Pediatric Nephrology

https://doi.org/10.1007/s00467-024-06287-8

ORIGINAL ARTICLE

Acute kidney injury in neonates with hypoxic ischemic

encephalopathy based on serum creatinine decline compared
to KDIGO criteria
Haejun C. Ahn1,2 · Adam Frymoyer3 · Derek B. Boothroyd4 · Sonia Bonifacio3 · Scott M. Sutherland1 · Valerie Y. Chock3

Received: 21 August 2023 / Revised: 27 December 2023 / Accepted: 28 December 2023

This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024

Abstract
Background Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for
acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI
based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given
the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on
rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to
examine associations with mortality and morbidity.
Methods A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single
center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury,
length of stay, and duration of respiratory support were compared between AKI groups.
Results Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not
meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality
and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support
compared to those without AKI.
Conclusions AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of
SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes.
Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney
injury in neonates with HIE + TH.

Keywords Neonatal · Acute kidney injury · KDIGO · Hypoxic ischemic encephalopathy · Neonatal asphyxia

Introduction and pediatric studies, AKI has been shown to be independently

Neonates with hypoxic ischemic encephalopathy (HIE) are at
high risk for developing acute kidney injury (AKI), with an
estimated incidence of around 30–40% [1–4]. In both adult
* Haejun C. Ahn
haejun.ahn@swedish.org
1
Division of Pediatric Nephrology, Stanford University
School of Medicine, Palo Alto, CA, USA
2
Present Address: Pediatric Nephrology, Swedish Health,
Seattle, WA, USA
3
Division of Neonatal and Developmental Medicine, Stanford
University School of Medicine, Palo Alto, CA, USA
4
Quantitative Sciences Unit, Stanford University School
of Medicine, Palo Alto, CA, USA
associated with worse outcomes, including increased mortality,
increased length of hospitalization, and prolonged duration of
respiratory support [5–12]. Long-term consequences of AKI in
children and adults can include development of hypertension,
chronic kidney disease, and, in some cases, kidney failure [7,
8]. In neonates with HIE, AKI has also been associated with
increased risk of neurologic disability later in life as well as
increased risk of abnormal brain MRI post-therapeutic hypo-
thermia [13, 14]. It is therefore imperative to diagnose AKI
in an accurate and timely manner and identify those neonates
who are at highest risk of developing poor clinical outcomes.
Currently, the Kidney Disease Improving Global Out-
comes (KDIGO) criteria are widely accepted as the con-
sensus definition for AKI based on either a rise in serum
creatinine (SCr) or decrease in urine output (UOP). The

