Keywords Neonates - Adverse event report - Drug exposure routes - Pharmacovigilance - FAERS
Introduction
According to data from the World Health Organization (WHO), over 2.3 million children
died within the first month of life in 2022, accounting for 47% of all deaths among
children under five years of age. The leading causes of neonatal mortality include
preterm birth, intrapartum complications, congenital anomalies, and infections, with
approximately 240,000 newborns dying from congenital disorders [1 ]. Due to ethical and technical
constraints, neonates are often excluded from clinical drug trials, resulting in
their pharmacotherapy being largely based on extrapolation from adult or older
pediatric dosing regimens as well as empirical use [2 ]. Consequently, off-label drug use
occurs in up to 90% of neonates, which is a significant risk factor for adverse drug
reactions (ADRs) in this population [3 ]
[4 ]
[5 ]. This issue is particularly critical
given the immature hepatic and renal function in neonates and their markedly
different pharmacokinetic profiles compared to other populations. These factors
contribute to distinct patterns of ADRs in neonates, posing major challenges for
their identification and monitoring [6 ]
[7 ]. Therefore, leveraging
real-world data to systematically mine and evaluate ADRs in neonates is of great
clinical and public health significance for ensuring medication safety in this
vulnerable population.
Previous studies have conducted preliminary investigations into ADRs in pediatric
populations, revealing distinct patterns in terms of severity, system organ class
(SOC) distribution, and medication use profiles [8 ]
[9 ]
[10 ]
[11 ]. A cross-sectional study comparing
ADR characteristics between adults and children as well as among pediatric subgroups
reported that neonates exhibited the highest proportion of serious ADRs (96.2%),
followed by infants (79.8%), young children (67.9%), older children (59.5%), and
adolescents (52.7%) [12 ]. However, most
existing research tends to focus on the broad category of "children" and
lacks stratified analyses targeting the high-risk neonate population with unique
pharmacological responses.
A prospective cohort study was carried out at the Hospital Clínico San Carlos in
Madrid (Spain), which adds that 17% neonates experienced an ADR, more than one-third
of ADRs needed specific treatment, and gastrointestinal problems were the most
common ADR [13 ]. Another study based on
data from a French pharmacovigilance database specifically analyzed the distribution
of drugs and affected organ systems in neonates with ADRs resulting from direct drug
exposure, explicitly excluding maternal-mediated (transplacental or
breastfeeding-related) exposure [14 ].
Most current studies on ADRs in neonates have not adequately accounted for the
various routes of drug exposure unique to this population. Neonates may be exposed
to medications through three primary pathways: (1) transplacental transfer during
the fetal period; (2) direct administration after birth via intravenous, oral, or
other routes; and (3) indirect exposure through breastfeeding. The risk of ADR
occurrence, the organ systems affected, and the spectrum of implicated drugs may
differ significantly depending on the route of exposure.
Furthermore, drug exposure during early and late pregnancy has fundamentally distinct
effects on the embryo and fetus. The early gestational period is critical for organ
formation, during which drug exposure primarily poses a risk of teratogenic effects,
leading to structural birth defects. For instance, a European study based on 2.1
million live births [15 ] found that
first-trimester exposure to selective serotonin reuptake inhibitors (SSRIs) was
significantly associated with an increased risk of various congenital heart defects.
In contrast, exposure during late pregnancy, particularly in the second and third
trimesters, is mainly linked to functional impairments or adaptation issues in
neonates. Similarly, evidence from a Danish nationwide cohort study [16 ] indicated that antibiotic exposure
during mid-to-late pregnancy was associated with an elevated risk of low birth
weight. Therefore, the timing of drug exposure is critical in determining its impact
on the fetus.
The study aims to characterize all reported ADRs associated with multiple drug
exposure pathways in neonates based on data from the FDA Adverse Event Reporting
System (FAERS). Furthermore, the study will perform stratified analyses according
to
neonatal sex, reported severity of ADRs, and mortality outcomes. These findings are
expected to provide a critical foundation for the development of a scientifically
sound risk assessment framework for drug use during the perinatal period.
Methods
Data source
FAERS is a publicly available database that collects AE and medication
error-associated reports submitted by healthcare professionals, consumers, and
drug manufacturers [17 ]. The FAERS
database is updated quarterly and contains Individual Case Safety Reports
(ICSRs), which include multiple fields such as basic patient information, drug
names, routes of administration, descriptions of adverse events, sources of
reports, and clinical outcomes.
