, diminishing the likelihood of confounding by indication. Thus, this study appeared to associate gestational use of acetaminophen with the hyperactive behavioral phenotype rather than with ASD. This is in line with research that has linked gestational acetaminophen exposure to ADHD risk.6
Summary
Many biological mechanisms have been proposed to explain why use of acetaminophen during pregnancy may increase the risk of ASD in the offspring. In 2 studies, population-level use of acetaminophen was associated with trends in the incidence/prevalence of ASD. In one study, gestational exposure to acetaminophen was linked to poorer neurodevelopment and hyperactivity, but not to social and emotional deficits. In one study, gestational exposure to acetaminophen was associated with an increased risk of ASD; the risk increased with greater cumulative duration of exposure. However, the increase in risk was evident only when ASD cases had a comorbid hyperkinetic disorder diagnosis. Thus, the limited evidence available at present does not support the conjecture that use of acetaminophen during pregnancy contributes to the suggested secular increase in autism incidence.
REFERENCES

  • 1. Andrade C. Antidepressant use in pregnancy and risk of autism spectrum disorders: a critical examination of the evidence. J Clin Psychiatry. 2013;74(9):940–941. PubMed doi:10.4088/JCP.13ac08607 Show Abstract
  • 2. Servey J, Chang J. Over-the-counter medications in pregnancy. Am Fam Physician. 2014;90(8):548–555. PubMed Show Abstract
  • 3. de Fays L, Van Malderen K, De Smet K, et al. Use of paracetamol during pregnancy and child neurological development. Dev Med Child Neurol. 2015;57(8):718–724. PubMed doi:10.1111/dmcn.12745 Show Abstract
  • 4. Brandlistuen RE, Ystrom E, Nulman I, et al. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 2013;42(6):1702–1713. PubMed doi:10.1093/ije/dyt183 Show Abstract
  • 5. Liew Z, Ritz B, Virk J, et al. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish National Birth Cohort study published online ahead of print December 21, 2015. Autism Res. PubMed doi:10.1002/aur.1591 Show Abstract
  • 6. Hoover RM, Hayes VA, Erramouspe J. Association between prenatal acetaminophen exposure and future risk of attention deficit/hyperactivity disorder in children. Ann Pharmacother. 2015;49(12):1357–1361. PubMed doi:10.1177/1060028015606469 Show Abstract
  • 7. Werler MM, Mitchell AA, Hernandez-Diaz S, et al. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol. 2005;193(3 pt 1):771–777. PubMed doi:10.1016/j.ajog.2005.02.100 Show Abstract
  • 8. Torres AR. Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? BMC Pediatr. 2003;3(1):9. PubMed doi:10.1186/1471-2431-3-9 Show Abstract
  • 9. Becker KG, Schultz ST. Similarities in features of autism and asthma and a possible link to acetaminophen use. Med Hypotheses. 2010;74(1):7–11. PubMed doi:10.1016/j.mehy.2009.08.033 Show Abstract
  • 10. Bauer AZ, Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health. 2013;12(1):41. PubMed doi:10.1186/1476-069X-12-41 Show Abstract
  • 11. Cannell JJ. Paracetamol, oxidative stress, vitamin D and autism spectrum disorders. Int J Epidemiol. 2014;43(3):974–975. PubMed doi:10.1093/ije/dyu004 Show Abstract
  • 12. Cheelo M, Lodge CJ, Dharmage SC, et al. Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Arch Dis Child. 2015;100(1):81–89. PubMed doi:10.1136/archdischild-2012-303043 Show Abstract
  • 13. Brandlistuen RE, Ystrom E, Nulman I, et al. Authors’ response: more research on paracetamol is required. Int J Epidemiol. 2014;43(3):975–976. PubMed doi:10.1093/ije/dyu015 Show Abstract
  • 14. Damkier P, Pottegård A, dePont Christensen R, et al. Annotations and reflections: pregnancy and paracetamol: methodological considerations on the study of associations between in utero exposure to drugs and childhood neurodevelopment. Basic Clin Pharmacol Toxicol. 2015;116(1):2–5. PubMed doi:10.1111/bcpt.12322 Show Abstract
  • 15. Brandlistuen RE, Ystrom E, Nulman I, et al. Annotations and reflections: response to “Pregnancy and paracetamol: methodological considerations on the study of associations between in utero exposure to drugs and childhood neurodevelopment.” Basic Clin Pharmacol Toxicol. 2015;116(1):6–8. PubMed doi:10.1111/bcpt.12339 Show Abstract

Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study.- 2015

Autism Res. 2015 Dec 21. doi: 10.1002/aur.1591. [[Epub ahead of print]
Liew Z1, Ritz B1,2, Virk J1, Olsen J1,3.
1Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles (UCLA), California.
2Department of Neurology, School of Medicine, UCLA, California.
3Section of Epidemiology, The Institute of Public Health, University of Aarhus, Aarhus, Denmark.