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KDIGO definition, however, is challenging to apply in
newborns because SCr at birth is reflective of the mother
and therefore already elevated. As part of normal physi-
ologic changes after birth, there is a subsequent decline in
SCr over the first weeks of life. Urine may also be difficult
to measure accurately, UOP is often minimal in the first
day of life, and oliguria is not always seen in neonates with
AKI [15–18]. To account for the SCr patterns unique to the
neonatal kidney, Gupta et al. proposed an alternative cri-
teria for the diagnosis of AKI in neonates with HIE based
on the rate of SCr decline from birth over the first 7 days
[15]. Reports on the application of the Gupta AKI criteria
in neonates with HIE are limited. Herein, we applied the
Gupta and KDIGO criteria to a cohort of neonates with
HIE and compared AKI rates and clinical outcomes. Our
hypothesis was that the Gupta AKI criteria would identify
additional neonates not captured by KDIGO. To answer
the question as to whether these neonates who met Gupta
AKI criteria and not KDIGO had clinically significant
AKI, we also examined their clinical outcomes compared
to those neonates without AKI.
Materials and methods
Study design
This was a retrospective chart review of neonates with HIE
who underwent therapeutic hypothermia at a university-
affiliated neonatal intensive care unit (NICU) between 2008
and 2020. The study was approved by Stanford University’s
Institutional Review Board.
Patients
Neonates ≥ 36 weeks’ gestation who met institutional criteria
for therapeutic hypothermia based on the National Institute
of Child Health and Human Development (NICHD) Whole-
Body Hypothermia trial eligibility criteria for moderate or
severe encephalopathy were included in the study [19].
The modified Sarnat scoring system was used to determine
the severity of HIE [19, 20]. We also included 36 late pre-
term neonates who were randomized to therapeutic hypo-
thermia as part of the NICHD Preemie Hypothermia trial
(NCT01793129). Neonates with congenital anomalies and
suspected chromosomal abnormalities were excluded from
the study. We also excluded neonates who died on the first
day after birth and thus did not have serial SCr data to clas-
sify their AKI status (Fig. 1). There were no major clinical
practice changes in HIE management over the period of the
study.
Pediatric Nephrology
Definition of the study groups
Patients were classified into one of three AKI groups based
on SCr and UOP data in the first 7 days of life (Table 1).
The control (No-AKI) group consisted of neonates who
did not meet KDIGO-AKI or Gupta-AKI definitions. The
KDIGO-AKI group included those who developed AKI
according to a modified neonatal KDIGO definition (SCr
rise of ≥ 0.3 mg/dl within any 48-h period, 1.5 × increase
in SCr, or urine output ≤ 1 ml/kg/hour over 24 h after the
first day of life) [21]. The GuptaOnly-AKI group included
those who did not meet KDIGO criteria but had a rate of
SCr decline of ≤ 33%, ≤ 40%, and ≤ 46% from birth at days
3, 5, or 7, respectively [15].
Outcomes
Our primary outcome was a composite of mortality and/
or moderate/severe brain injury as determined by MRI. We
examined this as a composite outcome as severity of neuro-
logic injury and prognosis may influence decisions regarding
goals of care and the mortality outcome. Secondary out-
comes included length of stay (LOS) to hospital discharge or
transfer and duration in days of positive pressure respiratory
support defined as high flow nasal cannula ≥ 2 lpm, continu-
ous positive airway pressure (CPAP), non-invasive positive
pressure ventilation (NIPPV), or mechanical ventilation.
Data collection
Neonatal demographic data collected included gestational
age, birth weight, race, and sex. Perinatal data included type
of delivery, birth location (inborn versus outborn), presence
of chorioamnionitis, resuscitation need, umbilical cord gas,
first blood gas, and 1-min and 5-min Apgar scores. Maternal
characteristics included presence of diabetes or hypertension.
Hospital course included need for inotropes (dopamine, epi-
nephrine, hydrocortisone, or other) in the first 3 days of life,
duration of mechanical ventilation or positive pressure sup-
port, and duration of hospitalization to discharge or transfer.
SCr values obtained in the first 7 days after birth were used
to assess the presence of AKI using KDIGO and Gupta cri-
teria. SCr was measured using Jaffe until 2016, after which
the IDMS-traceable enzymatic method was implemented.
UOP data were obtained in 6-h increments from time of birth
for the first week of life or until discharge or death if sooner
and used to assess the presence of AKI using KDIGO UOP
criteria. MRI brain severity of injury was classified as either
normal–mild or moderate–severe according to a standardized
scoring system by Barkovich et al. based on evaluation of
abnormal signals in the basal ganglia and watershed areas [22].
Pediatric Nephrology

Fig. 1  Consort diagram of

patients included in study

Table 1  Definitions of KDIGO

and Gupta AKI criteria
Neonatal AKI-KDIGO criteria
Stage Serum creatinine Urine output
1 1.5–1.9 times rise from previous lowest value > 0.5 to ≤ 1 ml/kg/h for 24 h
or ≥ 0.3 mg/dl within any 48-h period
2 2.0–2.9 times rise from previous lowest value > 0.3 to ≤ 0.5 ml/kg/h for 24 h
3 ≥ 3.0 times rise from previous lowest value ≤ 0.3 ml/kg/h for 24 h
or SCr ≥ 2.5 mg/dL or kidney replacement
therapy
AKI-Gupta criteria
Serum decline from birth:
≤ 33% on day of life 3
or
≤ 40% on day of life 5
or
≤ 46% on day of life 7

