Maternal prenatal paracetamol ingestion and scholastic attainments of the offspring

Background: Fetal exposure to paracetamol (acetaminophen) has been shown to be associated with asthma and other atopic disorders, as well as behavioural problems including hyperactivity, in childhood. However, there is little information on scholastic abilities among children exposed to paracetamol in pregnancy. Objectives: To determine whether there are any differences in scholastic abilities among the offspring of women who ingested paracetamol during pregnancy compared with non-exposed children. Methods: Mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) had recorded the frequency with which they had taken the medication over two time periods during pregnancy: i) the first 18 weeks and ii) 18–32 weeks. The offspring have been followed up ever since. For this study we use as outcomes: a) 14 tests of ability at reading and 2 of spelling using the study’s tests and the national education system test results; b) 6 of mathematical abilities including tests of arithmetic and mathematical reasoning, and c) 1 of scientific understanding. Multiple regression was used, adjusting for 15 different exposures including reasons for taking the medication as well as demographic features. Results: Almost all unadjusted and adjusted mean differences were negative (i.e., those exposed to maternal intake of paracetamol did less well), but negative associations for exposures between 18 and 32 weeks of gestation were much more evident than for exposures earlier in pregnancy. Of the later exposures, after adjustment, 12 of the 23 scholastic tests were associated with prenatal exposure to paracetamol at p < 0.05. These negative effects were found in the girls (12 tests at p < 0.05) but not boys (0 tests at p < 0.05). Conclusion: Evidence from this longitudinal study suggests that maternal exposure to paracetamol is associated with disadvantages to the offspring in scholastic abilities such as mathematics and reading at secondary school ages. This raises the question as to whether there are longer-lasting effects on educational attainment from age 15 years onwards, including at university level. Clearly these results should be tested in other settings, but meanwhile they add to a growing accumulation of known adverse effects of exposure to paracetamol in pregnancy.


I.
The Outcome Measures II.
The Descriptive Tables of associations between possible confounders and paracetamol ingestion III.Tables of adjusted standardised mean differences and E-values IV. References I.

The Scholastic Abilities Outcome Measures
The descriptions below are taken verbatim from the paper by Golding et al (2020) a) Spelling "At both the 7-and the 9-year clinics, a spelling test was administered immediately after the reading session by trained ALSPAC staff.A total of 15 words were chosen specifically for each age group after piloting on several hundred children by Peter Bryant and Terezinha Nunes of the Department of Education at the University of Oxford.The spellings involved regular and irregular words of different frequencies.They were given in order of increasing difficulty.For each, the word was read out aloud to the child, and then within a specific sentence incorporating the word, and then alone again.The child was asked to write down the spelling even if he/she thought they were just guessing.The spelling score was the number of words spelt correctly (range 0-15).The scores for each age included those who stopped early (usually because they had reached the limit of their ability) (Nunes et al., 2012).The scores were not normally distributed but did not have ceiling effects."

