Neurobehavioral disorders among children born to mothers exposed to illicit substances during pregnancy

doi:10.21203/rs.3.rs-4321069/v1

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Research Article

Neurobehavioral disorders among children born to mothers exposed to illicit substances during pregnancy

https://doi.org/10.21203/rs.3.rs-4321069/v1

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Background

Preventions may be schemed if pregnant mothers’ exposure status of substance use is associated with neurodevelopmental conditions. This study explores subsequent risks for intellectual disability, autistic disorders, and attention deficit and hyperactivity disorders in children born to mothers exposed to illicit substances before or during pregnancy.

Method

We identified women with illicit drug use by linking the police records from the ‘Substance Abuse Control Databases’ and Taiwan Birth Registration and Birth Notification records from 2004 to 2014. Children born by mothers identified from the police records were the ‘substance-exposed cohort’. A 1:1 child’s gender, child’s birth year, mother’s birth year, and child’s first use of the health insurance card exact matched comparison cohort and another ‘propensity score (PS)- matched’ comparison cohort of children born by substance-unexposed mothers were established. Multivariate Cox regression analyses with competing risk models were performed.

Results

Higher incidences of intellectual disability (aHR = 2.41, 95% CI: 1.15 ~ 5.03) and ADHD (aHR = 2.35, 95% CI: 1.63 ~ 3.28) were found in children born by mothers exposed to illicit substances during pregnancy compared to exact- matched non-exposed cohorts. Adjusted risks of ADHD were significantly higher in mothers exposed to substances during pregnancy (aHR = 1.77(1.42 ~ 2.21) and before pregnancy (aHR = 1.43 (1.14 ~ 1.80) compared to PS-matched unexposed cohorts after adjusting for covariates.

Conclusions and Relevance

This is the first study that used large population-based data that revealed overall increased risks of intellectual disability and ADHD in children with prenatal exposures of illicit substances compared to those exact and propensity scores matched unexposed controls. The attenuation of such excessive hazards after adjusting for covariates of preterm birth, low birth weight, and fifth-minute APGAR score might reflect that enhanced antepartum screening and appropriate medical care may help prevent subsequent neurobehavioral disorders.

pregnancy

prenatal exposure

illicit substance

children

intellectual disability

attention deficit and hyperactivity disorders

Illicit substance abuse or dependence causes huge impacts on public safety, family functions, or individual physical or mental health conditions. Substance abusers’ circulatory, respiratory, digestive, immune, or nervous systems may be damaged and may lead to excessive deaths compared to the general population (1, 2). In 2015, an estimated 280 million people aged 15 ~ 64 in the world had used at least one illicit substance (most prevalent ones are cannabis, amphetamine, and opioids) in the past year, accounting for 5% of this age group (3). According to Taiwan’s National Substance Abuse Survey, among the adult population aged 18 to 64, the lifetime prevalence of using any illicit substance (most prevalent ones are amphetamine, ketamine, and marijuana) was 1.33% (4).

Illicit substance users are predominantly male, and female users are mostly of childbearing age (5). Literature showed that compared to other women, those aged between 18 ~ 29 years have the highest risk of developing a substance use disorder (6). From 1992 to 2012, the rate of pregnant women seeking substance use treatments increased from 2–28% worldwide(6). Most illicit substances would affect embryos through the placenta and may cause obstetric complications, excess mortality, neonatal abstinence syndrome, abnormal physical problems, or neurodevelopment issues (7, 8). Prior research and our previous study have shown elevated risks of short-term neonatal outcomes, such as the abstinence syndrome, stillbirths, low birth weight (9), congenital heart defects, small head circumferences, or neural tube defects in children born by mothers exposed to opioid, heroin, or amphetamine during pregnancy (10–12). Few studies have mentioned the raised long-term risks of prenatal exposures of opioids or heroin on children’s intellectual functions or neurobehavioral disorders, such as autistic disorder or attention deficit hyperactivity disorder (ADHD) after birth (13, 14). The literature has described significantly lower scores on verbal, performance, or full intellectual quotient (IQ); as well as more school or behavioral problems among children with prenatal opioid exposures and followed at school ages of 3 to 15 years (11, 14, 15). However, an overall nonsignificant trend of poorer outcomes on cognitive or behavioral problems (effect sizes of 0.18, and 0.38, respectively; confidence interval contains 0) was found among opioid exposed preschool children in a meta-analysis that included five studies (8). They suggested that their results should be cautiously interpreted due to their stringent criteria of excluding intra-uterine exposures of multiple substances, and the findings of studies they included were assessed as moderate to weak quality. There was only one article on intra-uterine opioid exposure for school-aged children; a comparable analysis cannot be done. They were also unable to analyze other relatively rare outcomes of autistic disorders or ADHD (8). As for the use of amphetamines in pregnant women, although it is the second most commonly abused illicit substances in the world and is associated with up to 3.5-fold increased risks of low birth weight, microcephaly, or hypotonicity in newborns with intrauterine amphetamine exposure were revealed (16), only few literature described poorer academic achievements (17) or increased aggressions among school-age children with prenatal exposures of amphetamine (18).

