Paracetamol in pregnancy: ADHD, autism link?

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A study looking at a potential link between paracetamol use in pregnancy and ADHD and ASD in children has failed to establish causation, experts caution

Researchers from the Johns Hopkins University Bloomberg School of Public Health in the US examined umbilical blood samples for traces of paracetamol, and say they found an increased risk of Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in children where the medicine was present.

The study involved 996 mother-infant dyads, a subset of the Boston Birth Cohort, who were enrolled at birth and then followed up prospectively at the Boston Medical Center from October 1, 1998, to June 30, 2018.

“Three cord acetaminophen metabolites (unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-l-cystein-S-yl]-acetaminophen) were measured in archived cord plasma samples collected at birth,” the authors wrote.

“Of 996 participants (mean [SD] age, 9.8 [3.9] years; 548 [55.0%] male), the final sample included 257 children (25.8%) with ADHD only, 66 (6.6%) with ASD only, 42 (4.2%) with both ADHD and ASD, 304 (30.5%) with other DDs, and 327 (32.8%) who were neurotypical.

“Unchanged acetaminophen levels were detectable in all cord plasma samples. Compared with being in the first tertile, being in the second and third tertiles of cord acetaminophen burden was associated with higher odds of ADHD diagnosis (odds ratio [OR] for second tertile, 2.26; 95% CI, 1.40-3.69; OR for third tertile, 2.86; 95% CI, 1.77-4.67) and ASD diagnosis (OR for second tertile, 2.14; 95% CI, 0.93-5.13; OR for third tertile, 3.62; 95% CI, 1.62-8.60).

“Sensitivity analyses and subgroup analyses found consistent associations between acetaminophen buden and ADHD and acetaminophen burden and ASD across strata of potential confounders, including maternal indication, substance use, preterm birth, and child age and sex, for which point estimates for the ORs vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD.”

The authors found that cord biomarkers of foetal exposure to paracetamol were associated with “significantly” increased risk of childhood ADHD and ASD in a dose-response fashion. This warrants further investigation, they say.

A number of experts weighed in on the study, with Melbourne fertility specialist Joseph Sgroi saying that such studies “do little to decrease the anxiety that comes with being pregnant, undergoing childbirth and raising a child”.

“Causation has not been established in this study,” he said. “Any study such as this should be prospective and not seek answers to the question of causation by questionnaire nor a blood sample taken at the time of birth.

“Indeed it is difficult to establish if the paracetamol was taken 1 day before, the day of child birth, on one occasional or multiple occasions. Furthermore (without reviewing the study) there will no doubt be confounders such as other agents taken through pregnancy, family predisopostion or indeed social economic factors and education. 

“For this very reason caution is advisable when publishing such a study, and until a prospective well-documented study is performed then claims of its adverse effects should be tempered by common sense.”

Dr Alex Polyakov, a senior lecturer in the Department of Obstetrics and Gynaecology at The University of Melbourne and a Consultant Obstetrician, Gynaecologist and Fertility Specialist at the Reproductive Biology Unit at the Royal Women’s Hospital in Melbourne, said that despite the authors’ claim to the contrary, this was not a truly prospective study.

“Cord blood samples were collected at the time of birth, and some, but not all, children were followed up with neurodevelopmental testing for a number of years,” Dr Polyakov said.

“Only those children who had neurodevelopmental testing, which was not routine for the whole cohort, were included in the analysis. This significant selection bias is evident in extremely high prevalence of all neurodevelopmental conditions in this cohort, with only 32.8% of children that were included in this study not receiving a diagnosis of either ADHD, ASD, DD or some combination of the three.

“Therefore the applicability of the study’s findings to general population, where the prevalence of neurodevelopmental conditions is generally accepted to be less than 5%, is highly questionable.”

The method used to assess paracetamol exposure must also be queried, Dr Polyakov said.

“Cord blood levels would reflect maternal medication intake immediately or shortly before giving birth. It is unknown how long paracetamol and its metabolites are present in fetal circulation after maternal ingestion, but this window must be a few days long at most.

“Therefore, this study contributes nothing to the question of the effect of paracetamol exposure during pregnancy and not immediately before birth.

“Another interesting and somewhat surprising finding of the study is that all cord blood samples had some paracetamol and its metabolites detected. This implies that all women in this cohort took this medication around the time of giving birth.

“This may be standard care in the USA, where the study was conducted, but in Australia, paracetamol is not routinely given to women in labour and is not the drug of choice for pain relief.

“Due to the universal exposure to the drug in the cohort, researchers did not have a group of women who were not exposed to paracetamol in late pregnancy and around the time of childbirth.

“This is yet another major weakness of this study as all the comparisons were done between groups with some degree of drug exposure with no true control group. There are other multiple criticisms of the study methodology as related to statistical analysis and techniques used.”

Dr Polyakov said that nothing in the study indicates that an occasional intake of “a couple of Panadol tablets” while pregnant would have any effect on the child’s risk of ADHD or ASD.

Professor Norman Saunders, a developmental neurobiologist in the Department of Pharmacology and Therapeutics, School of Biomedical Sciences, University of Melbourne, said that the study was an improvement on previous data, because measurements of paracetamol and metabolites in placental cord blood were used, rather than self-reporting of taking paracetamol.

However, “an important limitation of the study is that although the blood measurements confirm whether or not the patient actually took paracetamol at around the time of childbirth, we know nothing of when else during pregnancy the paracetamol might have been taken”, he said.

“It is possible, but seems unlikely, that a few tablets of paracetamol taken around the time of birth would cause problems; it seems more likely that a longer period at a critical time in brain development would do so.”

He noted that a subgroup analysis suggests higher risks for lead and bottle feeding than for paracetamol, “something the authors do not comment on”.

“An important conclusion of the authors was that the results ‘warrant additional investigations’.

“It is a pity that there was no discussion of what these might be.”

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