b) Reading
Word reading at age 7 used the basic reading subtest of the WORD (Wechsler Objective Reading Dimension) for all children attending the ALSPAC clinic (Rust et al., 1993).The child was shown a series of four pictures by trained psychologists.Each picture had four short simple words underneath it.The child was asked to point to the word which had the same beginning or ending sound as the picture.This was then followed by a series of three pictures, each with four words beneath, each starting with the same letter.The child was asked to point to the word that correctly named the picture.Finally, the child was asked to read aloud a series of 48 unconnected words which increased in difficulty.If the child read the word incorrectly but pronounced it in a way that was phonetically plausible, this was also noted for each word.The reading task was stopped after the child had made six consecutive errors.8070 children completed the task; the score was the number of items the child responded to correctly.It ranged from 0 to 54, with mean 28.1 (SD 9.44).
Reading words and non-words.At age 9 years, the child was asked to read aloud ten real words, followed by ten non-words.Both the words and non-words were selected from a larger selection of words taken from previous research (Nunes et al., 2003).The two sets of words were specifically chosen for this study by Nunes and Bryant.The test-retest reliability of the word reading test is 0.8, and the scale has a correlation of 0.85 with the Schonell Word Reading Task (Schonell and Goodacre, 1971).Under test conditions, the child was shown each word in turn and asked to read the words aloud.The word reading score was calculated as the number of words read correctly.The score ranged from 0 to 10 and demonstrated a ceiling effect.
Reading comprehension was also measured at 9 years using the revised Neale Analysis of Reading Ability (NARA II) (Neale, 1997) to assess the child's reading skills and comprehension.It was administered by trained psychologists using Form II.The testing took place in a quiet room.Wherever possible, parents were asked not to accompany their child into the testing room to minimize distractions and interruptions.A similar structure was used for all test passages.A booklet was used from which each child read a passage.They were then asked a series of questions about the content of the story they had just read.The tester recorded the time (in seconds) it took the child to read the passage.Any errors made by the child during reading were noted on the data sheet.The child was prompted by the tester if they: (a) mispronounced a word; (b) substituted a word; (c) refused to say a word; (d) made an addition (only if it altered the meaning of the story); (e) made an omission; or (f) reversed a word.Administration of the test was undertaken following the instruction manual.If the child made more than 17 errors on the practice passage, the tester did not ask the child the comprehension questions but moved straight on to the level one story.All other children moved on to the level two story unless the tester felt that they had difficulty with reading the practice passage.If the child made less than three errors on the level two story the tester moved on to level three.If, however, the child made three or more errors on level two, the comprehension questions were administered but the tester moved down to the level one story (only moving on to level three if the child completed level one within the permissible number of errors).For the remaining test passages the child was not asked the comprehension questions if they made more than 16 errors (20 on level six) and the session was ended.The comprehension questions were asked as soon as the child had finished reading.For each question the child was given 10-12 seconds to respond; they could refer to the text to assist them.The raw comprehension score was obtained by summing the number of correct answers the child gave for each passage.If the permissible number of errors was exceeded for the final passage, the comprehension questions were not asked so no score was given for that passage.The conversion of the raw score to a score standardised for age used the test authors' criteria.It was approximately normally distributed.It should be noted that 48 children were unable to attempt the test and have been excluded.
Reading speed was calculated from the comprehension reading task.The rate of words per minute was computed for each child.This was based on only those passages read where no more than 16 errors were made (20 for passage 6) and was created as: Total no.words read × 60 / Total time taken (sec) The reading speed standardised for age was approximately normally distributed with mean 105.1 (SD 12.6) words per minute.
Reading fluency or sight-word efficiency was estimated at the 13-year assessments.A word reading task (the TOWRE task) provides a test of sight-word efficiency (Torgesen et al., 1999).A list of 104 words was given to the child to read, and the number read accurately within 45 seconds was recorded.The score, identifying the number of words read in the time (but not necessarily the accuracy), was approximately normally distributed.