Statistical analysis
Patient and maternal characteristics are reported as the
mean ± SD for continuous variables and as proportions for
categorical variables. Univariate analysis for mortality was
done using Fisher’s exact test. Logistic regression was used
to examine the relationship between AKI and the composite
outcome of death and/or moderate/severe brain injury. For
the continuous outcomes of LOS and duration of positive
respiratory support, linear models of log(outcome) were fit
with estimates (and confidence intervals) exponentiated to
estimate the multiplicative ratios. Since LOS is different
 Pediatric Nephrology

for those who die versus survivors, we chose to condition
LOS models on survival. Confounders were chosen a pri-
ori, with only a single covariate (lowest cord pH) in the
logistic models to avoid overfitting given the low number of
events. Linear models were adjusted for the lowest cord pH,
5-min Apgar score, and gestational age. Because we found
in descriptive results that the use of inotropes on day 1 was
very different across the three AKI groups (Table 3), we per-
formed post hoc models using inotrope use as a confounder
instead of pH in the logistic model and added inotrope use
in the linear models. A p value of ≤ 0.05 was considered
statistically significant. Statistical analyses were performed
using R version 4.1.3.
Results
This study included 225 neonates with moderate/severe
HIE who underwent therapeutic hypothermia. KDIGO-
AKI was diagnosed in 64/225 (28%) neonates and
Table 2  Combination of AKI categories and number of neonates in
each category
KDIGO-AKI YES KDIGO-AKI NO
Gupta-AKI in 115/225 (51%) neonates (Table 2). Of the
neonates who met Gupta criteria, 69 (31% of total neo-
nates) did not meet KDIGO-AKI criteria and comprised
the GuptaOnly-AKI cohort. There were 18 neonates who
met KDIGO-AKI criteria only (6 based on SCr and 12
based on UOP) and not the Gupta criteria as they showed a
normal rate of SCr decline and all had SCr ≤ 0.6 by DOL7.
Demographics and clinical characteristics by AKI catego-
rization are shown in Table 3.
Clinical outcomes
Clinical outcomes are reported in Table 4. We observed a
total of 19 deaths, with three in the No-AKI group, six in the
GuptaOnly-AKI group, and ten in the KDIGO-AKI group.
For the composite outcome of death or moderate/severe MRI
brain injury, a higher rate was seen in each AKI group com-
pared to No AKI (12.2% No AKI, 28.4% GuptaOnly-AKI,
42.2% KDIGO-AKI). Similarly, both survivor length of stay
and survivor duration of respiratory support trended higher
in the AKI groups compared to the No-AKI group.
Mortality or moderate/severe MRI brain injury

Gupta-AKI YES 46 (20%) 69 (31%)* For the composite outcomes of mortality or moderate/severe
Gupta-AKI NO 18 (8%) 92 (41%) MRI brain injury, in the unadjusted analysis, those who met
*
GuptaOnly-AKI had an OR of 2.84 (95% CI 1.25–6.48)
GuptaOnly-AKI cohort in bold

