The Journal of Maternal-Fetal & Neonatal Medicine

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Neonatal hypoxic–ischemic encephalopathy:

emerging therapeutic strategies based on
pathophysiologic phases of the injury

Qiuli Wang, Hongyan Lv, Lixin Lu, Pengshun Ren & Lianxiang Li

To cite this article: Qiuli Wang, Hongyan Lv, Lixin Lu, Pengshun Ren & Lianxiang Li (2018):
Neonatal hypoxic–ischemic encephalopathy: emerging therapeutic strategies based on
pathophysiologic phases of the injury, The Journal of Maternal-Fetal & Neonatal Medicine, DOI:
10.1080/14767058.2018.1468881

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2018.1468881

REVIEW ARTICLE

Neonatal hypoxic–ischemic encephalopathy: emerging therapeutic strategies

based on pathophysiologic phases of the injury
Qiuli Wanga, Hongyan Lva,b, Lixin Luc, Pengshun Rena and Lianxiang Lib,d
a
Department of Neonatology, Handan Maternal and Child Health Care Hospital, Handan, PR China; bDepartment of Neonatal
Pathology, Handan Maternal and Child Health Care Hospital, Handan, PR China; cDepartment of Pediatrics, Handan 7th Hospital,
Handan, PR China; dDepartment of Neural Development and Neural Pathology, Hebei University of Engineering School of Medicine,
Handan, PR China

ABSTRACT ARTICLE HISTORY

Neonatal hypoxic ischemic encephalopathy (HIE) is an important cause of neonatal death and Received 5 February 2018
disability. At present, there is no unified standard and specialized treatment method for neonatal Accepted 20 April 2018
HIE. In clinical practice, we have found that a gap remains between preclinical medical research
KEYWORDS
and clinical application in the treatment of neonatal HIE. To promote an organic combination of
Cerebral hypoxic ischemic;
preclinical research and clinical application, we propose the different phases as intervention tar- erythropoietin; hypothermia;
gets, based on the pathophysiologic changes in phases I, II, and III of neonatal HIE; moreover, newborn; rehabilitation;
we suggest transformative medicine as a principle that may improve the therapeutic effect by stem cell transplantation;
blocking the progression of the disease to an irreversible stage. For instance, in phase I, mild therapeutics
hypothermia, free radical scavenger (erythropoietin, hydrogen-rich saline), excitatory amino acid
receptor blocker, and neuroprotective agents should be administered to neonates with moder-
ate/severe HIE; in phase II, following phase I treatment, anti-inflammatory agents, neuroprotec-
tive or nerve regeneration agents, and stem cell transplantation should be administered to
patients; in phase III, anti-inflammatory agents, neuroprotective or nerve regeneration agents,
and stem cell transplantation should be administered to patients. As soon as the patient’s condi-
tion has stabilized, acupuncture, massage, and rehabilitation training should be performed.
Following further study of stem cells, stem cell transplantation is expected to become the most
promising therapeutic candidate for treatment of severe neonatal HIE with its sequelae.

Introduction additionally, the intervention methods are inadequate,

Neonatal hypoxic–ischemic encephalopathy (HIE) is a
kind of brain injury caused by the severe reduction of
cerebral oxygen and/or blood supply in the perinatal
period [1]. According to current reports, approximately
1 million newborns worldwide die from neonatal HIE
each. The incidence of neonatal HIE is 1–2/1000 live
births, of which 10–15% of the infants succumb and
25–30% suffer permanent neurological damage,
including cerebral palsy, epilepsy, mental disorders,
vision and hearing impairment, and cognition and
learning disabilities [2,3]. Thus, it places a great mental
and economic burden on the family and has become
one of the primary global medical problems. In the
face of this challenge, a large number of scholars have
conducted numerous animal experiments and clinical
studies. Nonetheless, therapy for neonatal HIE remains
largely unsatisfactory, which partly arises from the lack
of a unified standard treatment for newborn HIE;
since the intervention targets and critical time window
are not fully known. Additionally, there is a certain
gap between preclinical medical research and its clin-
ical application.
Animal experimentation indicates that pathophysio-
logical changes in neonatal HIE can be divided into
phases I, II, and III. There are significant differences in
the pathophysiology and biochemistry of the brain tis-
sues in each of these phases. According to the patho-
physiological changes of the different phases, a
corresponding intervention is administered, which has
been closely designed based on the experimental
pathology outcome. The time of hospitalization after
onset of the injury for each patient is highly inconsist-
ent in clinical practice, suggesting that the pathophysi-
ology phases are also different within different
patients. Without consideration of these factors, there
is a degree of blindness in the therapeutic process,
which, ultimately, prevents achievement of the

