Original Research
Otolaryngology–
Cleft Lip and Palate in Newborns
Diagnosed With Neonatal
Abstinence Syndrome
David O’Neil Danis III1, Kevin Bachrach1,
Jacquelyn Piraquive, MD2, Alexander P. Marston, MD3,
and Jessica R. Levi, MD1,2
Abstract
Objective. Cleft lip and/or cleft palate (CLP) is the most
common major congenital malformation of the head and
neck. Previous studies suggested an association between fetal
opioid exposure and CLP. This study seeks to evaluate the
associations between CLP and neonatal abstinence
syndrome (NAS) in the United States.
Study Design. Population-based inpatient registry
analysis.
Setting. Academic medical center.
Subjects and Methods. Kids’ Inpatient Database (2016)
was used to identify weighted in-hospital births with
diagnoses of CLP or NAS. Demographic information
was obtained.
Results. Among 3.8 million weighted in-hospital births,
preva- lence rates of CLP in the NAS and non-NAS
populations were 3.13 and 1.35 per 1000, respectively.
The odds ratios for patients with NAS developing CLP,
isolated cleft palate, isolated cleft lip, and cleft lip and
palate when compared with the reference population
were 2.33 (95% CI, 1.87-2.91;
P \.001), 4.97 (95% CI, 3.84-6.43; P \.001), 1.01 (P = .
98),
and 0.80 (P = .46). Independent predictors of CLP
within the NAS population included median household
income for patients’ zip code, race, hospital region,
payment method, and maternal use of tobacco or other
drugs of addiction. The binary logistic regression model
accounting for possible confounding variables produced
an odds ratio of 1.74 (95% CI, 1.36-2.23; P \ .001) for
the association between NAS and CLP.
Conclusion. Our study found an association between NAS
and CLP, specifically isolated cleft palate, suggesting that pre-
natal exposure to opioids may be an environmental risk
factor in the development of CLP.
Keywords
pediatric, cleft lip, cleft palate, cleft lip and palate,
neonatal abstinence syndrome
Received May 1, 2020; accepted July 2, 2020.
Head and Neck Surgery
1–7
© American Academy of
Otolaryngology–Head and Neck
Surgery Foundation 2020
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599820944899
http://otojournal.org
C
left lip and/or cleft palate (CLP) is the most common
major congenital malformation of the head and neck,
affecting approximately 1 in 700 live births.1 Based
on the etiology, embryology, genetics, and recurrence risk,
this malformation is typically categorized into 1 of 2 groups:
isolated cleft palate and cleft lip with or without cleft palate.
According to World Health Organization data, the incidence
of isolated cleft palate and cleft lip with and without cleft
palate is 0.5 and 0.79 per 1000 live births, respectively. 2
Cleft lip with or without cleft palate occurs at variable rates
among different ethnicities, whereas the incidence of cleft
palate is relatively constant.3 While CLP can be associated
with other congenital abnormalities and known syndromes,
the majority of cases are isolated. 4-6 Genetic and environ-
mental risk factors have been described; however, their role
in the development of CLP is not fully understood. Some of
the environmental risk factors that have been associated with
CLP include maternal smoking, maternal alcohol use, antic-
onvulsant drugs, retinoid drugs, lack of prenatal care, and
nutritional deficiencies—some of which include folate, vita-
min B6, and zinc.4
Previous studies have suggested an association between
fetal opioid exposure and CLP.7-11 A systematic review of
68 studies evaluating the association between prenatal opioid
use and congenital malformations found that CLPs were
among the most commonly reported findings associated with
prenatal opioid use.12 However, the teratogenicity of opioids
remains unknown. A better understanding of the role of envi-
ronmental risk factors for CLP development will promote
1
School of Medicine, Boston University, Boston, Massachusetts, USA
2
Department of Otolaryngology–Head and Neck Surgery, Boston Medical
Center, Boston, Massachusetts, USA
3
Department of Otolaryngology–Head and Neck Surgery, Tufts