Table 3  Demographics and perinatal characteristics

No AKI (n = 92) GuptaOnly-AKI (n = 69) KDIGO-AKI (n = 64) p value*

Male sex, n (%) 57 (62) 46 (67) 35 (55) 0.36

Race, n (%) 0.08
White 35 (38) 32 (46) 37 (58)
Black 6 (7) 1 (1) 3 (5)
Other 51 (55) 36 (52) 24 (37)
Gestational age, weeks (mean ± SD) 39.1 ± 1.5 38.5 ± 1.8 38.7 ± 1.7 0.04
Preterm < 37 weeks 11 (12) 14 (20) 12 (19) 0.31
Birth weight, g (mean ± SD) 3229.3 ± 576.6 3355.4 ± 666.7 3243.4 ± 662.9 0.59
Median Apgar 5 min (range) 4 (0–9) 4 (0–9) 4 (0–9) 0.35
Vaginal delivery, n (%) 42 (46) 19 (28) 13 (20) 0.002
Outborn, n (%) 68 (74) 58 (84) 47 (73) 0.23
Cord pH (mean ± SD) 6.96 ± 0.18 6.95 ± 0.18 6.90 ± 0.18 0.15
Cord base excess (mean ± SD) − 14.1 ± 5.6 − 15.4 ± 6.4 − 15.1 ± 6.5 0.50
Intubated at birth, n (%) 55 (60) 48 (70) 47 (73) 0.17
Day 1 inotrope use, n (%) 19 (21) 43 (62) 31 (48) < 0.001
Clinical seizure, n (%) 24 (26) 32 (46) 30 (47) 0.008
Chorioamnionitis, n (%) 16 (17) 5 (7) 10 (16) 0.16
Maternal diabetes, n (%) 18 (20) 12 (17) 11 (17) 0.91
Maternal hypertension, n (%) 19 (21) 8 (12) 5 (8) 0.06
*
Significant values (p < 0.05) in bold. Chi-square test was used for categorical variables and Kruskal–Wallis test for continuous variables
Pediatric Nephrology

Table 4  Clinical outcomes by AKI category

No-AKI GuptaOnly-AKI p*** KDIGO-AKI p***

Death in hospital, N/total (%)* 3/92 (3.3) 6/69 (8.7) 0.012 10/64 (15.6) 0.15
Death or moderate/severe MRI, N/total (%)*† 11/90 (12.2) 19/67 (28.4) 0.0001 27/64 (42.2) 0.013
Survivor length of stay in days, mean ± SD** 13.0 ± 10.9 20.0 ± 13.0 0.0003 18.8 ± 13.4 0.0001
Survivor length of respiratory support in days, 3.8 ± 9.3 6.5 ± 6.0 0.004 5.3 ± 5.6 0.0001
mean ± SD**
*
Chi-square test
**
Kruskal–Wallis test
***
Significant values (p<0.05) in bold
†
Four survivors without MRI results, two in No-AKI and two in GuptaOnly-AKI

when compared with patients who did not experience AKI.
KDIGO-AKI had an OR of 5.24 (95% CI 2.35–11.69)
compared to No-AKI. After adjusting for cord pH, AKI
remained significantly associated with an increased odds of
the composite outcome of death or moderate/severe brain
injury compared to No-AKI (Fig. 2). The aOR was 2.72
(95% CI 1.18–6.26) and aOR 4.78 (95% CI 2.12–10.77) for
GuptaOnly-AKI and KDIGO-AKI, respectively. The stand-
ardized MRI scoring system for neonatal brain injury by
Barkovich et al. is referenced in the “Methods” section for
more detail.
Length of stay (LOS) to discharge or transfer
Among survivors, both GuptaOnly-AKI and KDIGO-
AKI groups had a significantly longer LOS to discharge
or transfer compared to the No-AKI group. In the unad-
justed analysis, the GuptaOnly-AKI cohort experienced a
1.49 times longer LOS (95% CI 1.24–1.79) compared to
No-AKI. Similarly, the KDIGO-AKI cohort experienced a
1.43 times longer LOS (95% CI 1.18–1.73) compared to the
No-AKI group. The analysis adjusted for pH, 5-min Apgar
score, and gestational age yielded similar findings, with the
GuptaOnly-AKI group estimated to have a 1.43 times longer
length of stay (95% CI 1.18–1.72) and the KDIGO-AKI
group estimated to have a 1.43 times longer length of stay
(95% CI 1.18–1.73) when compared to the No-AKI group.
Duration of respiratory support
There were four neonates among the survivors (three No-
AKI, one KDIGO-AKI) that did not require any posi-
tive pressure support beyond resuscitation in the deliv-
ery room and were excluded from the respiratory support
analysis. Both AKI groups had a significantly longer
duration of respiratory support compared to the No-AKI
group. In the unadjusted analysis, GuptaOnly-AKI was
estimated to have 1.95 times longer duration of respira-
tory support (95% CI 1.40–2.72), and KDIGO-AKI was
estimated to have 1.68 times longer duration of respira-
tory support (95% CI 1.19–2.38). After adjusting for pH,
5-min Apgar, and gestational age, GuptaOnly-AKI had
a 2.04 times longer length of respiratory support (95%
CI 1.45–2.87) and KDIGO-AKI had a 1.74 times longer
length of respiratory support (95% CI 1.22–2.48) com-
pared to No-AKI.