CONTACT Hongyan Lv 3581479478@qq.com Departments of Neonatology and Neonatal Pathology, Handan Maternal and Child Health Care
Hospital, No. 6, Li Ming Street, Peace Road, Handan City, Hebei Province, China
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 Q. WANG ET AL.
desired results. Another problem arises when the inter-
vention results of animal experiments are transformed
into clinical practice, as there often remains a gap in
treatment. If the preclinical medical research is organ-
ically combined with clinical applications, it is clearly
beneficial to the patient. Therefore, this review is
designed to describe the changes in pathophysiologic
phases I, II, and III of neonatal HIE; further, in the con-
text of transformative medicine, the intervention tar-
gets in different periods are discussed, with the aim of
achieving a better therapeutic effect.
Intervention measures and pathophysiology
phases of neonatal hypoxic–ischemic
encephalopathy
The pathological and biochemical changes of neonatal
HIE constitute a cascading reaction process, where
apoptosis or necrosis of nerve cells is the final out-
come of brain damage. Animal experiments show that
the pathophysiological process of neonatal HIE is div-
ided into three phases as follows: (1). primary energy
failure phase (phase I): this phase occurs 0–6 h after
the hypoxic–ischemic injury. Under normal circumstan-
ces, maintenance of the cerebral blood flow is
dependent on systemic blood pressure; however, due
to insufficient blood supply in the placenta (such as
umbilical cord around the neck, dystocia, placenta pre-
via), a variety of changes occur, including hypoxia–i-
schemia and acidosis in tissues and organs, reduced
myocardial contractility, decreased arterial blood pres-
sure, and reduced cerebral blood flow [4]. Due to brain
tissue hypoxia–ischemia, glucose anaerobic fermenta-
tion is enhanced in nerve cells, thereby reducing the
adenosine triphosphate (ATP) in the cells. This leads to
high energy storage depletion; ion pump dysfunction;
and Naþ, Ca2þþ transport hindrance; it also causes
accumulation of lactic acid, free radicals, and excitatory
amino acids, as well as mitochondrial dysfunction,
nerve cell edema, and eventual apoptosis (or cell
death) [5,6]. Therefore, the treatment strategies during
phase I utilize conventional methods: patients should
be treated with hypothermia, free radical scavengers
(e.g. melatonin, erythropoietin, hydrogen-rich saline, or
coenzyme Q10), excitatory amino acid receptor block-
ing agents, and/or neuroprotective agents. (2)
Secondary energy failure phase (phase II): this phase
occurs 6–72 h after hypoxia–ischemia. Excitatory neuro-
transmitters and free radicals continue to be released,
mitochondrial dysfunction becomes more serious, and
large phosphorus reserves are depleted [7]; as the
phase progresses, cytochrome C escapes from mito-
chondria, the cascade reaction is activated, and nerve
cell apoptosis begins. In addition, as inflammatory fac-
tors become involved and brain injury is more sub-
stantial [8], phase II has a close relationship with the
onset of epileptic seizures. Therefore, the treatment
strategies during phase II follow the treatments
employed during phase I: patients should be treated
with anti-inflammatory agents, neuroprotective, or
nerve regenerating agents (e.g. nerve growth factor),
and stem cell transplantation. (3) Injury repair or
chronic inflammation phase (phase III): this phase
occurs >72 h after the onset of neonatal HIE, and lasts
for days or months. In accordance with the severity of
the disease, the duration of hypoxia–ischemia, and the
effects of prior therapeutic interventions, there are
generally two outcomes: one involves recovery, where
the damaged brain tissue enters the repair process,
and the surviving neurons and glial cells begin to dif-
ferentiate, proliferate, and regenerate; in the other out-
come, the injured tissue continues to deteriorate. Here,
as inflammation continues to increase and persist, the
damaged brain tissues lose the support of neuro-
trophic factors. Surviving microglia and astrocytes con-
tinue to release harmful cytokines, which promote
additional neuronal death and axonal injury, leading
to further aggravation of the injured brain tissues [9].
Therefore, if a patient continues to deteriorate upon
reaching phase III, treatment should include anti-
inflammatory agents, neuroprotective, or nerve regen-
erating agents (e.g. nerve growth factor), and stem cell
transplantation. Once the patient’s condition has stabi-
lized, acupuncture, massage, and rehabilitation should
be administered to the patient as early as possible
(Figure 1).
Evidence of the neuroprotective effects of
existing intervention measures
Free radical inhibitors and scavengers
Melatonin
Melatonin is an amine hormone secreted by the pineal
gland, with strong anti-inflammatory and free radical-
scavenging effects. Notably, melatonin can directly
induce the production of glutathione peroxidase,
glutathione reductase, 6-phosphate glucose dehydro-
genase, and superoxide dismutase; moreover, it
increases the efficiency of mitochondrial electron
transport. Animal experiments have shown that mela-
tonin can reduce the recruitment and activation of
glial cells after neonatal hypoxic brain injury [10]; it
can also promote the formation of myelin sheath and
improve the survival of brain neurons [11].
Importantly, melatonin is much more capable of