Medical Center, Boston, Massachusetts, USA
Corresponding Author:
Jessica R. Levi, MD, School of Medicine, Boston University, BCD Building,
Fifth Floor, 800 Harrison Ave, Boston, MA 02118, USA.
Email: Jessica.levi@bmc.org
2 Otolaryngology–Head and Neck
Table 1. ICD-10-CM Diagnosis Codes.
Diagnoses
Neonatal withdrawal symptoms from maternal use of drugs of addiction
Cleft lip and/or cleft palate
Isolated cleft palate
Q35.9
Isolated cleft lip
Cleft lip and palate
Q37.4,
Congenital malformation syndrome due to known exogenous causes
Newborn small for gestational age
Late newborn, not heavy for gestational age
Abnormal findings on neonatal screening
Newborn (suspected to be) affected by noxious substances transmitted
via placenta or breast milk
Newborn affected by other maternal medication
Newborn affected by maternal use of tobacco
Newborn affected by maternal use of alcohol
Newborn affected by maternal use of drugs of addiction
Newborn affected by maternal noxious substance, unspecified
Newborn affected by maternal conditions that may be unrelated to
present pregnancy
Newborn affected by maternal infectious and parasitic diseases
Newborn affected by maternal nutritional disorders
Newborn affected by other maternal conditions
Abbreviation: ICD-10-CM, International Classification of Diseases, 10th Revision, Clinical Modification.
more effective maternal counseling and prenatal interven-
tions to minimize the risk of CLP and its consequences.
Neonatal abstinence syndrome (NAS) is described as
postnatal withdrawal from substances that the mother used
during pregnancy.13 Clinical features of NAS can vary
widely in onset, manifestation, and severity, but they typi-
cally begin within the first few days after birth and include
autonomic dysregulation (fever, sweating, tachypnea), gas-
trointestinal symptoms (diarrhea, vomiting, poor feeding),
and central nervous system findings (irritability, tremor, sei-
zures).14 From 2009 to 2016, the rate of NAS in the United
States increased from 2.9 to 7.0 per 1000 newborn hospitali-
zations.15 A retrospective cohort study involving 11,599 hos-
pital births at West Virginia University’s tertiary care center
found a correlation between NAS and CLP, suggesting that
in utero exposure to opioids is an environmental risk factor
for developing CLP.16 In our retrospective study, a nation-
wide database was used to evaluate the associations between
CLP and NAS in the United States.
Methods
The study examined nationwide in-hospital births in 2016
with the Kids’ Inpatient Database (KID), Healthcare Cost
and Utilization Project, Agency for Healthcare Research and
Quality.17 The Healthcare Cost and Utilization Project has
many contributing partners. 18 Boston Medical Center and
Boston University Medical Campus Institutional Review
Board did not require approval or exemption, as the KID is a
Surgery
ICD-10-CM codes
P96.1
Q35, Q35.1, Q35.3, Q35.5, Q35.7,
Q36, Q36.0, Q36.1, Q36.9
Q37, Q37.0, Q37.1, Q37.2, Q37.3,
Q37.5, Q37.8, Q37.9
Q86, Q86.0, Q86.1, Q86.2, Q86.8
P05.1
P08.2
P09
P04, P04.0, P04.1, P04.2, P04.3,
P04.4, P04.5, P04.6, P04.8, P04.9
P04.1
P04.2
P04.3
P04.4
P04.9
P00, P00.0, P00.1, P00.2, P00.3, P00.4,
P00.5, P00.6, P00.7, P00.8, P00.9
P00.2
P00.4
P00.8
public database and research with publicly available data
does not meet the definition of human subjects research at
our institution under 45 CFR 46. Data was obtained from the
most recent version of the KID, which provides data on
nationwide inpatient discharges in 2016. Only patients with
in-hospital births were included in this study. An in-hospital
birth was defined as a principal or secondary diagnosis code
indicating a live birth in the hospital; all transfers were
excluded.19 The International Classification of Diseases,
10th Revision, Clinical Modification (ICD-10-CM) codes for
neonatal withdrawal symptoms from maternal use of drugs
of addiction (P96.1) and diagnoses representing CLP (Table
1) were used to collect data of interest. Data with ICD-10-
CM codes for congenital malformation syndromes due to
known exogenous causes (within Q86 code category) were