Using the same nationwide, population-based criminal database of illicit substance use as our previous research(9), with linkages to several governmental birth, household registrations, and data on health and medical utilizations in Taiwan, the present study investigates the risks of intellectual disability and relatively rarer neurobehavioral outcomes of autistic disorders and ADHD from birth to age of 13 among cohorts of children born by mothers exposed or unexposed to heroin, amphetamine, ketamine, or other substances.

Study subjects

Children born to mothers with illicit drug use before or during pregnancy were our study cohort. (9), We established the study cohort by identifying pregnant women being arrested by the police due to illicit substance use from the ‘Substance Abuse Control Databases’.

The period of pregnancy was confirmed by information using birth date and the number of gestational weeks recorded in the Birth Registration files. Mothers were arrested by police between conception date and birthdates of children: these were defined as the ‘substance-exposed during pregnancy cohort’. Mothers who were identified before the conception date were categorized as the 'substance-exposed before pregnancy cohort.'

The comparison cohort comprised children born by women who were not exposed to substances (substance-unexposed cohort) and were not in the ‘Substance Abuse Control Databases’. Given the reason to select a comparison cohort that was representative of the population and has various characteristic parameters similar to the exposed group to be able to control for potential confounding factors, two stages of the exact- and propensity score (PS)- matching process were applied. In the first stage of exact- and PS-matching, unexposed subjects with similar demographic, comorbidities, and propensity scores were matched with the exposed cohort. The propensity scores were calculated by entering all covariates into a logistic regression model to estimate the probability (propensity score) of each individual based on the selected covariates. To further mitigate the impact of confounders and ensure comparability between substance-exposed DP or BP groups and unexposed groups, we further categorized the exposed cohort into substance-exposed during or before pregnancy subgroups, and selected exact- and PS-matched subjects from the unexposed cohort for comparisons in the second stage of matching (detailed flow chart of our matching process is demonstrated in our previous work(9)). To avoid choosing the extreme cases, children who did not use the health insurance in exposed and unexposed cohorts were not included.

Study database

This study linked the Household Registration files to obtain the mother’s basic demographic data, the National Health Insurance Research Database (the NHIRD, a population-based and comprehensive healthcare database that contains de-identified registration files and claims data from the National Health Insurance program in Taiwan) to obtain the mother’s and the child’s health and medical utilizations and medical expenses from emergency visits, outpatient and hospitalization records, the ‘Substance Abuse Control Database’ that contained crime records for information on illicit substance uses in women, the Nation’s Birth Registration and Birth Notification files, and the Death Registration files. The whole research process was conducted in the ‘Statistic Science Center’ (from now on referred to as the ‘Center’) of the Statistics Department of the Ministry of Health and Welfare in Taiwan. The Science Center was responsible for integrating all the above databases and provided data to the research team after re-scrambling National Identification codes for de-identifications. All personal information, including ID numbers and other data, was encrypted, ensuring no specific identifications could be obtained. The research team went into the Science Center, performing statistical analyses only on the data the Center provided by the Center’s regulations. Since no personal identifications are possible, informed consent was waived by the Institutional Review Board of National Taiwan Normal University (IRB number: 202002HM010).

Outcome variables

Having at least three diagnoses from outpatient records, or one discharge diagnosis from hospitalization records of neurodevelopmental disorders, including intellectual disability (ICD-9-CM: 319; ICD-10: F79), autistic disorders (ICD-9-CM: 299; ICD-10: F84), and attention deficit and hyperactivity disorders (ADHD, ICD-9-CM: 314.01; ICD-10: F90), between birth to the school age of 13, identified from the NHIRD among children born to mothers in the exposed before or during pregnancy or unexposed groups were ascertained as our main outcome. Prior literature indicated that an over 74% of positive predictive value of a diagnosis is enhanced when it is confirmed through three to four separate outpatient visits from the NHIRD (19).

Covariates

Covariates included the age and health status of the parents, mothers’ age at birth, education and income levels, marital status, the city where the mother is currently living, the number of births, the number of gestation weeks, Charlson’s comorbidity index (CCI), health and medical utilizations, including days of hospitalization, outpatient or emergency visits, medical expenses during pregnancy, medications harmful to the fetus prescribed during pregnancy; the child's gender, the city of child’s birth (as a proxy of levels of urbanization or accessibility of healthcare), birth weight, the method of delivery (Caesarean or natural birth), the physical status of the baby at birth (fifth-minute APGAR score), and the child's year at first use of the health insurance card (as a proxy of how the child might be affected by his congenital conditions). The CCI provides a method to quantify the burden of comorbid diseases that may influence the health status of pregnant women and the risk of adverse pregnancy outcomes (20). The APGAR score is used to evaluate a newborn’s health condition. At a total of 10 points, an APGAR score of less than 7 requires clinical first-aid evaluation. These covariates were also used in the calculation of propensity scores.