In a broad sense, ADR refers to unintended responses to a drug when used at
normal doses. In the study, an ADR case was defined as an individual FAERS
report meeting the following criteria:
The patient population was restricted to neonates (identified in the DEMO
table by an AGE value of ‘0–28’).
The report included one and only one “Primary Suspect” drug (listed in
the DRUG table with a ROLE_COD of ‘PS’).
The report contained at least one adverse event (coded by a Preferred
Term [PT] in the REAC table using the Medical Dictionary for Regulatory
Activities, MedDRA v27.1).
Target drug screening for the neonatal population
The study population consisted of neonates (0–28 days) within the FAERS database.
For each case, the unique “Primary Suspect (PS)” drug was designated as the
“Target Drug.” All database drug names were then standardized to generic names
using the WHO Drug Dictionary (September 2024 version), and the screening was
conducted following this standardization.
Study design
In this study, FAERS data from the first quarter of 2004 to the fourth quarter of
2024 were utilized. The original ASCII-format datasets were downloaded for data
mining and statistical analysis. Reports of adverse drug reactions in neonates
(defined as age≤28 days) were identified, and data deduplication and report
exclusion were performed in accordance with the FDA’s official guidance [18 ]. Adverse event terms were coded
using the MedDRA v27.1. Reports related to neonatal drug exposure were extracted
and analyzed to investigate the risk characteristics and potential safety
signals associated with medication use during the perinatal and early postnatal
periods.
Ethical compliance
This research is a secondary analysis of the de-identified FAERS database, which
is publicly accessible. Since the data do not contain personal identifiers and
the analysis does not involve direct human subject interaction, this study was
exempt from ethical approval in accordance with the Declaration of Helsinki and
other internationally recognized ethical guidelines.
Statistical analysis
This study evaluated the signal strength of various adverse events to neonates
through the application of commonly utilized disproportional analysis
techniques, which included the reporting advantage ratio (ROR), the proportional
reporting ratio (PRR), the Bayesian Confidence Propagation Neural Network
(BCPNN), and the Multi-Item Gamma Poisson Shrinker (MGPS) [19 ]
[20 ]
[21 ], with the particular formulas
and screening criteria employed for this analysis outlined in [Table 1 ]. Data processing and
analysis were conducted using SAS 9.4 Vision.
Table 1 Disproportionality analysis.
Target Adverse Event
Other Adverse Events
Total
Suspected Drug
a
b
a+b
Other Drugs
c
d
c+d
Total
a+c
b+d
N=a+b+c+d
a: Number of ADR cases attributable to the suspected drug; b: Number of
ADR cases attributable to other drugs; c: Number of other ADR cases
attributable to the suspected drug; d: Number of other ADR cases
attributable to other drugs.
Results
Baseline characteristics of ADR reports
Between Q1 2004 and Q4 2024, a total of 15,456 neonatal reports were identified,
with 60,611 adverse event occurrences recorded. As shown in [Table 2 ], the male-to-female ratio
was approximately 1:1.3. The median body weight was 2.87 kg (IQR: 2.08–3.38 kg).
Of all reported events, 95.45% were classified as serious, and 11.08% resulted
in fatal outcomes. The majority of reports originated from Germany (29.34%) and
the United States (20.57%), with 81.49% submitted by healthcare professionals.
The median time from drug exposure to the onset of adverse events was 231 days
(IQR: 1.00–271.00 days), while the time to death among fatal cases was 2 days
(IQR: 0.00–13.00 days). Analysis by exposure route revealed significant
differences in the median time-to-onset of adverse drug reactions in neonates,
with the following specific results: placental transmission (264.00 days, IQR:
231.00–276.00 days); routes including breast milk, intravenous, and others (1.00
day, IQR: 0.00–12.00 days); intramuscular and oral administration (2.00 days,
IQR: 0.00–9.00 days); and inhalation (3.00 days, IQR: 1.00–8.00 days).
Table 2 The baseline characteristics of neonate FAERS
ICSRs.
