Supplementary Methods
Additional information about participants
The study included mainly children who were placed in stable foster- or adoptive
homes from an early age. There was not enough variation within the sample to investigate
whether stability of care was an important factor. However, to facilitate generalizability,
results are shown, both for the total sample, and separately for the children who moved early
to stable foster- or adoptive parents. As often common in clinical samples there is a lack of
concurrent information about the care environment. Thus, the study has a focus on which
changes happened, and less on what predicted these changes.
Information about the mother’s use of drugs during pregnancy was based on
information from the mother’s medical and social records and from interviews with the
mothers. As common for such clinical samples, regular toxicological test results during
pregnancy for the mothers were not available. Because of heavy substance abuse and other
related factors, it was difficult to get reliable information from the mothers about amount,
frequency and timing of the drug use, so we have no reliable measure of such details
concerning their drug use during the pregnancy. For these reasons, we only include
information about what is possibly the most reliable information: the women’s main drug of
choice during pregnancy, and information about which drugs they had used during pregnancy.
The total sample of mothers who used drugs during pregnancy used on average 3.3 different
drugs, including tobacco (Supplementary Table S2). The subsample of 30 mothers who had
heroin as their main drug of choice and for which the children moved to permanent foster- or
adoptive homes before 1 year of age used on average 2.9 different drugs. For this subgroup,
most frequent reported drugs to have been used during pregnancy were benzodiazepines
(56.7%), cannabis (36.7%) and amphetamines (23.3%). Only three (10.0%) women in this
subgroup reported to have used alcohol during the pregnancy.
Due to number of participants, combination of drugs used, and lack of information
about amount and timing, it is impossible to discriminate between the effects of each
substance. Smoking could be a confounding factor, but could not be controlled for as all
mothers of the drug exposed children also smoked during pregnancy. However, other studies
have found that smoking cannot fully explain reduced fetal growth in prenatally opioid
exposed children (1).
Addition information about measures of cognitive abilities
For the purpose of analyzing changes in cognitive abilities over time, a set of
commonly used age appropriate general cognitive assessment tools were used. We choose to
assess general cognitive abilities rather than more specific problems often found in some age
groups of prenatally drug-exposed children. This was partly due to problems assessing
reliable the same specific ability through infancy and into childhood. It is very difficult to find
reliable tests assessing the same specific features, such as inhibition of behavior, across such
developmental periods. There are also so few studies of prenatal opioid and poly-substance
exposed children that very little is known about which specific features should be assessed
over time.
As common for longitudinal studies (2,3), cognitive abilities were assessed with
different measures over time because different age groups require different tools for
measuring general cognitive abilities. Even though the used measures are some of the most
commonly used for assessing general cognitive abilities of at similar age, it is possible that the
different measure does not assess the same abilities. Thus, when controlling for earlier
cognitive abilities in Model 4 in the multiple regression analyses in Table 2 and
Supplementary Table S1, it is possible that the cognitive tests at 1, 2, 3 and 4 ½ years of age
did not control exactly for the same features as measured by WISC-R at 8 ½ years of age. As
mentioned in the limitations, it is also possible that the mixed effects analyses of changes of
group differences may have been influenced by a possible change in the tests sensitivity over
time. The fact that there were stable group differences for the boys from 1 year of age indicate
however that the tests were sensitive to group differences already at that age.
Addition information about statistical procedures
All correlations between the different cognitive tests over time were quite similar to
other longitudinal studies of cognitive changes using the same tests (e.g. 2), with correlations
from .29 (between 1 and 8 ½ years) to .60 (between all assessments at 2, 3 and 4 years) (all p
≤ .01). There were no substantial differences in correlations across changes in instruments.
Thus, mixed effects models could be used for analyzing changes over time within a linear
regression perspective. The mixed effects model takes into account the given information at
each time point; thus, no imputation for missing cognitive data was necessary.
Due to possible gender differences (4), the mixed effects models are replicated
separately for girls and boys. The analysis were repeated separately by gender instead of
including a three-way interaction effect of group*time*gender to facilitate comprehensibility
for the reader of such complex interactions.
Both the mixed effects models and the multiple linear regression analysis were rerun
on a subsample (nopioid and polysubstance exposed = 30) excluding children who did not move to
permanent adoptive or foster homes before 1 year of age (n = 20) or whose mothers did not
have heroin as their main drug during pregnancy (n = 33). The exclusion of children who did
not move to permanent adoptive or foster homes were excluded to be certain the results were
not unduly influenced by children living with their biological parents or by changes of care
after one year of age. The exclusion of children of mothers with other than heroin as main
drug of choice was done to see if the results were generalizable also for this subgroup. There
is a lack of knowledge about children born of mothers using heroin during pregnancy. This
group of children does also have a high risk of neonatal abstinence syndrome as for example
compared to children born of mothers using cocaine during pregnancy. It is however
important to remember that the children in the drug exposed group had mothers who used
multiple drugs during pregnancy, both within the subsample of mothers with heroin as main
drug of choice and mothers with other drugs of choice. Both exclusion criteria in the
subsample were done simultaneously to save space in the manuscript. Thus, one analysis was
done on the subsample of children who moved to foster- or adoptive homes before one year of
age and who were also born of mothers who used heroin as main drug of choice.
All mixed effects models and multiple regression analyses controlled for birth weight
and gestation age. The perinatal factors of low birth weight and early gestation age have been
found to be predictors for later cognitive abilities (5) and brain volume, even for normal
variation of birth weight (6). Birth weight and gestation age can be seen as an indicator of the
child’s prenatal environment, and is for example related to maternal stress during pregnancy
(7) and maternal use of substances during pregnancy, for example smoking (8). It is however
also probable that maternal use of opioids and multiple substances will influence birth weight
and gestation age (9). Thus, even though we control for perinatal factors to try to avoid other
prenatal factors influence on cognitive abilities, it is possible that the inclusion of birth weight
and gestation age as covariates may underestimate the effect of prenatal opioid and
polysubstance exposure. Gestation age and birth weight are highly related. As the effect of the
perinatal factors per se is not the topic of the present article, both perinatal factors were
included as covariates to control for the possible direct effect of perinatal factors.
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