excluded, as we are interested in CLP not associated with
other congenital malformation syndromes due to external
causes, including fetal alcohol syndrome, fetal hydantoin
syndrome, and dysmorphism due to warfarin. To demon-
strate national estimates, discharge weights provided in
the KID must be applied to each discharge data value.
Stratifying variables used to produce discharge weights were
geographic region, urban/rural location, teaching status, bed
size, ownership, and children’s hospital.18 All statistical
analysis in this study was done with the KID’s discharge
weights. Python 3.7.4 in a Jupyter Notebook was used to
conduct data analysis.20,21 SciPy, NumPy, pandas, Matplotlib,
and icd10 were Python packages used for data analysis.22-26
Prevalence rates and odds ratios (ORs) were used to quantify pregnancy includes maternal periodontal disease, anemia,
associations between CLP groups in the general hospital intrauterine
birth population and in the NAS population. Prevalence rates
and ORs were also calculated for subgroups with isolated
cleft palate, isolated cleft lip, and cleft lip and palate together.
A chi-square test was used to determine if ORs were
statistically significant (P \ .05). When the expected value
of any of the cells in a contingency table was \5, Fisher’s
exact test was used to determine significance of ORs. SPSS
Statistics (v 26; IBM Corp) was used to create binary logistic
regression models for variables suspected to potentially
affect CLP pre- sentation, including NAS, sex, race, region,
median household income quartile, and other possible
confounding variables based on ICD-10-CM codes.
Statistical significance of vari- ables within the binary
logistic regression models was deter- mined with a Wald chi-
square test (P \ .05). 3,743,917 without NAS
Results 25,355 with NAS
There were 3,769,641 weighted in-hospital births in the
2016 KID. A total of 369 weighted in-hospital births with
ICD-10-CM codes for congenital malformation syndromes
due to known exogenous causes were excluded, resulting in
a data set of 3,769,272 weighted in-hospital births. Among 79 with CLP
patients in our data set, 0.673% (25,355) had NAS; 0.136%
(5115) had CLP; and 0.002% (79) had NAS and CLP. The
prevalence rates of CLP in the NAS and non-NAS popula-
tions were 3.13 and 1.35 per 1000 in-hospital births, respec- Prevalence Rate: 3.13
tively (Figure 1). The OR for NAS patients developing per 1,000 weighted in-hospital births
CLP when compared with the reference population was 2.33
(95% CI, 1.87-2.91; P \ .001). The ORs for developing iso-
lated cleft palate, isolated cleft lip, and cleft lip and palate
were 4.97 (95% CI, 3.84-6.43; P \ .001), 1.01 (P = .98),
and 0.80 (P = .46; Table 2).
Demographic and birth-related information between cases
of CLP with NAS and cases of CLP without NAS was ana-
lyzed with ORs (Table 3). Possible confounding variables
were analyzed with ORs between the cohorts (Table 4).
Baseline characteristics to compare the cohorts are presented
in Table 1. Among patients with CLP, a comparison of
those with and without NAS showed statistically significant
differences in the following: median household income for
patients’ zip code \$43,000 (OR, 2.12; 95% CI, 1.36-3.30;
P = .001), race (white and Hispanic; ORs, 2.33, 0.08; 95%
CI, 1.43-3.79, 0.01-0.43; P \ .001), Northeast hospital
region
(OR, 1.83; 95% CI, 1.07-3.13; P = .024), payment method
(Medicaid and private insurance, including HMO [health
maintenance organization]; ORs, 4.68, 0.20; 95% CI, 2.63-
8.31, 0.10-0.38; P \ .001), maternal use of tobacco (OR,
9.56; 95% CI, 4.06-22.53; P \ .001), maternal use of drugs
of addiction (OR, 9.78; 95% CI, 4.92-19.46; P \ .001),
new- born affected by other maternal medications (OR,
10.18; 95% CI, 2.71-38.19; P = .030), noxious substances
transmitted via placenta or breast milk (OR, 10.75; 95% CI,
6.29-18.40; P \
.001), and other maternal conditions unrelated to present
preg- nancy (OR, 2.99; 95% CI, 1.31-6.79; P = .027). The
category of other maternal conditions unrelated to present
 3,769,641 weighted in-hospital births