Statistical Analyses

This is a retrospective cohort study which takes account of death as a competing risk. A chi-square test was used to compare subjects’ characteristics, neurodevelopmental outcomes, and logistic regression model calculated propensity scores. Cox regression with a competing risk model was used to compare the hazards of neurodevelopmental disorders between substance-exposed and -unexposed cohorts. The starting point was the date of birth; the endpoints were the first diagnoses of neurodevelopmental disorders of intellectual disability, autistic disorders, or attention deficit and hyperactivity disorders, death, immigration, or December 31, 2017. Since there were still some residual imbalances after the PS-matching, we performed a double adjustment, where covariates were included in the Cox regression model to remove any remaining confounding (21). Two adjustment models were compared. Covariates adjusted in Model 1 included the child’s gender, birth year, the year that first used a health insurance card, mothers’ year of birth, age at giving birth, education, income, and urbanization levels, marital status (from the Household Registration Files), Charlson Comorbidity Index, medical utilization (including days of hospitalizations, or outpatient or emergency visits), medical expenses, medications proven harmful to fetus prescribed during pregnancy, and Cesarean section. Covariates in Model included those adjusted in Model 1 and whether the child had diagnoses of preterm, low birth weight, and fifth-minute APGAR scores. Both adjustment models applied to exact- and PS-matched comparisons.

Among the 1,969,040 newborns identified from the Birth Registration and Birth Notification files between 2004 to 2014, 34 did not have any records in the National Health Insurance Research Database. Among the remaining 1,969,006 newborns, 18,235 were born by mothers caught by police for illicit drug use between 2001 and 2015 through linkage to the ‘Substance Abuse Control Databases’. Of these 18,235 mothers, 2,078 of them were found to have been exposed to and being caught with illicit drug use during pregnancy; and 8,772 of them have been exposed to and caught with illicit drug use within the year before pregnancy.

After the first stage of exact- matching, 1,776 newborns from the substance-exposed before pregnancy cohort, 1,776 newborns from the substance-exposed during pregnancy cohort, and 3,552 unexposed cohort were selected and exact- matched by child ’s gender, birth year, mother ’s birth year, and child ’s first use of the health insurance card. Characteristics of child’s gender, birth year, child’s first use of the health insurance card, and mother’s birth year were matched without significant differences (all p > 0.99). Characteristics and covariates that were not matched or still showed significant differences among the three cohorts are shown in Table 1. The substance-exposed mothers had significantly higher proportions of elementary or junior high school education levels, single, lives in rural places, higher Charlson comorbidity index, lower income, received Cesarean section, being prescribed with medications possibly but not proven to be harmful to the fetus from animal or human trials, gave birth at clinics rather than hospitals, fewer outpatient visits during pregnancy, preterm birth, had low birth weight child, and had newborns with fifth minute APGAR score < 7 than substance-unexposed mothers. Under such exact matching, newborns from the substance-exposed cohort had significantly higher incidences of intellectual disability (2.70%, 1.46% and 0.68% for exposed during pregnancy, before pregnancy, and unexposed, respectively) and attention deficit and hyperactivity disorders (7.43%, 5.97% and 2.76% for exposed during pregnancy, before pregnancy, and unexposed, respectively) (all p < 0.001, Table 1). Autistic disorders did not reveal higher incidences in the exposed than the unexposed cohort (0.56%, 0.73%, and 0.68% for exposed during pregnancy, before pregnancy, and unexposed, respectively).