Fig. 2  Adjusted odds ratio or ratio of clinical outcomes by AKI cate- cord pH. Length of stay and length of respiratory support in survivors
gory when compared to neonates with No-AKI. Death in hospital and was adjusted for cord pH, 5-min Apgar, and gestational age
composite of death or moderate/severe MRI injury were adjusted for

Post hoc analysis
In a post hoc analysis, we added day 1 inotrope use (yes/
no) to our multivariate analysis (Fig. 3). For the composite
outcome of mortality or moderate/severe MRI brain injury,
KDIGO-AKI vs. No-AKI remained significant (OR 4.02,
95% CI 1.75–9.23); however, GuptaOnly-AKI vs. No-AKI
did not (OR 1.77, 95% CI 0.73–4.29). Similarly, for LOS
to transfer or discharge, adjusting for day 1 inotrope use
eliminated the significant difference between GuptaOnly-
AKI vs. No-AKI and decreased the effect of KDIGO-AKI
vs. No-AKI (1.28 times longer compared to 1.43 without day
1 inotrope). For duration of respiratory support, including
day 1 inotrope use resulted in non-significant results.
Discussion
In this study, we compared the rates of AKI in neonates with
HIE undergoing hypothermia using the current consensus
KDIGO definition along with the proposed Gupta definition
which evaluates the rate of SCr decline in the first week of
life. We hypothesized that there would be neonates who did
not meet KDIGO-AKI criteria but still had impaired kidney
function based on the Gupta definition and that these neo-
nates were at a higher risk for worse clinical outcomes. In
our cohort, 28% of neonates met KDIGO AKI criteria and
an additional 31% met Gupta AKI criteria only (and not
KDIGO criteria). As expected from existing AKI literature,
those with KDIGO defined AKI had worse clinical outcomes
compared to those without AKI. Interestingly, however,
those who met only the Gupta AKI criteria, and thus did not
have KDIGO-AKI, also had worse clinical outcomes com-
pared to those without AKI. This GuptaOnly-AKI group, as
well as the KDIGO-AKI group, experienced an increased
Fig. 3  Post hoc analysis adding day 1 inotrope use to adjusted models
of the odds ratio or ratio of clinical outcomes by AKI category when
compared to neonates with no AKI. Death in hospital and composite
of death or moderate/severe MRI brain injury were adjusted for day 1
Pediatric Nephrology
odds of death or moderate/severe injury on MRI, longer
LOS, and longer duration of respiratory support compared
to the No-AKI group.
Our results align with the findings in Gupta et al. [15] and
support the concept that a lack of or a delayed physiologic
SCr decline in neonates may represent clinically relevant
kidney injury. Specifically, our study highlights a poten-
tially underrecognized group of neonates with HIE who
receive hypothermia that have underlying kidney impair-
ment and are at higher risk for adverse clinical outcomes.
These GuptaOnly-AKI neonates, in addition to those with
KDIGO-AKI, likely warrant close monitoring and longitu-
dinal follow-up of kidney function. Identification of these
high-risk neonates who would otherwise have been missed
by the KDIGO criteria may allow us to improve their short-
term NICU outcomes, by heightening awareness of their
fluid and electrolyte status and exercising more caution when
considering nephrotoxic medications. In a similar study, Per-
azzo et al. used a SCr rate decline threshold of < 31% by
DOL 7 to identify neonates with HIE with impaired kidney
function [23]. These neonates, compared with those with no
kidney injury, also had worse outcomes, including longer
LOS and duration of mechanical ventilation.
Regarding potential long-term outcomes, studies on kid-
ney outcomes of neonates with HIE are still lacking. One of
the only studies examining the long-term kidney outcomes
in neonates with HIE treated with hypothermia found no
differences at 10–12 years in the incidence of low eGFR
(< 90 ml/min/1.73 ­m2), albuminuria, or hypertension in
those with and without a history of neonatal AKI [2]. Of
note, this was a small single-center study with 42 patients
(72% of survivors), and the majority had stage 1 AKI. Given
these limitations, the authors state that long-term follow-up
is still warranted, as kidney dysfunction may not manifest
until later in life. Many studies in older children and adults
inotrope use. Length of stay and length of respiratory support in sur-
vivors was adjusted for day 1 inotrope use, cord pH, 5-min Apgar,
and gestational age
Pediatric Nephrology