Characteristics
Number (%)
Gender
Female (%)
5763(37.29)
Male (%)
7549(48.84)
Not Specified (%)
2144(13.87)
Age
Median (Q1, Q3)
0.00(0.00,0.02)
Serious report
Serious (%)
14753(95.45)
Non-Serious (%)
703(4.55)
Reporter
Physician (%)
5835(37.75)
Other health professional (%)
3324(21.51)
Consumer (%)
2706(17.51)
Pharmacist (%)
2290(14.82)
Lawyer (%)
197(1.27)
Not Specified (%)
1104(7.14)
Patient’s Continent
Europe (%)
28145(46.40)
Unknown (%)
19628(32.43)
North America (%)
8648(14.33)
Asia (%)
3039(5.02)
South America (%)
538(0.96)
Africa (%)
379(0.61)
Oceania (%)
234(0.46)
Outcomea
Life-Threatening (%)
1314(8.50)
Hospitalization – Initial or Prolonged (%)
4665(30.18)
Disability (%)
323(2.09)
Death (%)
1712(11.08)
Congenital Anomaly (%)
4298(27.81)
Required Intervention to Prevent Permanent Impairment/Damage
(%)
161(1.04)
Other (%)
9701(62.77)
Adverse event occurrence time – Date of administration
(days)
Median (Q1, Q3)
231.00(1.00,271.00)
Inhalation (Q1, Q3)
3.00(1.00,8.00)
Intramuscular (Q1, Q3)
2.00(0.00,9.00)
Intravenous (Q1, Q3)
1.00(0.00,3.00)
Oral (Q1, Q3)
2.00(0.00,12.00)
Other (Q1, Q3)
1.00(0.00,6.00)
Transmammary (Q1, Q3)
1.00(0.00,12.00)
Transplacental (Q1, Q3)
264.00(231.00,276.00)
Weight (kg)
Median (Q1, Q3)
2.87(2.08,3.38)
a: The outcome proportion is defined as the number of occurrences of a
specific outcome divided by the total number of patients.
The composition of adverse events
The top 50 PT signals were categorized according to the SOC classification as
shown in [Fig. 1 ]. The most
frequently reported SOC was “Injury, poisoning and procedural complications.”
The PTs linked to this SOC largely consisted of fetal exposure during pregnancy
(ROR>1). Despite this PT not indicating a specific ADR, outcome analysis
revealed its association with serious medical events and congenital anomalies as
shown in [Fig. 2 ]. The second most
frequent SOC was “Congenital, familial and genetic disorders,” accounting for
15.96% of the signals. Representative conditions included ventricular septal
defect, patent ductus arteriosus, dysmorphic features, hypospadias, and
cryptorchidism. Further analysis of exposure pathways delineated the origins of
signals in this SOC as shown in [Fig.
3 ]: 50% stemmed from intrauterine (placental) exposure, 20% from drugs
transmitted through breastfeeding, and a proportion—equivalent to that of
intrauterine exposure—originated from direct extrauterine exposure.
Additionally, the SOC “Pregnancy, puerperium and perinatal conditions”
constituted 8.65% of the reports, including preterm birth, small for gestational
age, macrosomia, and fetal growth restriction. A notable finding was the
relatively high proportion (3.88%) of all PT events associated with “off-label
use” in the neonatal population. Off-label use refers to the administration of a
medication outside the specifications of its officially approved labeling,
necessitating further evaluation of the potential association between such usage
and adverse events. As shown in [Table
3 ], the most frequently implicated medications in off-label use
reports were propranolol, levetiracetam, ibuprofen, valganciclovir, and
azithromycin.
Fig. 1 The top 50 most frequent PTs. X-axis: represents the ROR
value. Triangles: indicate that both the ROR value and its confidence
interval exceed the upper limit of the axis scale. Squares: represent
the point estimate of the ROR, with the ends of the line denoting the
upper and lower bounds of the confidence interval. Red vertical line:
corresponding to ROR=1, serving as the reference line. This study
focuses on the neonatal population. ROR>1: indicates a positive
association of the PT with the neonatal population, suggesting a
potential safety signal. ROR=1: suggests no significant association of
the PT with the neonatal population. ROR<1: implies that the
reporting proportion of the PT is lower in the neonatal population than
in other populations.
Fig. 2 Outcomes by PTs. X-axis: the outcome. The sum of
proportions exceeds 100% because individual patients can contribute to
more than one outcome category. Y-axis: PT adverse events. The color bar
(right): case numbers.
Fig. 3 The distribution of administration by SOCs. X-axis: drug
exposure routes. Y-axis: the SOCs. The color bar (right): case
numbers.
Table 3 The top 10 drugs of “off-label-use”.