Table 1

Characteristics and covariates that were still significantly different after the first stage exact- and propensity- matching (Total N = 7104)
Variable		Exposed before pregnancy (n = 1776), n (%)	Exposed during pregnancy (n = 1776), n (%)	Unexposed, (n = 3552) n (%)	P value
Mother, Heroin use
During pregnancy		0	863	0
Before pregnancy		769	787	0
Mother, Amphetamine use
During pregnancy		0	931	0
Before pregnancy		815	775	0
Mother, Ketamine use
During pregnancy		0	149	0
Before pregnancy		85	71	0
Mother, education					< 0.001
Elementary, Junior high school		774 (43.58)	881 (49.61)	427 (12.02)
Senior high school		873 (49.16)	831 (46.79)	1404 (39.53)
College		129 (7.26)	64 (3.6)	1721 (48.45)
Mother, marital status					< 0.001
Single		359 (20.21)	595 (33.5)	264 (7.43)
Married		1146 (64.53)	814 (45.83)	3208 (90.32)
Divorce, widowhood		271 (15.26)	367 (20.66)	80 (2.25)
Mother, Charlson comorbidity index					< 0.001
0		1532 (86.26)	1511 (85.08)	3171 (89.27)
1		189 (10.64)	185 (10.42)	342 (9.63)
≥ 2		55 (3.1)	80 (4.5)	39 (1.1)
Mother, levels of income					< 0.001
< 20,000 $NTD		955 (53.80)	1336 (75.22)	547 (15.40)
20,000–39,999 $NTD		755 (42.51)	421 (23.7)	2216 (62.39)
≥ 40,000$NTD		66 (3.72)	19 (1.07)	789 (22.21)
Mother, residence					< 0.001
Rural		374 (21.06)	460 (25.9)	545 (15.34)
Urban		1402 (78.94)	1316 (74.1)	3007 (84.66)
Mother, hospital days during pregnancy					< 0.001
0		108 (6.08)	171 (9.63)	162 (4.56)
1–3		795 (44.76)	699 (39.36)	1709 (48.11)
> 3		873 (49.16)	906 (51.01)	1681 (47.33)
Mother, outpatient visits during pregnancy					< 0.001
0–10		372 (20.95)	813 (45.78)	133 (3.74)
11–20		489 (27.53)	494 (27.82)	1000 (28.15)
> 20		915 (51.52)	469 (26.41)	2419 (68.1)
Mother, medical expenditure					< 0.001
0–19,999 $NTD		205 (11.54)	333 (18.75)	234 (6.59)
20,000–39,999 $NTD		897 (50.51)	758 (42.68)	2086 (58.73)
≥ 40,000 $NTD		674 (37.95)	685 (38.57)	1232 (34.68)
Mother, prescription used during pregnancy that are harmful to the fetus					< 0.001
No		985 (55.46)	1114 (62.73)	2081 (58.59)
Yes		791 (44.54)	662 (37.27)	1471 (41.41)
Mother, prescription used during pregnancy that are harmful to the fetus in an animal or human experiment					< 0.001
No		638 (35.92)	761 (42.85)	1274 (35.87)
Yes		1138 (64.08)	1015 (57.15)	2278 (64.13)
Children, order of this birth					0.135
1		1764 (99.32)	1758 (98.99)	3507 (98.73)
≥ 2		12 (0.68)	18 (1.01)	45 (1.27)
Children, birth place					< 0.001
Hospital		1049 (59.07)	1078 (60.7)	2392 (67.34)
Clinic		715 (40.26)	662 (37.27)	1156 (32.55)
Other		12 (0.68)	36 (2.03)	4 (0.11)
Children, caesarean section					< 0.001
No		1069 (60.19)	1148 (64.64)	2389 (67.26)
Yes		707 (39.81)	628 (35.36)	1163 (32.74)
Children, 5th minimum APGAR score					< 0.001
< 7		15 (0.84)	24 (1.35)	9 (0.25)
	≥ 7	1761 (99.16)	1752 (98.65)	3543 (99.75)
Children, death					< 0.001
No		1766 (99.44)	1756 (98.87)	3543 (99.75)
Yes		10 (0.56)	20 (1.13)	9 (0.25)
Children, attention deficit hyperactivity disorder, ADHD					< 0.001
No		1660 (93.47)	1624 (91.44)	3445 (96.99)
Yes		106 (5.97)	132 (7.43)	98 (2.76)
Children, Intellectual disability					< 0.001
No		1740 (97.97)	1708 (96.17)	3519 (99.07)
Yes		26 (1.46)	48 (2.70)	24 (0.68)
Children, autistic disorder					< 0.001
No		1753 (98.7)	1746 (98.31)	3519 (99.07)
Yes		13 (0.73)	10 (0.56)	24 (0.68)
ADHD: Attention deficit and hyperactivity disorder
The comparison cohort was selected by two-stages of exact- and propensity score (PS) matching. The first stage exact- and propensity- matching by mother’s year of birth, child’s gender, child’s year of birth, and child’s first use of health insurance card (all p > 0.99 after exact matching) of mothers exposed to substances before pregnancy (n = 1776, the ‘substance-exposed before pregnancy cohort’), mothers exposed to substances during pregnancy (n = 1776, the ‘substance-exposed during pregnancy cohort’), and the comparison cohort (‘substance-unexposed mothers’, n = 3552). More details may be referred to our previous work (Lee et al., 2023).

Table 2 showed that 4,156 newborns from the substance-unexposed cohort were selected, exact-, and PS-matched to the substance-exposed cohort separated by the time of exposure (exposed before pregnancy, n = 2,078; during pregnancy, n = 2,078) Characteristics of child’s gender, child’s birth year, the year of child’s first use of health insurance card, birth orders, birth place, mother’s age at giving birth, mother’s urbanization levels, mother's education level, mother's marital status, Charlson comorbidity index, mothers’ levels of income, mother’s days of hospitalization, outpatient visits, medication prescribed during pregnancy, the method of delivery (Caesarean or natural birth) showed similar distribution between 3 cohorts (Table 2).

