Evaluation of Autism Spectrum Disorder Risk in Infants with Intraventricular Hemorrhage

doi:10.21203/rs.3.rs-1975928/v1

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Evaluation of Autism Spectrum Disorder Risk in Infants with Intraventricular Hemorrhage

https://doi.org/10.21203/rs.3.rs-1975928/v1

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Objective: To evaluate the ASD risk in infants with intraventricular hemorrhage (IVH) using the Modified Checklist for Autism in Toddlers-Revised with Follow Up (M-CHAT-R/F).

Study Design: Retrospective cohort study. Infants with IVH admitted to the Baylor Scott & White Health NICU from January 2014 through June 2020. M-CHAT-R/F questionnaire results for ASD risk assessment was used, in addition to the cranial ultrasound findings at NICU discharge.

Results: M-CHAT-R/F screening results were found in 165 infants, 80 children had IVH and 85 children had no IVH, 35 infants failed (ASD Risk) and 130 infants passed the M-CHAT-R/F (No-ASD risk). Median birth weight and gestational age were significantly lower in ASD risk group. ASD risk and cerebral palsy were significantly associated with severe IVH. Based on discharge cranial ultrasound findings, ASD risk of infants with resolved IVH was comparable to No-IVH group.

Conclusions: The ASD risk increases with lower gestational age, lower birth weight and severe IVH.

Autism spectrum disorder (ASD) is a biologically based neurodevelopmental disorder characterized by persistent deficits in social communication, social interaction and restricted, repetitive patterns of behavior, interests and activities [1, 2]. ASD affects more than 5 million Americans, with an estimated prevalence of approximately 1.7% in children [3]. The prevalence of ASD is almost 4 times higher in infants born preterm compared to those born at term [4, 5]. ASD has been proposed to be associated with congenital factors, such as genomic mutations [7, 8, 9, 10], maternal factors such as mental illness, epilepsy, obesity, hypertension, diabetes, polycystic ovary syndrome, infection, asthma, assisted fertility, hyperemesis and younger maternal age and neonatal factors such as birth asphyxia, prematurity and low gestational age etc [11, 12].

Various neonatal morbidities may contribute to the increased risk of ASD. Among these complications are forms of perinatal brain injury such as germinal matrix hemorrhage (GMH), intraventricular hemorrhage (IVH), parenchymal lesions that reflect focal ischemic or hemorrhagic injury to white matter, and ventricular enlargement that are detectable with neonatal cranial ultrasound (CUS) [15]. Although magnetic resonance imaging (MRI) is more sensitive than CUS for detection of white matter damage, CUS is safer, more efficient, and significantly less expensive than MRI [37]. The specific brain abnormalities on routine CUS in low gestational age infants are associated with cerebral palsy and other neurodevelopmental impairments [24, 25]. The reported incidence of IVH is about 15–45% in very low birth weight (< 1500 g) and 30–40% in very preterm (born < 32 weeks of gestation) infants [ 22, 23]. Severe IVH especially Papile’s grades 3 and 4 is associated with significant neurodevelopmental impairment in about 43% of affected infants [14].

It has been reported that intensive early intervention programs can improve cognitive and language abilities as well as adaptive behavior in children with ASD [16, 17, 18]. The American Academy of Pediatrics (AAP) recommends screening all children for symptoms of ASD through a combination of developmental surveillance at all visits and standardized autism specific screening tests at 18 and 24 months of age in their primary care visits. Children with ASD can be identified as toddlers and early intervention can improve outcomes [20]. Parent-completed questionnaires are the most common screening tests used in primary care. The Modified Checklist for Autism in Toddlers (M-CHAT) is the most studied and widely used tool for screening toddlers for ASD [21].

However, there is a mixed and paucity of data on the risk assessment of ASD in children whose neonatal course is complicated by IVH. This study aims to evaluate the ASD risk in preterm and full-term infants discharged from the neonatal intensive care unit (NICU) with IVH using the screening tool, M-CHAT-R/F at primary care clinic at 16 to 30 months of chronological age and CUS findings at hospital discharge.