Figure 1. Pathophysiology phases of neonatal hypoxic-ischemic encephalopathy and its treatment strategies.
scavenging hydroxyl radicals than mannitol, glutathi-
one, or vitamin E. Recent clinical trials have shown
that, for neonates with moderate/or severe HIE, mela-
tonin therapy combined with mild hypothermia can
reduce oxidative stress, thereby improving survival and
neurodevelopmental outcomes at 6 months of age
[12]. Therefore, as melatonin is a safe, non-toxic, effect-
ive, and promising neuroprotective drug for neonatal
HIE, it is worth popularizing.
Erythropoietin (EPO)
EPO is a 34-kDa glycoprotein hormone, which is widely
used in treatment of anemia, renal failure, cancer, pre-
maturity, and chronic inflammatory diseases. More
recently, EPO has been shown to exhibit an obvious
neuroprotective effect. Many animal experiments have
demonstrated that EPO can promote neuron differenti-
ation and regeneration in cases of neonatal HIE; more-
over, it can inhibit nerve cell apoptosis, as well as
reduce and regulate the inflammatory response and
anti-oxidative damage, thereby promoting vascular
regeneration and improving microcirculation.
Additionally, EPO can prevent glutamic excitotoxicity
and brain edema. Our previous study showed that, for
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
neonates with moderate/or severe HIE, EPO (200 IU/kg)
can promote the early recovery of neonatal neuro-
logical function [13] and improve infant fine motor
and language skills, as well as the development of per-
ception [14]. The use of EPO (300 or 500 IU/kg) for
neonates with HIE can improve intelligence and motor
development, thus reducing the incidence of cerebral
palsy and the rate of disability [15]. Low doses of
erythropoietin for neonatal HIE have been demon-
strated to be safe. Recently, a phase II EPO trial
showed that high doses of EPO (1000 IU/kg) for neo-
nates with HIE can alleviate the severity of brain injury
(as detected by magnetic resonance imaging) and
improve motor function at 1 year of age [16]. EPO
may serve as a neuroprotective drug for neonatal HIE;
however, the optimal dosage, the long-term effect of
nerve function improvement, and the therapeutic
mechanism of EPO still require further study.
Hydrogen-rich saline
Hydrogen is one of the most renowned medical gases,
as it exhibits a powerful ability to scavenge free radi-
cals, and can improve the activity of peroxidase dismu-
tase, enhance the activity of mitochondrial respiratory
4 Q. WANG ET AL.
chain enzyme, and provide an anti-apoptotic effect. In
a rat model of cerebral ischemia, different concentra-
tions of hydrogen-rich saline have been shown to
reduce the infarct size and expression of inflammatory
factors [17], as well as to improve cognitive function
[18]. Because the study of hydrogen as a therapy for
neonatal HIE is still in the initial stages, further investi-
gation is needed regarding the ideal dosage and form
of hydrogen to be administered to infants; moreover,
the range of therapeutic time, standard application
method, pharmacokinetics, and toxicology remain to
be determined.
Anti-inflammatory treatment
Minocycline
In vitro cell culture and in vivo animal experiments
have shown that minocycline can protect neurons by
inhibiting the proliferation and activation of microglia,
thereby reducing neuronal death [19,20]. If a patient is
treated with a sufficient dose of minocycline within a
few hours to days after the onset of HIE, the patient
may experience a reduction in brain tissue damage
caused by an excessive inflammatory reaction.
Glucocorticoid hormone
Glucocorticoid can increase the use of glucose in the