Table 2

Characteristics and covariates that were not matched or were still significantly different after the second stage exact- and propensity- matching (Total N = 8312)
Variable		Exposed before pregnancy (n = 2078), n (%)	Exposed during pregnancy (n = 2078), n (%)	Unexposed (n = 4156) n (%)	P value
Mother, age at this childbirth (year)					< 0.001
14–17		23 (1.11)	32 (1.54)	162 (3.9)
18–34		1848 (88.93)	1829 (88.02)	3353 (80.68)
≥ 35		207 (9.96)	217 (10.44)	641 (15.42)
Mother, Heroin use
During pregnancy		0	1027	0
Before pregnancy		991	902	0
Mother, Amphetamine use
During pregnancy		0	1106	0
Before pregnancy		1168	895	0
Mother, Ketamine use
During pregnancy		0	153	0
Before pregnancy		81	71	0
Mother, education					0.012
Elementary, Junior high school		1081 (52.02)	1052 (50.63)	2079 (50.02)
Senior high school		930 (44.75)	953 (45.86)	1982 (47.69)
College		67 (3.22)	73 (3.51)	95 (2.29)
Mother, marital status					0.826
Single		654 (31.47)	678 (32.63)	1347 (32.41)
Married		977 (47.02)	949 (45.67)	1941 (46.7)
Divorce, widowhood		447 (21.51)	451 (21.7)	868 (20.89)
Mother, Charlson comorbidity index					0.409
0		1824 (87.78)	1784 (85.85)	3590 (86.38)
1		180 (8.66)	205 (9.87)	405 (9.74)
≥ 2		74 (3.56)	89 (4.28)	161 (3.87)
Mother, insurance premium					0.012
< 20,000 $NTD		1563 (75.22)	1564 (75.26)	3243 (78.03)
20,000–39,999 $NTD		491 (23.63)	494 (23.77)	888 (21.37)
≥ 40,000$NTD		24 (1.15)	20 (0.96)	25 (0.6)
Mother, residence					0.352
Rural		515 (24.78)	531 (25.55)	1099 (26.44)
Urban		1563 (75.22)	1547 (74.45)	3057 (73.56)
Mother, hospital days during pregnancy					0.884
0		217 (10.44)	209 (10.06)	420 (10.11)
1–3		846 (40.71)	820 (39.46)	1667 (40.11)
> 3		1015 (48.85)	1049 (50.48)	2069 (49.78)
Mother, outpatient visits during pregnancy					< 0.001
0–10		372 (20.95)	813 (45.78)	133 (3.74)
11–20		489 (27.53)	494 (27.82)	1000 (28.15)
> 20		915 (51.52)	469 (26.41)	2419 (68.1)
Mother, medical expenditure					0.036
0–19,999 $NTD		979 (47.11)	992 (47.74)	1895 (45.6)
20,000–39,999 $NTD		616 (29.64)	580 (27.91)	1156 (27.82)
≥ 40,000 $NTD		483 (23.24)	506 (24.35)	1105 (26.59)
Mother, prescription used during pregnancy that are harmful to the fetus					0.171
No		1313 (63.19)	1309 (62.99)	2704 (65.06)
Yes		765 (36.81)	769 (37.01)	1452 (34.94)
Mother, prescription used during pregnancy that are harmful to the fetus in an animal or human experiment					0.006
No		858 (41.29)	884 (42.54)	1882 (45.28)
Yes		1220 (58.71)	1194 (57.46)	2274 (54.72)
Children, order of this birth					0.154
1		2068 (99.52)	2060 (99.13)	4117 (99.06)
≥ 2		10 (0.48)	18 (0.87)	39 (0.94)
Children, birth place					0.004
Hospital		1209 (58.18)	1251 (60.2)	2530 (60.88)
Clinic		850 (40.9)	787 (37.87)	1550 (37.3)
Other		19 (0.91)	40 (1.92)	76 (1.83)
Children, caesarean section					0.918
No		1345 (64.73)	1345 (64.73)	2708 (65.16)
Yes		733 (35.27)	733 (35.27)	1448 (34.84)
Children, 5th minimum APGAR score					< 0.001
< 7		31 (1.49)	32 (1.54)	57 (1.37)
≥ 7		2047 (98.51)	2046 (98.46)	4099 (98.63)
Children, death					0.023
No		2036 (97.98)	2030 (97.69)	4098 (98.6)
Yes		42 (2.02)	48 (2.31)	58 (1.40)
Children, ADHD					< 0.001
No		1911 (91.96)	1883 (90.62)	3916 (94.23)
Yes		125 (6.02)	147 (7.07)	182 (4.38)
Children, mental retardation					0.009
	No	2000 (96.25)	1971 (94.85)	4007 (96.41)
	Yes	36 (1.73)	59 (2.84)	91 (2.19)
Children, autistic disorder					0.103
No		2023 (97.35)	2019 (97.16)	4073 (98)
Yes		13 (0.63)	11 (0.53)	25 (0.60)
ADHD: Attention deficit and hyperactivity disorder. The comparison cohort was selected by two-stages of exact- and propensity score (PS) matching. The second stage exact- and propensity- matching by mother’s year of birth, child’s gender, child’s year of birth, and child’s first use of health insurance card (all p > 0.99 after exact matching) of mothers exposed to substances before pregnancy (n = 2078, the ‘substance-exposed before pregnancy cohort’), mothers exposed to substances during pregnancy (n = 2078, the ‘substance-exposed during pregnancy cohort’), and the comparison cohort (‘substance-unexposed mothers’, n = 4156).