Drug Name
Number (%)
Drug Name
Number (%)
Propranolol
84(11.95%)
Paracetamol
14(1.99%)
Levetiracetam
70(9.96%)
Sildenafil
14(1.99%)
Ibuprofen
51(7.25%)
Amiodarone
13(1.85%)
Valganciclovir
21(2.29%)
Amphotericin B
13(1.85%)
Azithromycin
16(2.28%)
Nitric Oxide
13(1.85%)
The outcome of adverse events
[Fig. 2 ] shows the patient outcomes
associated with different PTs for adverse events. It is important to note that
the MedDRA terminology system is designed for precise medical descriptions and
includes a large number of PTs with similar or related meanings. As shown in
[Table 2 ], among the various
patient outcomes, the highest proportions are “hospitalization” (30.18%) and
“congenital malformations” (27.81%), excluding “other serious.” A further
analysis of [Fig. 2 ] reveals that
the top five PTs leading to hospitalization are as follows: fetal exposure
during pregnancy, neonatal drug withdrawal syndrome, preterm infants, and atrial
septal defect. The top five PTs leading to congenital malformations are: fetal
exposure during pregnancy, atrial septal defect, patent ductus arteriosus,
preterm infants, and small for gestational age infants. These results highlight
a new and significant warning: in addition to previously concerned adverse
events such as restricted fetal growth and development, congenital malformations
related to the cardiovascular system also pose a significant medication risk and
should be given high attention during clinical monitoring and assessment.
Distribution of drug exposure
The statistical data for the primary PTs corresponding to the top 20 drugs are
shown in [Table 4 ]. The majority
were medications acting on the nervous system (34.27%) and the sensory organs
(26.49%). The 10 most frequently reported drugs as the primary suspected agents
were, in descending order: venlafaxine, sertraline, lamotrigine, quetiapine,
citalopram, valproic acid, levetiracetam, methadone, fluoxetine, and
escitalopram. To characterize the temporal pattern of ADRs following
intrauterine versus extrauterine drug exposures, we analyzed the median time to
ADR onset across different administration routes in [Table 2 ]. Placental drug transfer,
representing intrauterine exposure, was associated with a markedly prolonged
median ADR latency of 264 days. In contrast, extrauterine exposures demonstrated
substantially shorter median times (1–3 days). These results clearly demonstrate
distinct temporal dynamics in ADR manifestation between intrauterine and
extrauterine drug exposures, reflecting the unique pharmacokinetic and
pharmacodynamic profiles of drug transfer during gestation. The reported
outcomes were primarily classified as other serious medically important events
and congenital anomalies, as shown in [Fig. 4 ]. The primary drugs associated with congenital malformations
were citalopram, lamotrigine, levetiracetam, escitalopram, and metoprolol. These
findings suggest that neonatal adverse events are predominantly associated with
utero exposure to maternal medications.
Fig. 4 Outcome of the top 50 reported drugs. X-axis: primary
suspected drug. Y-axis: the outcome. The color bar (right): case
numbers.
Table 4 Primary PTs of the top 20 drugs.
Drug (Number of occurrences)
Top 5 PTs
Number (%)
Venlafaxine (2909)
Fetal exposure during pregnancy
428(14.71%)
Atrial septal defect
153(5.26%)
Small-for-dates baby
131(4.50%)
Respiratory disorder neonatal
125(4.30%)
Selective eating disorder
100(3.44%)
Sertraline (2725)
Fetal exposure during pregnancy
367(13.47%)
Atrial septal defect
121(4.44%)
Small-for-dates baby
103(3.78%)
Respiratory disorder neonatal
96(3.52%)
Agitation neonatal
69(2.53%)
Lamotrigine (2515)
Fetal exposure during pregnancy
412(16.39%)
Atrial septal defect
136(5.41%)
Respiratory disorder neonatal