brain, alleviate the inflammatory response, and inhibit
apoptosis; thus, it has a significant ability to reduce
HIE. Currently, glucocorticoid is recommended for pre-
natal use, but cannot be used immediately after birth
[21]. Therefore, clinical data regarding glucocorticoid
therapy for neonatal HIE remain scarce. Notably, the
ideal dosage of glucocorticoid hormone, the optimal
timing of glucocorticoid application, and the ability of
glucocorticoid to improve prognosis in neonatal HIE,
are key areas for future research.
Neuroprotection and neural regeneration agents
Gangliosides
Gangliosides serve as an important component of
nerve tissue. Exogenous gangliosides exhibit a strong
affinity for brain tissue; they can promote the regener-
ation and repair of damaged nerves. In a rat model,
ganglioside treatment (0.02 mg) can increase the acidic
content of myelin basic protein and glial fibrillary
acidic protein in brain tissue; further, it can reduce
neurobehavioral abnormalities in neonatal rats [22]. In
addition, gangliosides can repair the structure of mye-
lin sheath and axon lipid rafts that incorporate
neurofascin 155 (NF 155), as well as related lipid rafts,
thereby preventing damage to the myelin sheath [23].
Clinical trials have shown that the ganglioside therapy
(20 mg/d) for neonates with HIE can significantly
shorten the recovery times of primitive reflexes,
muscle tension, and consciousness [24].
Nerve growth factor (NGF)
Animal experiments showed that, in neonatal HIE, NGF
therapy could inhibit neuronal apoptosis, promote the
activation and regeneration of endogenous neural
stem cells, and reduce the degeneration and necrosis
of neurons. NGF is effective in promoting the recovery
of nerve function and long-term nerve development
[25]; additionally, clinical trials have shown that NGF
can significantly improve neurological function and
reduce mortality in neonates with HIE [26].
Therapeutic hypothermia
Hypothermia is regarded as a good therapeutic meas-
ure for moderate/severe neonatal HIE. Currently, the
neuroprotection mechanism of hypothermia is not
clear; it may be related to a variety of factors: reduc-
tion of glutamate release, reduction of the metabolism
and energy consumption of brain tissue, reduction of
acidosis in neurons and promotion of protein synthe-
sis, reduction of the synthesis of leukotriene, reduction
of blood–brain barrier damage and brain edema,
inhibition of free radicals, inhibition of cell apoptosis,
and/or inhibition of free radical generation and lipid
peroxide reaction.
The best treatment window for hypothermia begins
within 6 h after birth and must be maintained for
48–72 h; the patient’s rectal temperature must be
maintained at 34.5–35  C. Most clinical trials have
shown that hypothermia can reduce the mortality and
risk of neurodevelopmental disabilities in neonates
with moderate/severe HIE [27–29]. However, some
reports indicate that, in neonates with HIE who have
undergone therapeutic hypothermia, 44–53% of
patients still died or were left with moderate or severe
neurological dysfunction [30]. There are also reports
that whereas hypothermia for neonates with HIE
(defined in those studies as cooling to 33–35  C for
72 h within the first 6 h of life) can improve the neuro-
logical outcome in survivors, it does not significantly
reduce the combined rate of death or severe disability
[31]. There have also been some adverse reactions
reported during hypothermia, including arrhythmias,
septic episodes, and epileptic attack [32]; in one
report, there was an increase in the risk of death in
neonates [33]. Despite this contradictory data,
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5