Results from competing risk Cox regression analyses of unadjusted and adjusted hazards for neurodevelopmental disorders between substance-exposed and unexposed cohorts with exact match are shown in Table 3 and Fig. 1. Unadjusted hazards of intellectual disability (HR = 4.48, 95% confidence interval (CI): 2.75 ~ 7.30; 2.24 (1.29 ~ 3.91) and ADHD (HR = 3.08, 95% CI: 2.37 ~ 3.99; 2.28, 1.73 ~ 3.00) were significantly higher in substance-exposed during pregnancy and before pregnancy cohorts than the unexposed cohorts, respectively. After adjusting for potential confounders, risks of intellectual disability (aHR = 2.41, 95% CI: 1.15 ~ 5.03) and ADHD (aHR = 2.35, 95% CI: 1.68 ~ 3.28) were significantly higher in the exposed during pregnancy than unexposed groups. The risk of ADHD remained higher in the exposed before pregnancy than unexposed groups (aHR = 1.92, 95% CI: 1.41 ~ 2.62). The increased risk of ADHD was found in the heroin (aHR: 2.00, 1.47 ~ 2.72), amphetamine (aHR: 2.01 (1.46 ~ 2.76)), and marijuana (aHR: 4.48, 1.20 ~ 16.68) exposed during pregnancy than unexposed groups.

Table 3

Competing risk adjusted Cox regression analysis of intellectual disability, autistic disorder, attention deficit and hyperactivity disorder (First stage, matched by child ’s gender, child ’s birth year, mother ’s birth year, and the year of child ’s first use of health insurance card) (Total N = 7104)
Variable	Exposed period	Unadjusted analysis		Adjusted analysis Model 1		Adjusted analysis Model 2
Variable	Exposed period	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
ADHD	Unexposed	1.00		1.00		1.00
	During pregnancy	3.08 (2.37 ~ 3.99)	< 0.001	2.43 (1.75 ~ 3.38)	< 0.001	2.35 (1.68 ~ 3.28)	< 0.001
	Before pregnancy	2.28 (1.73 ~ 3.00)	< 0.001	1.97 (1.45 ~ 2.68)	< 0.001	1.92 (1.41 ~ 2.62)	< 0.001
Intellectual disability	Unexposed	1.00		1.00		1.00
	During pregnancy	4.48 (2.75 ~ 7.30)	< 0.001	2.64 (1.29 ~ 5.39)	0.008	2.41 (1.15 ~ 5.03)	0.019
	Before pregnancy	2.24 (1.29 ~ 3.91)	0.004	1.53 (0.76 ~ 3.08)	0.236	1.45 (0.71 ~ 2.94)	0.307
Autistic disorder	Unexposed	1.00		1.00		1.00
	During pregnancy	0.90 (0.43 ~ 1.88)	0.776	0.95 (0.39 ~ 2.31)	0.916	0.99 (0.92 ~ 1.07)	0.827
	Before pregnancy	1.11 (0.56 ~ 2.17)	0.769	1.10 (0.49 ~ 2.45)	0.814	1.00 (0.93 ~ 1.06)	0.923
Adjusted analysis model 1: adjusted for child’s gender, child’s birth year, the year of child’s first use of health insurance card, birth orders, birth place, mother’s age at giving birth, mother’s urbanization levels, mother's education level, mother's marital status, Charlson comorbidity index, mothers’ levels of income, mother’s days of hospitalization, outpatient visits, medication prescribed during pregnancy, the method of delivery (Caesarean or natural birth) and mortality.
Adjusted analysis model 2: model 1 + the fifth minute APGAR score, premature birth and low birth weight.

Table 4 showed results from competing risk Cox analysis propensity score matched data. The significance results were similar with the previous exact match data analysis. However, the strength of association (HR) was reduced after potential confounders being further controlled.

Table 4

Competing risk adjusted Cox regression analysis of intellectual disability, autistic disorder, attention deficit and hyperactivity disorder (Second stage propensity score- matched, Total N = 8,312)
Variable	Espoused period	Unadjusted analysis		Adjusted analysis model 1		Adjusted analysis model 2
Variable	Espoused period	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
ADHD	Unexposed	1.00		1.00		1.00
	During pregnancy	1.78 (1.44 ~ 2.22)	< 0.001	1.80 (1.45 ~ 2.24)	< 0.001	1.77 (1.42 ~ 2.21)	< 0.001
	Before pregnancy	1.42 (1.13 ~ 1.79)	0.002	1.45 (1.16 ~ 1.82)	0.001	1.43 (1.14 ~ 1.80)	0.002
Intellectual disability	Unexposed	1.00		1.00		1.00
	During pregnancy	1.41 (1.01 ~ 1.95)	0.041	1.41 (1.01 ~ 1.96)	0.042	1.35 (0.97 ~ 1.88)	0.077
	Before pregnancy	0.81 (0.55 ~ 1.19)	0.274	0.82 (0.56 ~ 1.2)	0.298	0.79 (0.54 ~ 1.16)	0.233
Autistic disorder	Unexposed	1.00		1.00		1.00
	During pregnancy	0.93 (0.46 ~ 1.90)	0.851	0.93 (0.46 ~ 1.89)	0.834	0.88 (0.42 ~ 1.83)	0.733
	Before pregnancy	1.06 (0.54 ~ 2.07)	0.869	1.05 (0.54 ~ 2.06)	0.881	1.05 (0.53 ~ 2.05)	0.893
Unexposed and exposed groups distinguished by time were exact- and propensity score-matched by covariates included in propensity score matching for child’s gender, child’s birth year, the year of child’s first use of health insurance card, birth orders, birth place, mother’s age at giving birth, mother’s urbanization levels, mother's education level, mother's marital status, Charlson comorbidity index, mothers’ levels of income, mother’s days of hospitalization, outpatient visits, medication prescribed during pregnancy, the method of delivery (Caesarean or natural birth).
Adjusted analysis model 1: without regression controlling of fifth minute APGAR score, premature birth and low birth weight.
Adjusted analysis model 2: regression controlling of fifth minute APGAR score, premature birth and low birth weight.
ADHD: Attention deficit and hyperactivity disorder