do suggest that AKI is associated with long-term sequelae,
including hypertension and chronic kidney disease (CKD)
[5, 7, 8]. For example, in a single-center study of 126 chil-
dren who developed AKI while admitted to the ICU, the
rate of CKD was 10%, and 46.8% were identified as at risk
for CKD [24]. Similarly, in a meta-analysis of adult AKI
survivors, AKI was associated with an 8.8-fold higher risk
of CKD, with the risk of CKD increasing in a graded manner
with worsening severity of AKI [25]. Thus, the GuptaOnly-
AKI group may indeed have an increased risk for the devel-
opment of CKD in the future. By identifying these neonates
and providing longitudinal monitoring, it may be possible to
address modifiable risk factors for CKD, such as proteinuria,
anemia, and hyperuricemia, in a timelier manner and slow
the progression of CKD. Earlier identification of CKD in
children is also critical as it can affect their physical growth
and neurocognitive development, both of which have a finite
window of time in which they can be addressed. Further
studies with a larger number of patients are needed to gain a
better understanding of the long-term kidney consequences
in this neonatal population.
With respect to our post hoc analysis including day 1
inotrope use, which either diminished or eliminated sig-
nificant findings, there are several potential explanations.
One possibility is that the neonates who required inotrope
support on the first day of life were more hemodynami-
cally unstable resulting in worse outcomes, regardless of
the presence of AKI. Another consideration is the possible
effect of the inotropes on our specific patient population. In
a small study examining dopamine use in neonates with HIE
who have been cooled, dopamine was associated with an
increased trend towards more seizures compared to controls.
Dopamine use was not associated with isolated increased
severity of MRI injury or death; however, it appeared to
be significant when examined as a composite outcome with
death [26]. The effect of inotropes on this specific patient
population thus warrants further examination that is outside
the scope of our study.
We acknowledge several limitations in our study. This is
a retrospective study with a single-center experience, and
there may be potential confounders that were not taken into
consideration. Although to our knowledge, there were no
significant institutional changes in the management of neo-
natal HIE between 2008 and 2020, there may be evolutions
in clinical practice influencing AKI development that are not
readily apparent. Another limitation is that although we had
over 200 neonates in our study, the overall mortality rate was
low, making it challenging to detect intergroup differences
in outcomes. We also do not have mortality data on the 27
infants who were transferred prior to discharge; however,
none of them required positive pressure respiratory support
at time of transfer to a lower acuity of care facility, so we
presume that the mortality rate in this population was near
zero. The demographics of our study also revealed a low
percentage of self-reported Black patients, which may not
be representative of other populations.
The strengths of our study include the relatively robust
number of patients and the inclusion of patients up to the
year 2020. The contemporary nature of our cohort increases
the relevance of our results to current clinical practice. We
believe that our study adds value to the existing body of neo-
natal AKI literature and contributes to a collective effort to
devise an AKI definition that best captures clinically relevant
kidney injury in this unique patient population.
In conclusion, our study demonstrates the significance
of considering the rate of SCr decline during the first week
of life in neonates with HIE who have undergone therapeu-
tic hypothermia. Incorporating the rate of SCr decline may
increase identification of those who are at risk of developing
worse clinical outcomes that may be associated with AKI
not detected by the KDIGO criteria.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00467-0​ 24-0​ 6287-8.
Funding This work was supported by the Stanford Maternal and Child
Health Research Institute Clinical Trainee Grant.
Declarations
Conflict of interest Adam Frymoyer is a scientific advisor and holds
a financial interest in Halo Biosciences unrelated to the current work.
The other authors have no conflict of interest to declare.
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