Table 1. The summary of animal experiment outcome and clinical application of the stem cell transplantation for neonatal hypo-
xic–ischemic encephalopathy.
Receiving Delivery
Cell type subject Delivery time route Outcome Author [Reference]
NSCs
hFNSCs Rat 3 d after HIE CVD After stem cell transplantation, it is distribution in the Qu et al. [34]
damaged cortex and hippocampus, and stem cell
differentiate into neurons and astrocytes
hENSCs Rat 24 h after HIE F.D After stem cell transplantation, a lot of microglia cell Daadi et al. [35]
appear, and it can enhance the repair of endogen-
ous brain tissue, motor function is improved
ES-NPCs Rat 40 h after HIE DMC ES-NPCs can differentiate to cortical neurons with pyr- Shinoyama et al. [36]
amidal morphology, the deep layer-specific marker
is expressed, the motor function is improved
hENSCs Rat 24 h after HIE IND hNSCs extensively migrated into brain areas within Ji et al [37]
24 h after stem cell, delivery, hNSCs reduced the
up-regulation of cytosolic IL-1b, p-IjBa, and NF-jB
p65 level, neurological outcomes are improved
hFNSCs Human infant 75 d after HIE CVD twenty-eight days after stem cell transplantation, the Luan et al. [38]
patient’s myotonia is remarkable improved, the
patient’s intelligence the motor function
is improved
hNPCs Human newborn 4–20 d after HIE CVD Two days after transplantation, the sucking and swal- Luan et al. [39]
lowing reflex are appeared
gradually in all patients, muscular tension is also
improved, and convulsion
stopped. Six cases are followed up for 12 months,
four cases are normal
development in psychomotor cores of each scale
reached normal level,
two cases have cerebral palsy
hUCB-MCs
hUCB-MCs Rat 3 h after HIE PCD hUCB-MCs can promote sensorimotor reflexes of rats, Pimentel-Coelno Co,
the number of activated et al. [40]
microglial cells in the cerebral cortex is decreased,
neurological function is improved
hUCB-MCs Rat 24 h after HIE A.B Learning ability and long-term spatial memory are sig- Greggio et al. [42]
nificantly improved
hUCB-MCs Rat 7 d after HIE V.B hUCB-MCs can increase the neurotrophic factor, the Yasuhara et al. [44]
neurological behavior of rats are improved
HIE: neonatal hypoxic ischemic encephalopathy; NSCs: neural stem cells; hFNSCs: human fetal neural stem cells; hENSCs: human embryonic neural stem
cells; hNPCs: human neural precursor cells; ES-NPCs: embryonic stem cell-derived neural progenitor cells; hUCB-MCs: human umbilical cord blood mono-
nuclear cells; CVD: cerebral ventricle delivery; FD: forebrain deliver; IND: intranasally delivery; IHT: intrahippocampal delivery; ICD: intracardial delivery;
ICD: intracerebral delivery; PCD: peritoneal cavity delivery; VB: vein delivery; AB: artery delivery.