This is the first study to date that used nationwide criminal records with linkages to population- based birth registrations and datasets of health utilizations to compare risks of neurobehavioral disorders, including intellectual disability, autistic disorders, and ADHD, from birth to 13 years of age among children born by mothers exposed or unexposed to illicit substances during or before pregnancy. We showed overall increased risks of intellectual disability in children exposed to intrauterine illicit substances; and increased risks of ADHD in children born by mothers exposed to illicit substances during and before pregnancy compared to those exact- and PS- matched unexposed controls. The attenuation of such excessive hazards for intellectual disability after adjusting for covariates of preterm birth, low birth weight, and fifth- minute APGAR score may reflect that enhancing antepartum screening to identify and reduce risks of preterm or low birth weight might help prevent subsequent neurobehavioral disorders.

The finding that increased risks of ADHD occurred among children born by mothers exposed to illicit substances before or during pregnancy was in line with previous literature reporting higher rates of inattention, hyperactivity (14, 18), psychiatric comorbidities, aggressiveness, externalizing behavioral problems, or poorer academic performances in children with prenatal opioid, heroin, or amphetamine exposures compared with unexposed controls (22, 23). The aforementioned neuronal toxic effects of prenatal illicit substances exposures to the fetus’ developing brain may partly explain (24). Genetic heritability should also be taken into account. The comorbidity of ADHD in women with illicit substance use is generally higher than that in the general population (25). Adoption study showed that the presence of behavioral problem was still higher after adoption in children with prenatal illicit substances exposures than unexposed controls (14). It is still necessary to consider the interplays of genetic and environmental factors. Reasons for neurobehavioral outcomes among children with prenatal illicit substances exposures might be multifactorial and were also influenced by parental psychological or sociodemographic status of postpartum caregivers (8, 23). Hence, improving the care quality of families, increasing identifications for affected teens, and providing medical or social interventions for high-risk individuals may help modify social adaptations or learning conditions in these ADHD children (13, 22).

Our finding of increased risk of intellectual disability in children born by mothers exposed to illicit substances during pregnancy was in agreement with past studies describing children with intra-uterine exposures of cocaine, heroin, or opiate having intellectual impairments at pre-school or school age (26–28). While Baldacchino et al. reported a trend of poorer cognitive level in pre-school children born by mothers with opioid use than non- users in their meta- analysis, they commented that the non- significance may be because of small numbers and sample sizes of primary studies available (8). Impacts of intra-uterine exposures to opioid might be related to dosages, durations, or co-ingestions of other substances. The child’s condition may also worsen or improve with age. Comparing outcomes on the same basis may be difficult since various neurobehavioral assessment tools have been applied for different ages among previous studies (29).

Regarding possible mechanisms, where the fetus is exposed to methadone, opioids, heroin, or amphetamine, there is a higher risk of prematurity, and prematurity has been found to be negatively correlated with cognitive, language, visual-spatial developments, or memory (30). Animal and brain imaging studies have also revealed structural and metabolic abnormalities in the offspring of pregnant rats or humans with intra-uterine exposures of methadone or methamphetamine (12). Small brain sizes or striatal structures were also observed, and these are all possible risk factors related to intellectual ability (31). In addition, methadone or amphetamine may increase the releases of serotonin, acetylcholine, norepinephrine, or dopamine in the developing brain (22, 32), and may be toxic to neuronal proliferation, differentiation, or myelination, (12, 22, 33). These may also be related to impairments of children’s cognitive developments, including visual, spatial, attentional, or working memory processes (25). Some previous studies suggest that the intellectual disability in children born to mothers with heroin or opioid use were more associated with education or socioeconomic levels of their parents or postnatal caregivers, and not to the degree of perinatal complications or comorbidities (14). However, in Ornoy’s study, even cared by adoptive families after births, children with intra-uterine exposures of heroin still performed significantly poorer than that of the unexposed controls (11). Moe et al. also pointed out that substance-exposed children had weaker visual- motor and perceptual abilities than unexposed controls, and this may still be related to the influences of prenatal adversity (34). In any case, if adverse effects from prenatal exposures are difficult to prevent, perhaps efforts may be made to support and optimize the postnatal family environment or caregivers’ quality after the baby is born to ensure positive effects on the neurocognitive development of these children (11, 14, 34).