c) Mathematics and Science
The development of numeracy and mathematical skills is made up of several components which are built on in hierarchical ways over time (Duckworth, 2008).Even before children enter formal schooling, they intuitively start to piece together basic mathematical concepts such as relative size and counting.Much of the research on the development of mathematical skills has focussed on arithmetic or word problem solving but little is known about influences on the general course of mathematics performance in non-selected populations.To obtain data appropriate to the aims of ALSPAC, various advisors were asked for their opinions over time.These included expert researchers including Terezhina Nunes and Peter Bryant, as well as representatives of the local Avon Education Authorities and other expert contributors.The result was the recommendation to use tests devised for the study by Nunes and Bryant which would ensure the measurement of mathematical reasoning.
Mathematical reasoning.The aim of these tasks was to assess children's understanding and use of quantitative relations to solve mathematical problems.There were two different Mathematical Reasoning tasks: one, containing 17 items, was given to schoolchildren in Year 4 (mean age 8 years 9 months); the other, containing 35 items, was given to children in Year 6 (mean age 11 years 2 months) and again in Year 8 (mean age 12 years 8 months).The aim of these tasks was to assess children's reasoning about quantities and the relations between quantities in mathematical problems independently of their computational skills.None of the items in these tests contained difficult calculations, the children had to reflect on the relations between quantities in each item to decide how to solve the problem.All the items were presented with the support of drawings; the children could use counting to solve many of the problems if they did not know the number facts that might be used in the solution.All the problems were presented orally by the teachers to avoid an undue influence of reading difficulties on the children's performance (Nunes et al., 2009).
Three types of item were included in the Year 4 Mathematics Reasoning Task: additive reasoning items about quantities; additive reasoning items about relations; and multiplicative reasoning items about quantities.The assessments used in Years 6 and 8 included six types of item: additive reasoning items about quantities; additive reasoning items about relations; multiplicative reasoning items about quantities; multiplicative reasoning items involving relations (i.e.proportions); items about spatial reasoning and items about fractional quantities.Analyses of their internal consistency using Cronbach's α showed that on all three occasions the mathematics reasoning tasks had good levels of inter-item reliability: 0.74 at Year 4 (N=5275), 0.89 at Year 6 (N=7881) and 0.91 at Year 8 (N=2755).This high internal consistency justifies the addition of all the items in each school year into single scores.
Arithmetical ability was measured as part of the WISC verbal intelligence tests at age 8 years.The raw scores at age 8 were measured using alternate questions as for the WISC test in general (Golding et al., 2017).The data were approximately normally distributed.
National tests of mathematics.The results of the school-administered Standardised Attainment Test Scores (SATS) at age 10-11 years (known as "key stage 2", KS2) and at 13-14 years (known as "key stage 3", KS3) were linked to the relevant children.These tests were scored in each subject at levels 1-8.The UK government recommendations are that children should achieve a level 4 by KS2 and a level 5 by KS3 and that they should progress by at least 1.0 unit or level every 2 years (National curriculum assessments, 2007).Thus, a coefficient of 0.5 represents an average 1 year of progress.Scientific reasoning.A test of scientific reasoning was developed specifically for the study by Nunes and Bryant.The aim was to measure children's understanding that in a properly controlled scientific comparison, one variable is tested at a time while other variables are held constant.The test was administered in school Year 6 (age 11-12 years) by the class teacher.The pupils' scores successfully predicted their later progress in science even after allowance was made for age and IQ (Bryant et al., 2015)."

II.Descriptive Tables
For the studies on paracetamol intake during pregnancy, we started by using an exposome scan to identify those variables relating to the pregnant mothers which differed between those who did and did not take paracetamol between 18-and 32-weeks gestation at P<0.0001.We then dropped variables that did not contribute to a model predicting taking paracetamol and reduced the numbers of variables to 15 (described in Golding et al 2020).The tables below describe the differences between the women who took paracetamol and those who did not.Table S1 describes the various health conditions that they had, Tables S2 and S3 document the continuous and binary variables used to describe different facets of the women's lifestyles and social environments.The 15 factors that were included as confounders in the companion paper are in these tables together with others that are of interest.Those used as confounders are printed in red.
Table S1.The proportions of women having specific health conditions according to whether or not they took paracetamol in the period 18-32 weeks gestation.Independent factors used as confounders are printed in red.

Health Condition
Took  .80 [1.34, 2.41] a For details of dietary scores see Northstone et al., 2008; b For details of domestic cleaning score see Sherriff et al., 2002.Table S3.The proportion of women exposed to differing environmental conditions according to whether or not they took paracetamol in the period 18-32 weeks gestation.Independent factors used as confounders are printed in red.

III. Tables of adjusted standardised mean differences and E-values
Table S4.Standardised mean differences and e-values relating to the adjusted results for maternal paracetamol ingestion < 18 weeks gestation calculated from  S5. Standardised mean differences and e-values relating to the sex specific adjusted results for maternal paracetamol ingestion < 18 weeks gestation calculated from Table 5 of the main article.

Table S2 .
The mean measurements of environmental conditions of women according to whether or not they took paracetamol in the period 18-32 weeks gestation.Independent factors used as confounders are printed in red.
environmental tobacco smoke or passive smoking; b Measures other children have been born to the mother prior to the current pregnancy.
Table 4 of the main article

Table S6 .
Standardised mean differences and e-values relating to the adjusted results for maternal paracetamol ingestion 18 -32 weeks gestation calculated from Table6of the main article.

Table S7 .
Standardised sex specific mean differences and e-values relating to the adjusted results for maternal paracetamol ingestion 18 -32 weeks gestation calculated from Table7of the main article.