hypothermia is an indispensable method to treat neo-
natal HIE; it minimizes the brain tissue damage in the
acute phase of neonatal HIE and delays or curbs the
development of the disease, thereby providing valu-
able time to attempt other treatments.
Stem cell transplantation
Neural stem cells (NSCs)
NSCs widely exist in the embryonic and adult nervous
system; importantly, they can differentiate into neu-
rons, astrocytes, and oligodendrocytes, both in vivo
and in vitro. Exogenous stem cell transplantation for
neonatal HIE has aroused the interest of many scholars
and shows promising preliminary results (Table 1). The
delivery routes for stem cell transplantation include
intracerebral, intrathecal, arterial, intravenous, intraperi-
toneal, and intranasal approaches. When human
embryonic NSCs (hNSCs) are transplanted into the
ventricle of HIE neonatal rats, the hNSCs can reach the
areas of brain damage along the subventricle zone
and corpus callosum, especially in the cerebral cortex
and hippocampus; 85% of the transplanted cells form
hNuc-NF or hNuc-tubulin positive cells in the cerebral
cortex, whereas 60% of the transplanted cells differen-
tiate into hNuc-GFAP-positive cells [34]. Stem cells also
may facilitate endogenous brain repair [35]. When
neural precursor cells (derived from embryonic stem
cells) are implanted into the deep motor cortex of HIE
newborn rats, neural precursor cells can differentiate
into cortical neurons and motor function is improved,
within 3 weeks post-implantation [36]. When hNSCs
are implanted into the nasal cavity of HIE newborn
rats, hNSCs become widely distributed in different
brain regions; thus, multiple cytokines (LI-1b, P-Lkba,
NF-Kb, p65) exhibit decreased expression and neuro-
logical function is improved [37]. The noninvasive
nasal cavity implantation provides a simple and easy
6 Q. WANG ET AL.
method to perform stem cell transplantation in the
future. The clinical application of NSCs has been pre-
liminarily attempted in infants with HIE. Luan et al.
[38] reported that hNSCs were transplanted into one
infant with neurological disability that was caused by
severe HIE (implantation at 75 d after birth); 28 d after
stem cell transplantation, the infant’s myotonia, intelli-
gence, and movement were remarkably improved,
such that the infant became similar to normal infants
of the same age. In another study, human neural pro-
genitor cells were implanted in six cases of neonatal
HIE; the second day after cell transplantation, all
patients’ sucking and swallowing reflexes appeared,
convulsions stopped, and muscle tension was
improved. Importantly, all patients were re-examined
at 12 months of age; four cases exhibited normal men-
tal motor development, whereas two cases presented
with cerebral palsy [39]. The above studies have pro-
vided very valuable experience for further research
and clinical applications.
Cord blood mononuclear cells
Cord blood cell transplantation exhibits a strong
potential for nerve regeneration. Notably, these stem
cells are easier to obtain than other stem cells. Animal
experiments have shown that cord blood mononuclear
cells can reduce the activity of microglia, inhibit neur-
onal cell death, and promote the recovery of sensori-
motor reflex function [40]. Cord blood mononuclear
cells can promote the differentiation of endogenous
neural stem cells into mature neurons to aid in the
recovery and development of damaged neurons [41];
moreover, cord blood mononuclear cells significantly
improve learning ability and long-term spatial memory
in rats [42,43] and can promote the up-regulation of
neurotrophic factor in the brain after cell transplant-
ation [44]. Therefore, cord blood cell transplantation
may be the most potent therapeutic candidate for
neonatal HIE, with wide application prospects.
However, the optimal timing, dosage, and delivery of
stem cell transplantation for neonatal HIE will require
further study.
Acupuncture and massage
Acupuncture and massage are effective and unique
methods for many neurological diseases with sequelae.
These methods are very helpful for promoting the
recovery of neurological function and reducing the
degree of disability. In recent years, there have been
an increasing number of preliminary reports regarding
their usage in the treatment of neonatal HIE. Animal
experimentation has shown that acupuncture can
reduce neuronal apoptosis in the cerebral cortex and
hippocampus of rats with hypoxic-ischemic brain
injury [45], enhance learning and memory abilities,
and upregulate brain-derived neurotrophic factor
(BDNF) and glial cell-derived neurotrophic factor (NGF)
[46]. The therapeutic mechanism may be related to
the opening of K-ATP channels, inhibition of c-Fos and
c-Jun immediate genes in the early hypoxic–ischemic
stage, and inhibition of neuronal apoptosis.
Acupuncture for cerebral palsy in children can improve
fine motor skills by 67.7%, increase the grip index by
87.1%, and improve the visual perception index [47]. It
has been reported that the fine motor, gross motor,
language, and other aspects can be improved in cases
of early neonatal brain injury, using traditional Chinese
medicine massage [48]. However, a comprehensive
analysis indicated that the inclusion criteria and con-
trasting experiment regarding acupuncture in the
patient serve as defects in the design of the experi-
ment; thus, the authors of that analysis do not recom-
mend acupuncture for neonatal HIE [49]. The study
design regarding acupuncture and massage for neo-
natal HIE should be further improved, along with an
increase in the clinical sample size, to correctly evalu-
ate its effect.
Conclusion
To improve the clinical treatment of neonatal HIE, this
review aimed to provide the context of transform-
ational medicine, and to describe the pathophysiologic
changes of different phases in neonatal HIE as key
treatment targets for novel intervention strategies,
according to the different phases.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This study is supported by Health and Family Planning
Commission of Hebei (No 20150033). Science and
Technology Bureau of Handan, City, Hebei Province (No.
152810879-6); Science and Technology Department of Hebei
Province (No. 162777201).
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