Excluded 369 weighted in-hospital births with congenital malformation syndromes due to known exogenous causes

3,769,272 weighted in-hospital births

Figure 1. CONSORT diagram of weighted in-hospital births

regarding neonatal abstinence syndrome (NAS) and cleft lip
and/or cleft palate (CLP).
5,036 with CLP

Table 2. Comparing CLP in NAS and Non-NAS Populations

With Odds Ratio.
Prevalence Rate: 1.35
Cleft type Odds ratio 95% CI P value per 1,000 weighted in-hospital births

CLP 2.33 1.87-2.91 \.001

Isolated cleft palate 4.97 3.84-6.43 \.001
Isolated cleft lip 1.01 0.50-2.06 .976
Cleft lip and palate 0.80 0.45-1.43 .458

Abbreviations: CLP, cleft lip and/or cleft palate; NAS, neonatal abstinence
syndrome.

contraceptive device, cervicitis, pelvic inflammatory

disease, endometritis, autoimmune conditions, and enzyme-
level ab- normalities. A comprehensive list of conditions
can be found in the ICD-10-Mortality Perinatal Subset,
published by the Centers for Disease Control and
Prevention.27
The binary logistic regression model accounting for
possi- ble confounding variables produced an OR of 1.74
(95% CI, 1.36-2.23; P \ .001) for the association between
NAS and CLP. Variables used in the regression model,
ORs, 95% CIs,
 Table 3. Comparing Demographics and Birth-Related Information Table 4. Comparing Baseline Characteristics in the NAS and Non-
in the NAS and Non-NAS CLP Populations With Odds Ratio. NAS CLP Populations With Odds Ratio.
Demographics/birth-related Odds Odds
information Percentage ratio P value Baseline characteristic ratio P value

Female sex 43.2 1.02 .947 Abnormal findings on neonatal screening 2.73 .244a
Race Newborn (suspected to be) affected by 10.75 \.001a
White 51.2 2.33 \.001 noxious
substances transmitted via placenta or breast
Black 8.44 0.77 .561 milk
Hispanic 17.93 0.08 \.001 Newborn affected by other maternal 10.18 .030a