79(3.14%)
Selective eating disorder
68(2.70%)
Small-for-dates baby
57(2.27%)
Quetiapine (2412)
Fetal exposure during pregnancy
378(15.67%)
Small-for-dates baby
120(4.98%)
Respiratory disorder neonatal
114(4.73%)
Atrial septal defect
109(4.52%)
Drug withdrawal syndrome neonatal
66(2.74%)
Citalopram(2218)
Fetal exposure during pregnancy
398(17.94%)
Small-for-dates baby
151(6.81%)
Respiratory disorder neonatal
108(4.87%)
Atrial septal defect
108(4.87%)
Ventricular septal defect
81(3.65%)
Valproic acid (1873)
Exposure during pregnancy
94(5.02%)
Fetal anticonvulsant syndrome
92(4.91%)
Dysmorphism
65(3.47%)
Fetal exposure during pregnancy
62(3.31%)
Developmental delay
46(2.46%)
Levetiracetam (1553)
Fetal exposure during pregnancy
233(14.91%)
Small-for-dates baby
85(5.44%)
Off label use
69(4.41%)
Drug ineffective
69(4.41%)
Atrial septal defect
52(3.33%)
Methadone (1404)
Drug withdrawal syndrome neonatal
519(36.97%)
Fetal exposure during pregnancy
441(31.41%)
Premature baby
120(8.55%)
Maternal exposure during pregnancy
65(4.63%)
Maternal drugs affecting fetus
24(1.71%)
Fluoxetine (1343)
Fetal exposure during pregnancy
121(9.00%)
Exposure during pregnancy
65(4.84%)
Premature baby
44(3.27%)
Small-for-dates baby
38(2.83%)
Drug withdrawal syndrome neonatal
35(2.61%)
Escitalopram (1168)
Fetal exposure during pregnancy
250(21.40%)
Small-for-dates baby
118(10.10%)
Atrial septal defect
71(6.08%)
Premature baby
39(3.33%)
Drug withdrawal syndrome neonatal
39(3.33%)
Paroxetine (1071)
Fetal exposure during pregnancy
131(12.23%)
Atrial septal defect
43(4.01%)
Drug withdrawal syndrome neonatal
24(2.24%)
Patent ductus arteriosus
21(1.96%)
Maternal drugs affecting fetus
17(1.59%)
Olanzapine (858)
Fetal exposure during pregnancy
93(10.84%)
Exposure during pregnancy
46(5.36%)
Selective eating disorder
32(3.73%)
Small-for-dates baby
26(3.03%)
Atrial septal defect
26(3.03%)
Metoprolol (799)
Fetal exposure during pregnancy
150(18.77%)
Small-for-dates baby
86(10.76%)
Atrial septal defect
57(7.13%)
Hypoglycemia neonatal
31(3.88%)
Hypospadias
24(3.00%)
Indometacin (730)
Neonatal disorder
31(4.24%)
Gastrointestinal perforation
15(2.05%)
Drug ineffective
15(2.05%)
Oliguria
14(1.92%)
Renal failure
12(1.64%)
Aripiprazole (702)
Fetal exposure during pregnancy
174(24.78%)
Premature baby
21(2.99%)
Hypospadias
18(2.56%)
Small-for-dates baby
15(2.14%)
Large-for-dates baby
13(1.85%)
Nitric oxide (695)
Patent ductus arteriosus
36(5.18%)
Intraventricular hemorrhage neonatal
30(4.32%)
Neonatal disorder
27(3.88%)
Oxygen saturation decreased
23(3.33%)
Ibuprofen (619)
Off-label use
40(6.46%)
Intestinal perforation
35(5.65%)
Pulmonary hypertension
15(2.42%)
Product use issue
15(2.42%)
Oliguria
13(2.10%)
Mirtazapine (465)
Fetal exposure during pregnancy
81(17.42%)
Atrial septal defect
25(5.38%)
Small-for-dates baby
22(4.73%)
Drug withdrawal syndrome neonatal
19(4.09%)
Patent ductus arteriosus
17(3.66%)
Stratified analysis
We conducted a comparative analysis based on route of administration, sex, and
severity of reported adverse events. Among these factors, the route of
administration emerged as a key determinant of neonatal drug exposure patterns
and associated adverse outcomes, as shown in [Fig. 5 ]. Transplacental (i. e.,
intrauterine exposure) accounted for the highest proportion of cases (52.47%),
followed by intravenous injection (9.34%), oral administration (6.77%),
transmammary (1.80%), intramuscular injection (1.48%), and inhalation (1.29%).
Notably, venlafaxine, sertraline, quetiapine, lamotrigine, and levetiracetam
consistently ranked among the top five drugs involved in both intrauterine and
lactational exposures.
Fig. 5 The administration of adverse events. X-axis: drug exposure
routes. Y-axis: case numbers.