This retrospective cohort study was conducted on infants admitted to Level IV NICU at Baylor Scott & White Health in Temple, Texas, from January 2014 through June 2020 with follow-up in primary care clinic through December 2021. It was approved by the local institutional review board.

Infants diagnosed with IVH and controls matched on birthweight, birth year and gestational age were eligible for this study. Those born with multiple congenital anomalies, died or transferred out prior to hospital discharge and those with missing M-CHAT-R/F screening results were excluded.

Data was obtained from the hospital’s electronic medical record (EMR) system. Maternal data including age, ethnicity, insurance, mode of delivery, preeclampsia, diabetes, antenatal steroids, antenatal magnesium and psychiatric disorders were obtained. Infant data including gender, gestational age, birth weight, intubation at resuscitation, Apgar scores at 1 and 5 minutes, postnatal systemic steroids, duration of mechanical ventilation, length of NICU stay, ventriculoperitoneal (VP) shunt placement, cranial ultrasound findings of parenchymal lesions, IVH, Periventricular leukomalacia (PVL), hydrocephalus, patent ductus arteriosus (PDA), severe retinopathy of prematurity (ROP), hearing screen failure at NICU discharge, discharged home on oxygen monitor were reported. M-CHAT-R/F results, cerebral palsy, speech or language delays were obtained from chart review and ICD9/10 codes.

Based on the established clinical practice guidelines at our institution, infants born less than 32 weeks of gestation undergo at least 2 CUS; first, within 10 days of birth, mostly around 7 days of life and again at or about 36 weeks PMA or around the time of NICU discharge. Infants born more than 32 weeks of gestation undergo CUS as an aspect of diagnostic work up and clinical care (patients with seizure, hypoxic ischemic injury, suspected brain hemorrhage or infection). All CUS were performed by experienced technologists using high-frequency transducers and included multiple standard quasi coronal and parasagittal views using the anterior fontanel as the sonographic window. These ultrasounds were interpreted by at least 1 pediatric radiologist who has been trained in reading neonatal CUS to characterize the types and locations of abnormal findings of GMH, IVH, parenchymal lesions, PVL and hydrocephalus with detailed specifications for severity.

Infants were screened by primary care provider for ASD risk using Modified Checklist for Autism in Toddlers-Revised with Follow-Up (M-CHAT-R/F) questionnaire between 16 to 30 months of chronological age. Infants who scored < 3 considered pass or low risk for ASD and those who scored > 8 or continued to have 3–7 items positive on repeat screening were considered fail or high risk of ASD or another developmental disorder.

Primary outcome was ASD risk with M-CHAT-R/F screening tool assessed at 16 to 30 months of chronological age. Infants who failed the M-CHAT-R/F were determined to have ASD risk and those who passed formed the No-ASD risk cohort.

NICU discharge CUS findings were also used to determine the ASD risk.

Statistical analysis

Descriptive statistics included median and interquartile range for skewed continuous variables, and frequencies and percentages for categorical variables. For bivariate analysis, comparisons for non-ordinal categorical measures were conducted using χ2 or Fisher exact test, while comparisons for nonsymmetrical continuous variables were conducted using the Wilcoxon rank sum test. Logistic regression was conducted controlling for gestational age and birth weight to examine factors associated with ASD risk. These results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Stata/SE 12.1 (StataCorp LP, College Station, TX) was used for all statistical analyses. A p-value of < 0.05 was considered statistically significant.

Availability of Data and Materials: Upon request.

For this study, 386 infants were eligible, 193 infants with IVH (cases) and 193 infants with no IVH (controls). Of these infants, at 16 to 30 months of chronological age, M-CHAT-R/F screening test results were found for 80 children in IVH group and 85 children in No-IVH group. Based on the exclusion criteria, final sample looking at ASD risk to No-ASD risk included 165 infants, which was comprised of 35 infants in ASD risk group who failed M-CHAT-R/F and 130 infants in No-ASD risk group who passed M-CHAT-R/F.