We found that after adjusting for obstetric conditions of low birth weight, preterm birth, and fifth minute APGAR scores on top of mother’s demographic and medical utilizations, the risk of intellectual disability was no longer higher in the illicit substances exposed children than unexposed comparisons. Although many studies have reported an up to six-folds increase in the risk of obstetric complications including preterm delivery, intrauterine growth retardation, still births, microencephaly, or depressed APGAR scores in pregnant heroin users (35), none has demonstrated such robust attenuations in risks of intellectual disability after controlling for these factors. It was found that insufficient prenatal care in heroin or amphetamine pregnant women was associated with delayed managements of obstetric complications (12, 16, 36). Specifically, the fear for legal repercussions among pregnant women that use substances might cause them to forgo essential antepartum care during pregnancy, and might advertently lead to poorer fetal health outcomes. Our result pointed out the possibility that although preconceptual or prenatal exposures of illicit substances having already occurred, long-term adverse consequences on the child may be prevented not only by substance abuse treatment programs to mothers, but also by efforts to reduce comorbidities of preterm births or obstetric complications. Government policies and health providers should work on enhancing early identifications of pregnant women with substance exposures, decreasing barriers, and providing accesses to adequate antepartum medical care to reduce obstetric complications during delivery. Long-term postpartum follow ups with appropriate psychosocial social interventions to high risk families, children, and their teachers may also be helpful (13).

Strengths and limitations

Major strengths of this study included the large population-based records that linked mother’s and child’s data, and the follow up cohorts that assist statistical capabilities and further adjustments of potential confounders. Our propensity score matched multivariate analyses further allow different demographic or comorbid conditions be compared on more equal basis. The multi-dimensional linkages to various population- based datasets provided reliable and detailed information regarding substance exposure, medical diagnoses, and health care utilizations.

Key limitations are that, first, there are still some residual confounders cannot be completely matched even with propensity score matching. Second, possibilities of misclassification bias for outcome ascertainment or selection bias for exposure ascertainment cannot be completely ruled out. For instance, not all individuals using illicit substances would be arrested by the police thus missing some of the exposed. However, there is no exact ratio for the ones being prosecuted among pregnant women that used substances, and many cases may not be reported or recorded in official statistics. Nonetheless, this study excluded children who did not have any records of utilizing the health insurance; and included dates of the child’s first use of health insurance card as one of the matching variables in order to reduce selection biases from the comparison cohort. Second, although we have controlled and matched several covariates, there are still other risk factors, including smoking status, body mass index, alcohol use, or postnatal socioeconomic environment, that were not available in the dataset. Third, this study only included live births, and not stillbirths or miscarriages, into analyses; health hazards in children born by mothers with illicit substances use before or during pregnancy may be underestimated. Similarly, under-identification is still possible when there might be pregnant women with illicit substances use not caught by the police and were not included into our study subjects. Generalizations of our finding may be restricted. Finally, this is an observational study to examine whether risks of neurodevelopmental disorders were elevated comparing pregnant women with or without illicit substance use. Possible biological mechanisms still require further investigations.

In this large nation-wide cohort study, increased risks of intellectual disability and ADHD were found in children born by mothers exposed to illicit substances during or before pregnancy. More importantly, if incident prematurity or postnatal care can be improved by better antenatal physical exams or managements, preventions of neurodevelopment disorders may be more likely. Early detections of pregnant mothers’ exposure status and better access to antenatal care may aid protections of both maternal and fetus physical and neurodevelopmental conditions.

Ethics approval and consent to participate

This study linked the Household Registration files to obtain the mother’s basic demographic data, the National Health Insurance Research Database (the NHIRD, a population-based and comprehensive healthcare database that contains de-identified registration files and claims data from the National Health Insurance program in Taiwan) to obtain the mother’s and the child’s health and medical utilizations and medical expenses from emergency visits, outpatient and hospitalization records, the ‘Substance Abuse Control Database’ that contained crime records for information on illicit substance uses in women, the Nation’s Birth Registration and Birth Notification files, and the Death Registration files. All personal information, including ID numbers and other data, was encrypted, ensuring no specific identifications could be obtained. The research team went into the Science Center, performing statistical analyses only on the data the Center provided by the Center’s regulations. Since no personal identifications are possible, informed consent was waived by the Institutional Review Board of National Taiwan Normal University (IRB number: 202002HM010).

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Competing interests

All the authors have no non-financial interests that may be relevant to the submitted work.

Funding

This study was funded by Chang Gung Medical Foundation, Chiayi Chang Gung Memorial Hospital, and Chang Gung University, Chiayi, Taiwan, Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (CORPG6G0101 and CORPG6G0141). SIW was partly funded by Department of Medical Research, Mackay Memorial Hospital (MMH-109112, MMH-10914, MMH-108121, MMH-108146, MMH-TT-10804, MMH-TH-10804). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors' contributions

Authors Vincent Chin-Hung Chen and Charles Tzu-Chi Lee designed the study and wrote the protocol. Author Charles Tzu-Chi Lee conducted and checked the statistical analyses. Author Shu-I Wu wrote the first draft. All authors contributed to the writing and have approved the final manuscript.

Acknowledgments

None.

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No competing interests reported.

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Neurobehavioral disorders among children born to mothers exposed to illicit substances during pregnancy

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