Asian or Pacific Islander 5.49 —a .022b medication

Native American 1.10 1.48 .584b Newborn affected by maternal use of tobacco 9.56 \.001a
Other 5.41 0.86 .799b Newborn affected by maternal use of alcohol —b ..999a
Missing/invalid 10.43 — — Newborn affected by maternal use of drugs 9.78 \.001a
Median household income for of addiction
patient’s zip code, $ Newborn affected by maternal noxious 6.71 .171a
1-42,999 28.9 2.12 .001 substance, unspecified
43,000-53,999 25.4 0.85 .543 Newborn affected by maternal conditions that 1.41 .242
54,000-70,999 23.8 0.58 .077 may be unrelated to present pregnancy
≤71,000 20.8 0.74 .315 Newborn affected by maternal infectious 0.97 .947
H and
ospital region parasitic diseases
Northeast 13.7 1.83 .024 Newborn affected by maternal nutritional —b ..999a
Midwest 22.0 1.25 .393 disorders
South 39.7 0.81 .370 Newborn affected by other maternal 2.99 .027a
West 24.5 0.62 .108 conditions
Payer
Medicare 0.252 —a ..999 Abbreviations: CLP, cleft lip and/or cleft palate; NAS, neonatal abstinence
syndrome.
Medicaid 49.9 4.68 \.001 a
Calculated per Fisher’s exact test.
Private insurance, including HMO 42.7 0.20 \.001 b
Contingency table contained values of 0.
Self-pay 3.78 1.29 .768b
No charge \0.001 —a ..999
Other 3.17 —a .181 beneficial in identifying and characterizing risk factors for
Newborn small for gestational age 4.93 1.32 .594b CLP.1,4-6 Although previous studies have suggested an asso-
Late newborn, not heavy 3.78 0.82 ..999b ciation between NAS and CLP, to our knowledge, no exist-
for gestational age ing literature has used a nationwide pediatric database to
analyze the association between NAS and CLP.7-12,16
Abbreviations: CLP, cleft lip and/or cleft palate; HMO, health maintenance
organization; NAS, neonatal abstinence syndrome. A retrospective cohort study involving 11,599 hospital
a
Contingency table contained values of 0. births at West Virginia University’s tertiary care center from
b
Calculated per Fisher’s exact test. 2013 to 2017 found an association between NAS and CLP,
with 8 patients having NAS and CLP.16 When examining
rates of CLP within the study population, the authors found a
and P values can be found in Table 5. Statistically signifi- prevalence rate of 6.79 per 1000 live births with NAS and 1.63
cant independent predictors of CLP were newborn affected per 1000 live births without NAS (OR, 4.18; P = .0009). Our
by noxious substances transmitted via placenta or breast results agree with these findings, as we also found higher preva-
milk (OR, 1.35; 95% CI, 1.14-1.59; P \ .001), race (black, lence rates of CLP in neonates with NAS as compared with neo-
Hispanic, Native American, and other vs white; ORs, 0.53, nates without NAS (OR, 2.33; 95% CI, 1.87-2.91; P \ .001).
0.84, 1.33, 0.82; 95% CI, 0.48-0.59, 0.77-0.91, 1.01-1.76, 0.72- When examining subgroups of isolated cleft lip, isolated
0.93; P \.001, P \ .001, P = .041, P = .002), hospital region cleft palate, and cleft lip and palate together, the prior study
(Midwest, South, and West vs Northeast; ORs, 1.23, 1.20, 1.20; found a statistically significant association with NAS for iso-
95% CI, 1.11-1.36, 1.10-1.32, 1.09-1.32; P \ .001), and male lated cleft palate (OR, 3.79, P = .0535) and isolated cleft lip
sex (OR, 0.81; 95% CI, 0.76-0.86; P \ .001). (OR, 5.92; P = .0008). However, the analysis did not show a
significant association between cleft lip and palate together
Discussion and NAS (OR, 2.94, P = .3494). However, our study showed
This study evaluated nationwide associations between NAS a statistically significant association only between NAS and
and CLP. The genetic and environmental risk factors of CLP isolated cleft palate (OR, 4.97; 95% CI, 3.84-6.43; P \ .
are incompletely understood; a large study population is 001), while isolated cleft lip and cleft lip and palate were not
Table 5. Expected Odds Ratios for Variables in Binary Logistic Regression
Model.
Variable Odds ratio 95% CI P value

NAS 1.74 1.36-2.23 \.001

Newborn affected by noxious substances transmitted via placenta or breast 1.35 1.14-1.59 \.001
milk
Newborn affected by other maternal conditions 1.13 0.95-1.34 .169
Median household income for patient’s zip code, $
1-42,999 —a
43,000-53,999 0.99 0.92-2.08 .882
54,000-70,999 0.96 0.88-1.04 .338
≤71,000 0.97 0.88-1.06 .460
Race
White —a
Black 0.53 0.48-0.59 \.001
Hispanic 0.84 0.77-0.91 \.001
Asian or Pacific Islander 0.95 0.84-1.08 .428
Native American 1.33 1.01-1.76 .041
Other 0.82 0.72-0.93 .002
Hospital region
Northeast —a
Midwest 1.23 1.11-1.36 \.001
South 1.20 1.10-1.32 \.001
West 1.20 1.09-1.32 \.001
Payer
Medicare —a
Medicaid 1.51 0.85-2.69 .160
Private insurance, including HMO 1.18 0.66-2.11 .569
Self-pay 1.11 0.61-2.02 .724
No charge 0.76 0.12-4.86 .772
Other 1.44 0.79-2.63 .228
Sex
Male —a
Female 0.81 0.76-0.86 \.001
Abbreviations: HMO, health maintenance organization; NAS, neonatal abstinence syndrome.
a
Reference variable.