Median gestational age at delivery and median birth weight were statistically significant between the ASD risk and No-ASD risk groups (25.6 vs 29.4 weeks, p = 0.01) and (0.90 vs 1.18 kg, p=0.03) respectively. Statistically significant differences were also observed in receiving postnatal systemic steroids (60% vs 25%, p=0.0009), IVH (60% vs 45%, p=0.006), cerebral palsy (26% vs 3 %, p<0.0001), speech delay (57% vs 31%, p=0.004) and severe ROP (49% vs 21%, p=0.012). Infants in the ASD risk group were sicker, required longer length of stay in the NICU (median days, 82 days vs 47 days, p=0.0008), more days on mechanical ventilation (medians days, 13 vs 0, p=0.0003) and had significant 5-minute Apgar score (7 vs 8, p=0.021). Maternal age, antenatal steroids, antenatal magnesium, preeclampsia, maternal diabetes, race and ethnicity were comparable between both groups (Table 1). When infants were stratified by gestational age, 60% of the extremely preterm (22-<28 wks GA), 17% of the very preterm (28-<32 wks), 17% of the moderate to late preterm (32-<37 wks) and 6% of the term (>37 wks) infants were associated with ASD risk.

(Table 2) reports the neurodevelopmental outcomes associated with different grades of IVH. ASD risk (43% vs 20%, p=0.044) and cerebral palsy (19% vs 5%, p=0.004) were significantly associated with severe IVH. There were no differences in the speech delay, hearing screen failure at discharge and severe ROP in our cohort of mild and severe IVH infants.

ASD risk was almost 2 times higher in the severe IVH group (Odds Ratio of 1.75, 95% CI, 1.01-3.04) when controlled for both gestational age and birth weight (Table 3).

(Table 4) shows a distribution of M-CHAT-R/F screening results with respect to the IVH and No-IVH infants. Overall 26% of infants failed the M-CHAT-R/F compared to 16% of infants in the No-IVH group (p=0.125). The median age at first M-CHAT-R/F screening was 18 months (17 – 32 months) and the median age at follow up/second screening was 24 months (24-32 months).

CUS at 36 weeks PMA or discharge from NICU was found in 69 infants in IVH group. ASD risk of infants with resolved IVH on CUS was comparable to No-IVH group (18% vs 16%). Infants with PVL or hydrocephalus had 3 times the risk of ASD (OR-3.24, 95%CI-0.73-14.34), (OR- 3.11, 95%CI-0.57-16.79) and those with hydrocephalus needing VP shunt had almost 5 times the risk of ASD (OR-4.75, 95% CI-0.73-30.69) (Table 5).

In this retrospective cohort study, we examined the association between ASD risk and infant’s gestational age, weight at birth, IVH and CUS findings at NICU discharge assessed using the M-CHAT-R/F screening tool at 16-30 months of chronological age.

Many ASD screening tests are not diagnostic. However, they help the providers to identify children who are at risk for a diagnosis of ASD or identify other developmental delays that would require additional evaluation and benefit from intervention. M-CHAT has initially been validated in 2001 with sensitivity of 0.87, specificity of 0.99, positive predictive value of 0.8 and negative predictive value of 0.99. In 2014, it has been further validated with inclusion of follow up interview to decrease the number of cases who initially screened positive while maintaining high sensitivity. Children who screened with the M-CHAT-R/F are identified with ASD at younger ages than predicted by national statistics [32]. Previous studies of very preterm infants reported 21%-41% prevalence of positive M-CHAT questionnaire screens [34, 35]. Unlike the current study, these reports did not include a term reference group, nor did they include the M-CHAT follow-up interview. In the IVH group, overall 26% of the infants screened positive for ASD-risk; 20% in mild IVH group; 18% in the resolved IVH group; and 16% in the No-IVH group. The incidence is lower than prior studies as anticipated due to inclusion of follow up interview. Our results found no difference in the incidence of ASD risk in mild IVH, resolved IVH and No-IVH infants.

In examining the risk factors for screening positive for ASD, we found an inverse and predominant association with gestational age and weight at birth which is consistent with previous studies [4,5, 6,38]. When controlled for both gestational age and birth weight, our results have revealed that severe IVH has a strong association for ASD risk and being diagnosed with cerebral palsy.