A sex-difference analysis was conducted to ascertain the association patterns
between certain adverse events and gender. A complete case analysis was
performed, excluding the 14% of cases with missing gender data. As shown in
[Fig. 6 ], conditions such as
microcephaly, ventricular septal defect, and small-for-dates baby were reported
more frequently among female neonates, suggesting a higher susceptibility to
craniofacial and cardiac developmental abnormalities as well as intrauterine
growth restriction. In contrast, male neonates demonstrated a greater risk of
urogenital malformations, including hypospadias and cryptorchidism.
Additionally, the incidence of neonatal irritability was also higher in males,
which may be attributed to sex-related differences in hormonal regulation or
neurodevelopmental sensitivity.
Fig. 6 Volcano plot comparing male and female groups. X-axis: fold
change (Log2 ROR). Larger absolute values indicate a greater
magnitude of difference between groups. Y-axis: p -value, with
p -value<0.05 considered statistically significant. The
horizontal gray dashed line: points above it represent
p <0.05.
Analysis of the severity of reported adverse events revealed notable differences
across exposure types and clinical conditions as shown in [Fig. 7 ]. Drug exposures via
breastfeeding were predominantly associated with non-serious reports, whereas
prenatal drug use, atrial septal defects, and neonatal withdrawal syndrome were
more frequently linked to serious adverse event reports. These findings suggest
that in utero exposure during critical periods of fetal development carries a
substantially higher risk of severe outcomes compared to lactational exposure.
This may be attributed to the greater vulnerability of organogenesis and central
nervous system development during gestation, as well as the higher systemic drug
concentrations typically associated with transplacental transfer.
Fig. 7 Volcano plot comparing non-serious and serious groups.
X-axis: fold change (Log2 ROR). Larger absolute values
indicate a greater magnitude of difference between groups. Y-axis:
p -value, with p -value<0.05 considered statistically
significant. The horizontal gray dashed line: points above it represent
p <0.05.
Discussion
Due to the challenges in conducting clinical trials in the neonatal population, many
drug labels lack specific information regarding neonatal use. Therefore,
computer-based risk signal detection for neonatal drug safety assessment is
particularly critical. This study analyzed reports of ADRs in neonates resulting
from both maternal and direct drug exposure, utilizing data from the FAERS database
spanning the first quarter of 2004 to the fourth quarter of 2024. Among the target
population of 15,456 neonatal patients, a total of 60,611 adverse events were
reported. Strikingly, 95.45% of these events were classified as serious, and 11.08%
of reports documented a fatal outcome. These findings underscore the urgent need to
address perinatal medication safety, particularly in the highly sensitive neonatal
population. Furthermore, a marked increase in neonatal ADR reports has been observed
since 2014. This trend may be associated with multiple factors, including shifts in
prescribing patterns, incidence rates of adverse events, the number of newly
approved drugs, advancements in industry-funded initiatives, enhanced public
awareness, and evolving regulatory policies [22 ]
[23 ]
[24 ]
[25 ]. The study further analyzed the
geographic distribution bias of neonatal adverse drug reaction reports by continent.
The vast majority of reports originated from Europe (42.64%) and North America
(14.09%), which highlights significant global disparities in neonatal
pharmacovigilance capacity. The high reporting rates from developed regions reflect
their well-established monitoring networks and standardized reporting protocols,
providing actionable models for regions with less mature surveillance systems to
reference and adapt.
Given that the majority of neonatal ADRs occur within the NICU, 81.49% of reports
were submitted by healthcare professionals, resulting in generally more
comprehensive and standardized documentation. Additionally, literature reviews
indicate that pediatric ADRs predominantly occur within the first few years of life
[11 ]
[26 ]
[27 ]
[28 ]
[29 ], which aligns with our findings.
Moreover, the study identified orders of magnitude differences in reaction times
between in utero (264.00 days) and extrauterine (1.00–3.00 days) drug exposure in
neonates, reflecting distinct mechanisms of “delayed developmental effects” versus
“acute toxic reactions.” This underscores the need for route-specific monitoring
windows in neonatal drug safety assessment.
The results of this study indicate that SOC categories involved in neonatal ADRs are
predominantly concentrated in congenital disorders and perinatal conditions,
accounting for approximately 43.25% of all cases. Current research data suggest that
65%–75% of birth defects are of unknown origin and are generally thought to arise
from multifactorial interactions between genetic predispositions and environmental
influences. The most common identifiable genetic etiologies are single-gene
disorders (15%–20%) and chromosomal abnormalities (5%). Approximately 10% of birth
defects are linked to environmental exposures, including pharmaceuticals, maternal
conditions, infectious pathogens, electromagnetic radiation, and environmental
contaminants [30 ]
[31 ]. It is imperative to recognize that
pharmaceutical exposures hold a unique status among these etiologies due to their
potential for prevention through careful medication management before and during
pregnancy.