associated with NAS (P = .976 and 0.458, respectively). It is
worth noting a difference in demographics between the stud-
ies. One hundred percent of the patients with NAS and CLP
in the West Virginia study were white, as compared with
51.2% of the patients in the present study. The West Virginia
study had a majority of females (64%), while ours had a
minority of females (43.2%). Differences in the distribution
of females to males between these studies are perhaps
responsi- ble for the varied statistical results with respect to
the cleft lip findings. Females are less likely to carry a
diagnosis of cleft lip with or without cleft palate and are
underrepresented in our study as compared with the West
Virginia report. Therefore, the lack of a significant association
between NAS and isolated cleft lip and cleft lip and palate
together in the present report may be affected by sex
composition differences.
When compared with the West Virginia University study,
our study had a much larger sample size, which enabled us
to more effectively detect statistically significant differences
among variables with lower prevalence rates. Additionally,
using a national database allows the findings in this report to
have better external validity and generalizability. In a report
released by the CDC on the incidence of NAS in 28 states,
West Virginia in 2013 had the highest incidence of NAS at
33.4 per 1000 hospital births, as well as the third-highest
annual change in incidence rate.28 Therefore, trends in those
data may not be indicative of nationwide trends, as the rate
of NAS in the United Sates in 2013 was 5.8 per 1000 new-
born hospitalizations and increased to 7.0 in 2016, which is
much lower than the reported incidence in West Virginia.15
The West Virginia study did not identify any statistically
significant confounding variables with respect to the reported
associations between NAS and CLP. However, in our data
set, we found multiple statistically significant associations
with potentially confounding variables, including race,
median household income for patient’s zip code, hospital
region, method of payment for hospital care, as well as
newborn exposures to noxious substances via placenta or
breast milk and to maternal conditions not related to
pregnancy. Interestingly, being of Hispanic race appears to
have a protective effect on CLP in the NAS population,
with an OR of 0.08 (P \ .001). Also, having private insur-
ance (including HMO) appears to have a protective effect,
while having Medicaid is positively associated with CLP in
the NAS population, as the ORs were 0.20 (P \ .001) and
4.68 (P \ .001), respectively. These discrepancies among
payment groups may be explained by the effect of nonpri-
vate insurance on health outcomes, but prior studies have
shown inconclusive and variable results on the association
between insurance type and health outcomes.29
Based on a binary logistic regression model to account
for potentially confounding variables, there was a decrease
in the strength of association between NAS and CLP from
2.33 to 1.74; however, the association remained statistically
significant (95% CI, 1.36-2.23; P \ .001). As the variables
listed here appear to play a role in CLP development in new-
borns with NAS, this information could be used clinically
for risk stratification of pregnant mothers and prenatal coun-
seling during pregnancy. Furthermore, maternal opioid use
frequently coexists with polysubstance use, psychiatric ill-
ness, poor prenatal care and nutrition, chronic medical con-
ditions, and lower socioeconomic status, which also may
mediate this effect.14,30
Our study focused on newborn characteristics based on
ICD-10-CM codes listed in the KID, which includes diag-
noses and demographic information specific to newborns but
does not contain any maternal health information. This is a
potential limitation, as we were unable to characterize mater-
nal factors, including folic acid and prenatal care, which
may also act as confounders or mediate the development of
CLPs. Another limitation to our study is the use of ICD-10-
CM codes to characterize diagnoses within our data set. This
classification system is frequently being updated, which may