The etiology of ASD in preterm and low birth weight children is poorly understood. Aberrant brain development [15,42], reduced brain volume [43], intracranial injuries [39], neonatal pain and stress [41, 42] are the associated factors described in studies. Like earlier studies, numerous other factors including low Apgar scores [13], cerebral palsy [25], postnatal systemic steroids [19], more days on mechanical ventilation [44], longer length of NICU stay [44] were also found to be associated with increased ASD risk in our study.

With respect to the stability of ASD risk, there are reports of challenges in identifying the ASD risk earlier particularly among preterm infants. A study reported that few preterm infants who were classified as having ASD risk at an early age had little-to-no ASD related concern on later assessment [33]. Our data also exhibited the similar findings, 13 children who were screened positive for ASD at median age of 18 months, were screened negative at 24 months of chronological age. These findings have emphasized the importance of examining the ASD risk over time and consider screening assessment at 16 to 30 months of corrected gestational age rather than chronological age in preterm infants.

ASD is considered a neurodevelopmental disorder of cortico-striatal circuits [26]. A previous study reported that in very preterm infants, CUS abnormalities were associated with higher ASD screening score on the social communication questionnaire [27]. In our study, infants with discharge CUS findings of PVL or hydrocephalus have demonstrated a three-fold increased risk for positive ASD screen over those with no evidence of CUS abnormality which is consistent with a prior study in which author reported that any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positive for ASD compared with no cranial ultrasound abnormalities [15].

Strengths and Limitations

The strength of our study is that we included new version of M-CHAT-R/F screening tool which has improved sensitivity and specificity. Additionally, our cohort was not restricted like other preterm studies, we included both preterm and full-term infants. We examined the ASD risk not only according to the gestational age and birth weight but also based on severity of IVH and type of brain abnormalities on CUS.

However, we realize that our study has few limitations as well, such as it is a single center retrospective chart review study. Sample size is small. Our study focus was the ASD risk assessment only, given that the M-CHAT-R/F is intended to be used as a screening tool for determining whether further evaluation is necessary, we could not include confirmatory diagnostic assessment in the present study and therefore, were unable to ascertain ultimate autism diagnosis in those with positive ASD screen. We did not have objective developmental tool like Bayley Scales of Infant and Toddler Development (BSID-III) during study time period, which is commonly used in NICU follow up clinic to assess the neurodevelopment of NICU graduates which might be a better tool for cognitive, language, motor, socio-emotional, adaptive behavior assessment.

Infants with IVH have an overall elevated risk of ASD. The ASD risk increases with lower gestational age, lower birth weight and severe IVH. This study results should support providers in counselling the parents on risk of ASD in infants with prematurity, low birth weight, IVH and abnormal CUS findings. Providers should also bear in mind the importance of timely screening for ASD with follow up screening as needed and referrals for diagnostic confirmation and intervention to improve long-term neurocognitive and developmental outcomes.

Conflict of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics approval and consent to participate: Baylor Scott and White Institutional review board approved the study. Consent requirement was waived for this retrospective study.

Funding: None

Author Contributions: IS and MR conceptualized and designed the study. IS, MR, IJ did the chart review. MR did the statistical analysis. IS and MR wrote the manuscript. MR,NV,VG and AC contributed by reviewing the manuscript and providing feedback. All authors approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgements: none

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Table 1: Characteristics of infants discharged from NICU and assessed for ASD risk by M-CHAT-R/F screening tool