Acetaminophen (paracetamol) is the most commonly used pain and fever medication during pregnancy. Previously, a positive ecological correlation between acetaminophen use and autism spectrum disorders (ASD) has been reported but evidence from larger studies based on prospective data is lacking. We followed 64,322 children and mothers enrolled in the Danish National Birth Cohort (DNBC; 1996-2002) for average 12.7 years to investigate whether acetaminophen use in pregnancy is associated with increased risk of ASD in the offspring. Information on acetaminophen use was collected prospectively from three computer-assisted telephone interviews. We used records from the Danish hospital and psychiatric registries to identify diagnoses of ASD. At the end of follow up, 1,027 (1.6%) children were diagnosed with ASD, 345 (0.5%) with infantile autism. We found that 31% of ASD (26% of infantile autism) have also been diagnosed with hyperkinetic disorders. More than 50% women reported ever using acetaminophen in pregnancy. We used Cox proportional hazards model to estimate hazard ratio (HR) and 95% confident interval (CI). Prenatal use of acetaminophen was associated with an increased risk of ASD accompanied by hyperkinetic symptoms (HR = 1.51 95% CI 1.19-1.92), but not with other ASD cases (HR = 1.06 95% CI 0.92-1.24). Longer duration of use (i.e., use for >20 weeks in gestation) increased the risk of ASD or infantile autism with hyperkinetic symptoms almost twofold. Maternal use of acetaminophen in pregnancy was associated with ASD with hyperkinetic symptoms only, suggesting acetaminophen exposure early in fetal life may specifically impact this hyperactive behavioral phenotype.

Prenatal and perinatal analgesic exposure and autism: an ecological link - Bauer May 2013

Environ Health. 2013 May 9;12:41. doi: 10.1186/1476-069X-12-41.
Bauer AZ1, Kriebel D.
1Department of Work Environment, School of Health and Environment, University of Massachusetts- Lowell, 1 University Avenue, Lowell, MA 01854, USA. Ann_Bauer at student.uml.edu

BACKGROUND:
Autism and Autism Spectrum Disorder (ASD) are complex neurodevelopmental disorders. Susceptibility is believed to be the interaction of genetic heritability and environmental factors. The synchronous rises in autism/ASD prevalence and paracetamol (acetaminophen) use, as well as biologic plausibility have led to the hypothesis that paracetamol exposure may increase autism/ASD risk.
METHODS:
To explore the relationship of antenatal paracetamol exposure to ASD, population weighted average autism prevalence rates and paracetamol usage rates were compared. To explore the relationship of early neonatal paracetamol exposure to autism/ASD, population weighted average male autism prevalence rates for all available countries and U.S. states were compared to male circumcision rates - a procedure for which paracetamol has been widely prescribed since the mid-1990s. Prevalence studies were extracted from the U.S. Centers for Disease Control and Prevention Summary of Autism/ASD Prevalence Studies database. Maternal paracetamol usage and circumcision rates were identified by searches on Pub Med.
RESULTS:
Using all available country-level data (n = 8) for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism/ASD prevalence (r = 0.80). For studies including boys born after 1995, there was a strong correlation between country-level (n = 9) autism/ASD prevalence in males and a country's circumcision rate (r = 0.98). A very similar pattern was seen among U.S. states and when comparing the 3 main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision.
CONCLUSIONS:
This ecological analysis identified country-level correlations between indicators of prenatal and perinatal paracetamol exposure and autism/ASD. State level correlation was also identified for the indicator of perinatal paracetamol exposure and autism/ASD. Like all ecological analyses, these data cannot provide strong evidence of causality. However, biologic plausibility is provided by a growing body of experimental and clinical evidence linking paracetamol metabolism to pathways shown to be important in autism and related developmental abnormalities. Taken together, these ecological findings and mechanistic evidence suggest the need for formal study of the role of paracetamol in autism.
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Tylenol in Pregnancy Doubles Risk of Autism - 2019

Mercola

  • Abnormal hormonal exposures in pregnancy can influence fetal brain development, and research published in 2014 warned acetaminophen is in fact a hormone disruptor
  • According to that 2014 study, use of acetaminophen during pregnancy was associated with a 37% increased risk of the child being diagnosed with hyperkinetic disorder, a severe form of attention deficit hyperactivity disorder (ADHD)
  • A 2019 study found that, compared to children of mothers with the lowest acetaminophen burden, children of mothers with the greatest exposure had a 286% higher risk for ADHD and a 362% higher risk for autism spectrum disorder (ASD) by the time they were about 9 years old
  • Findings published in 2016 revealed use of acetaminophen at 18 and 32 weeks of pregnancy were associated with a 42% higher risk of conduct problems and a 31% higher risk of hyperactivity symptoms in the child
  • Another 2016 investigation found children of both sexes whose mothers used acetaminophen during pregnancy were 41% more likely to present with ADHD symptoms at age 5. Boys were also more likely to have ASD
  • Although it was initially hailed as a safe drug for pain, by 2013 lawsuits were piling up, citing 50,000 trips to the emergency room every year, all due to Tylenol causing liver and kidney failure.
  • Tylenol in Pregnancy May Double or Triple Risk of Autism A study 9,10,11 published online October 30, 2019, in JAMA Psychiatry further strengthens the link between acetaminophen use and ADHD, while also noting an increased risk for autism spectrum disorder (ASD)
    • "estimates for the Odds Ratios vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD"
    • https://doi.org/10.1001/jamapsychiatry.2019.3259

Prenatal exposure to acetaminophen accelarates puberty in females - 2018

Science Daily 10.1093/aje/kwy193
The investigators found that prenatal exposure to acetaminophen accelerated puberty in females by as much as three months, especially if the mother took the drug more than 12 weeks. Exposure to the drug did not appear to affect the onset of puberty in males.

Tylenol associated with both low vitamin D and Autism        
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