make it challenging for health care providers to consistently
identify the most accurate ICD-10-CM code for a patient’s
diagnosis and hospital care. 31 Furthermore, there are dis-
crepancies among criteria that health care providers use for
diagnoses. Some clinicians and researchers define NAS as
prenatal exposure to opioids, while others use a broader defi-
nition that includes prenatal exposure to nonopioid
substances, such as antidepressants, alcohol,
benzodiazepines, barbitu- rates, methamphetamines, cocaine,
and inhalants.13,14,32,33 This discrepancy in definitions used for
NAS produces challenges in classification, diagnosis, and
treatment of neonates with prena- tal substance exposure, as
many current guidelines and studies are targeted toward infants
exposed to opioids in utero.14,34
In our study, we excluded patients who had a congenital
malformation syndrome due to a known exogenous cause, so
we could isolate congenital CLP, rather than CLP acquired
from known teratogens. However, some of these excluded
patients could be those who had CLP (a congenital malfor-
mation) secondary to opioid exposure during pregnancy (an
exogenous cause). Due to this concern, we compared CLP
and NAS within our data set without the exclusion criteria
and obtained similar results, with no changes in statistical
significance of our results.
While we found a statistically significant association
between NAS and CLP, specifically isolated cleft palate, the
mechanism of this association remains unclear. Further stud-
ies need to be conducted to understand this association.
Conclusions
Our study found an association between NAS and CLP, spe-
cifically isolated cleft palate, in a nationwide database repre-
senting weighted discharges throughout the United States.
This suggests that prenatal exposure to opioids may be an
environmental risk factor in the development of CLP. As a
mechanistic explanation of this association is not currently
known, future translational and clinical studies need to be
conducted to better characterize this relationship. This
current study will enable clinicians to stratify risk and offer
more effective maternal counseling and prenatal
interventions to minimize the risk of CLP and its neonatal
consequences.
Author Contributions
David O’Neil Danis III, developed study hypothesis and design;
major role in organization, statistical analysis, and interpretation of
data, contributions in drafting, editing, and finalizing manuscript,
agreement to be accountable for all aspects of work; Kevin
Bachrach, input on study design; substantial assistance in organi-
zation and statistical analysis of data, contributions in drafting,
editing, and finalizing manuscript, agreement to be accountable for
all aspects of work; Jacquelyn Piraquive, input on study design;
substantial assistance in organization and interpretation of data,
contributions in drafting, editing, and finalizing manuscript, agree-
ment to be accountable for all aspects of work; Alexander P.
Marston, verified feasibility of study hypothesis and design; major
role in data presentation and interpretation, contributions in draft-
ing, editing, and finalizing manuscript, agreement to be accounta-
ble for all aspects of work; Jessica R. Levi, developed study
hypothesis and design; major role in data presentation and interpre-
tation, contributions in drafting, editing, and finalizing manuscript,
agreement to be accountable for all aspects of work.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.
References
1. Crockett DJ, Goudy SL. Cleft lip and palate. Facial Plast Surg
Clin North Am. 2014;22(4):573-586.
2. Mossey PA, Catilla EE. Global Registry and Database on
Craniofacial Anomalies: Report of a WHO Registry Meeting
on Craniofacial Anomalies. World Health Organization; 2001.
3. Mai CT, Cassell CH, Meyer RE, et al. Birth defects data from
population-based birth defects surveillance programs in the
United States, 2007 to 2011: highlighting orofacial clefts. Birth
Defects Res A Clin Mol Teratol. 2014;100(11):895-904.
4. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft
lip and palate. Lancet. 2009;374(9703):1773-1785.
5. Calzolari E, Pierini A, Astolfi G, et al. Associated anomalies in