Drugs associated with congenital disorders and perinatal conditions were mainly those
targeting the nervous system, representing 34.27%. Among different routes of
administration, transplacental exposure accounted for the highest proportion.
Notably, antidepressants were the most frequently implicated drugs, regardless of
whether the exposure occurred in utero or postnatally. This finding differs markedly
from the ADR profiles observed in children and adolescents. Previous studies have
shown that ADRs in pediatric populations are primarily associated with “General
disorders and administration site conditions” and “Nervous system disorders,” with
anti-infective agents being the most commonly implicated drug class [12 ].
According to published literature, depression during pregnancy is relatively
prevalent, with an overall incidence rate as high as 39.0%. Approximately 9.02% of
pregnant women experience moderate depression, and the incidence of postpartum
depression ranges between 10% and 15% [32 ]
[33 ]. Most
antidepressants exert their therapeutic effects by modulating the levels of
serotonin, norepinephrine, and dopamine in the body. From a pharmacokinetic
perspective, selective serotonin reuptake inhibitors (SSRIs) and
serotonin-norepinephrine reuptake inhibitors (SNRIs) can cross the placental barrier
and be excreted into breast milk, thereby directly affecting neonatal development
[34 ]. The timing of drug exposure
is a key determinant for fetal and neonatal outcomes, necessitating a differential
risk assessment between first-trimester teratogenicity and late-pregnancy neonatal
adaptation problems. A cohort study conducted in Canada further demonstrated that
infants born to women who used serotonergic antidepressants during early pregnancy
were at an increased risk of developing structural abnormalities in the
cardiovascular, musculoskeletal, and respiratory systems [35 ]. Therefore, in the neonatal
population, special attention should be given to maternal exposure to
antidepressants during early pregnancy.
In neonatal ADRs, intravenous drug exposure accounts for 9.34%, ranking only behind
transplacental and breast milk-mediated exposures. The most frequently implicated
intravenous medications include levetiracetam, zidovudine, ibuprofen, and
indomethacin. Notably, among anti-infective agents, antiretroviral drugs used for
HIV treatment pose the highest risk. Zidovudine, a first-line antiretroviral agent
for the prevention of mother-to-child transmission of HIV [36 ], is primarily associated with
adverse effects involving the hematologic and gastrointestinal systems [37 ]. Additionally, ibuprofen and
indomethacin are commonly used to treat patent ductus arteriosus in preterm infants;
however, both are administered off-label in this population. These drugs may cause
serious adverse effects, including neonatal renal impairment, necrotizing
enterocolitis, and gastrointestinal perforation [38 ]. Off-label drug use is widely
recognized as a major contributor to ADRs in pediatric clinical practice, and such
use is even more prevalent among neonates. Therefore, the clinical use of these
medications in neonates should be carried out with caution, ensuring rational
prescribing practices and enhanced pharmacovigilance.
There are certain limitations to this study. Although the database offers advantages
such as a large sample size and broad coverage, several limitations remain. First,
as a spontaneous reporting system, FAERS is subject to underreporting, incomplete
information, and challenges in establishing definitive causal relationships. Second,
the absence of key clinical variables such as birth weight, gestational age, and
specific dosage limits the ability to conduct an in-depth analysis of ADR risk
factors.
Conclusions
The study presents a distinctive overview of ADRs associated with neonatal drug
exposure. Maternal use of antidepressants during pregnancy was identified as a
prominent risk factor for neonatal ADRs. Moreover, particular attention should be
paid to ADRs resulting from direct neonatal exposure to antiretroviral agents,
antiepileptic drugs, and medications used for patent ductus arteriosus closure, as
the majority of these drugs are administered off-label in this vulnerable
population. Given these findings, predictive models for placental permeability of
antidepressants and fetal risk assessment tools can be developed to optimize risk
management of medication use during pregnancy. Furthermore, this study highlights
the urgent need to address the systemic challenges neonates face within global drug
safety monitoring systems. We advocate for the creation of an international
pharmacovigilance network specifically for neonates. Its efforts should be directed
towards standardizing reporting requirements, establishing robust mechanisms for the
transnational exchange of anonymized data, and implementing advanced signal
detection methodologies to uncover subtle risks in this distinct patient group.