Characteristics	ASD Risk (N=35), No. (%)	No-ASD risk (N=130 No. (%)	P value
Infant:
*Birth weight (kg)	0.90 (0.49-2.86)	1.18 (0.46-5.21)	0.033
*Gestational Age (wks)	25.6 (23.4-39.0)	29.4 (22.5-40)	0.01
22- <28 wks	21 (60)	51 (39)	0.028
28- <32 wks	6 (17)	45 (35)	0.047
32- <37 wks	6 (17)	14 (11)	0.305
>37 wks	2 (6)	20 (15)	0.135
Inborn	20 (57)	93 (72)	0.09
Male	20 (57)	78 (60)	0.722
Intubated at birth	20 (57)	58 (45)	0.188
Discharge on O2 monitor	14 (40)	29 (23)	0.039
Caucasian	18 (51)	61 (47)	0.946
African American	10 (29)	37 (28)
Hispanic	6 (17)	27 (21)
Others	1 (3)	5 (4)
*Apgar 1 min	5 (0-9)	5 (0-9)	0.257
*Apgar 5 min	7 (2-9)	8 (1-9)	0.021
*Mechanical ventilation, days	13 (0-85)	0 (0-95)	0.0003
*Length of stay in NICU, days	82 (1-166)	47 (2-370)	0.0008
Post-natal steroids	21 (60)	33 (25)	0.009
PDA	16 (46)	49 (38)	0.389
IVH (all grades)	21 (60)	59 (45)	0.006
Cerebral palsy	9 (26)	4 (3)	<0.0001
Speech delay	20 (57)	40 (31)	0.004
Hearing screen failure at discharge	5 (14)	10 (8)	0.228
Severe ROP	17 (49)	27 (21)	0.012
Maternal:
*Maternal Age (yrs.)	28 (17-40)	28 (17-46)	0.842
Antenatal steroids	27 (77)	87 (67)	0.246
Antenatal Magnesium	17 (49)	61 (47)	0.862
Public Insurance	17 (61)	44 (44)	0.184
Pre-eclampsia	2 (6)	17 (13)	0.226
Gestational diabetes	3 (9)	9 (7)	0.739
Singleton birth	8 (26)	26 (20)	0.711
Cesarean delivery	28 (80)	90 (69)	0.210
Maternal psychiatric diagnosis:
Major depression	8 (23)	46 (35)	0.161
Anxiety disorder	12 (34)	49 (38)	0.711
Bipolar disorder	1 (3)	11 (8)	0.257
Schizophrenia	0	2 (1)	0.460

ASD risk-Autism spectrum disorder risk as assessed by M-CHAT-R/F questionnaire, PDA-Patent ductus arteriosus, IVH-Intraventricular hemorrhage, ROP-Retinopathy of prematurity

* -Median values reported with range in parentheses.

Table 2: Intraventricular hemorrhage grades of infants and neurodevelopmental outcomes

IVH categories	MILD IVH -59, No. (%)	SEVERE IVH-21, No. (%)	P value
ASD risk	12 (20)	9 (43)	0.044
Cerebral palsy	6 (5)	8 (19)	0.004
Speech delay	28 (22)	9 (21)	0.896
Hearing screen failure at discharge	17 (14)	6 (14)	0.911
Severe ROP	33 (26)	13 (31)	0.781

Mild IVH- Grade 1 & 2, Severe IVH-grade 3 & 4

Table 3: Risk of ASD in infants with IVH controlled for gestational age and birthweight

	ASD Risk, No. (%)	OR	95% CI
IVH 1&2 (Mild)	12 (20)	0.32	0.11-0.98
IVH 3&4 (Severe)	9 (43)	1.75	1.01-3.04

Table 4: M-CHAT-R/F results distribution in IVH and No- IVH groups

MCHAT	IVH (n=80), No. (%)	No- IVH (n=85), No. (%)	P-value
M-CHAT failed	29 (36)	19 (22)	0.276
M-CHAT passed	51 (64)	66 (78)
M-CHAT failed, then passed on follow up	8 (10)	5 (6)
Overall M-CHAT failed	21 (26)	14 (16)	0.125

Table 5: Risk of ASD in the IVH infants based on the discharge CUS findings

CUS abnormalities	n	ASD Risk (n (%))	OR	95% CI
IVH resolved	39	7 (18)	0.78	0.28-2.11
HYDH (no VP shunt)	9	3 (33)	3.11	0.57-16.79
HYDH + VP Shunt	7	3 (42)	4.75	0.73-30.69
PVL	14	4 (28)	3.24	0.73-14.34

HYDH-Hydrocephalus, VP shunt-Ventriculoperitoneal shunt, PVL-Periventricular leukomalacia

There is NO conflict of interest to disclose.

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Evaluation of Autism Spectrum Disorder Risk in Infants with Intraventricular Hemorrhage

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