multi-malformed infants with cleft lip and palate: an epidemiologic
 study of nearly 6 million births in 23 EUROCAT registries. Am J
Med Genet A. 2007;143(6):528-537.
6. Calzolari E, Bianchi F, Rubini M, Ritvanen A, Neville AJ.
Epidemiology of cleft palate in Europe: implications for genetic
research. Cleft Palate Craniofac J. 2004;41(3):244-249.
7. Thomas DB. Cleft palate, mortality and morbidity in infants of
substance abusing mothers. J Paediatr Child Health. 1995;
31(5):457-460.
8. Meyer MC, Johnston AM, Crocker AM, Heil SH. Methadone
and buprenorphine for opioid dependence during pregnancy: a
retrospective cohort study. J Addict Med. 2015;9(2):81.
9. Bracken MB, Holford TR. Exposure to prescribed drugs in
pregnancy and association with congenital malformations.
Obstet Gynecol. 1981;58(3):336-344.
10. Saxe´n I. The association between maternal influenza, drug
con- sumption and oral clefts. Acta Odontol Scand.
1975;33(5):259-267.
11. Saxe´n I. Associations between oral clefts and drugs
taken
during pregnancy. Int J Epidemiol. 1975;4(1):37-44.
12. Lind JN, Interrante JD, Ailes EC, et al. Maternal use of opioids
during pregnancy and congenital malformations: a systematic
review. Pediatrics. 2017;139(6):e20164131.
13. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics.
2014;134(2):e547-e561.
14. McQueen K, Murphy-Oikonen J. Neonatal abstinence syn-
drome. N Engl J Med. 2016;375(25):2468-2479.
15. Healthcare Cost and Utilization Project. HCUP fast stats.
Published December 2019. http://www.hcup-us.ahrq.gov/fast
stats/nas/nasquery.jsp?setting1=IP&location=US
16. Mullens CL, McCulloch IL, Hardy KM, Mathews RE, Mason
AC. Associations between orofacial clefting and neonatal absti-
nence syndrome. Plast Reconstr Surg Glob Open. 2019;7(1):
e2095.
17. Healthcare Cost and Utilization Project. HCUP Kids’ Inpatient
Database. Published 2016. http://www.hcup-us.ahrq.gov/kido
verview.jsp
18. Healthcare Cost and Utilization Project. Publishing With
HCUP Data. Agency for Healthcare Research and Quality;
2018.
19. Healthcare Cost and Utilization Project. KID description of
data elements. Published 2018. https://www.hcup-us.ahrq.gov/
db/nation/kid/kiddde.jsp
20. Van Rossum G, Drake FL. The Python Language Reference
Manual. Network Theory Ltd: 2011.
21. Kluyver T, Ragan-Kelley B, Pe´rez F, et al. Jupyter Notebooks—
a publishing format for reproducible computational workflows.
ELPUB. 2016:87-90.
22. Virtanen P, Gommers R, Oliphant TE, et al. SciPy 1.0: funda-
mental algorithms for scientific computing in Python. Nat
Methods. 2020;17(3):261-272.
23. Oliphant TE. A Guide to NumPy. Trelgol Publishing; 2006.
24. McKinney W. Data structures for statistical computing in
Python. Proceedings of the 9th Python in Science Conference.
2010;445:51-56.
25. Hunter JD. Matplotlib: a 2D graphics environment. Computing
in Science and Engineering. 2007;9(3):90.
26. PyPI.ICD-10 CM, version 0.0.4. Published July 21, 2019.
Accessed April 29, 2020. https://pypi.org/project/icd10-cm/
27. National Center for Health Statistics, Centers for Disease
Control and Prevention. ICD-10-Mortality Perinatal Subset.
Published 2017. Accessed April 29, 2020. https://www.cdc
.gov/nchs/data/dvs/perinatal_subset_2017.pdf
28. Ko JY, Patrick SW, Tong VT, Patel R, Lind JN, Barfield WD.
Incidence of neonatal abstinence syndrome—28 states, 1999-
2013. MMWR Morb Mortal Wkly Rep. 2016;65(31):799-802.
29. Levy H, Meltzer D. The impact of health insurance on health.
Annu Rev Public Health. 2008;29:399-409.
30. Forray A. Substance use during pregnancy. F1000Res. 2016;5:
F1000.
31. Utter GH, Cox GL, Owens PL, Romano PS. Challenges and
opportunities with ICD-10-CM/PCS: implications for surgical
research involving administrative data. J Am Coll Surg. 2013;
217(3):516-526.
32. Tenenbein M, Casiro OG, Seshia MM, Debooy VD. Neonatal
withdrawal from maternal volatile substance abuse. Arch Dis
Child Fetal Neonatal Ed. 1996;74(3):F204-F207.
33. Behnke M, Smith VC, Committee on Substance Abuse.
Prenatal substance abuse: short-and long-term effects on the
exposed fetus. Pediatrics. 2013;131(3):e1009-e1024.
34. Wachman EM, Schiff DM, Silverstein M. Neonatal abstinence
syndrome: advances in diagnosis and treatment. JAMA. 2018;
319(13):1362-1374.