The Journal of Maternal-Fetal & Neonatal Medicine

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Congenital Hypothyroidism

Mohammad Al-Qahtani

To cite this article: Mohammad Al-Qahtani (2020): Congenital Hypothyroidism, The Journal of
Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2020.1838480

To link to this article: https://doi.org/10.1080/14767058.2020.1838480

Published online: 28 Oct 2020.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2020.1838480

REVIEW ARTICLE

Congenital Hypothyroidism
Mohammad Al-Qahtani
College of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Kingdom of Saudi Arabia

ABSTRACT ARTICLE HISTORY

Congenital hypothyroidism (CH) is the commonest preventable cause of mental retardation in Received 29 July 2020
human species. It is so important for clinician to know its etiology epidemiology, clinical mani- Revised 14 September 2020
festation and treatment strategies. Since it is one of the rare serious diseases that should not be Accepted 14 October 2020
diagnosed clinically because late clinical features corresponds to advanced mental retardation,
KEYWORDS
the neonatal screening detection is the best and preferable way of early diagnosis of this con- Congenital hypothyroidism;
genital disease. Confirmatory laboratory and radiological diagnostic tests should be performed infants; mental retardation;
immediately after the positive neonatal screening test. In order to prevent mental defects and neonatal screening
to maintain long term clinical as well as biochemical euthyroidism in affected children its diag-
nosis approach, medical treatment and follow-up should be well established knowledge to all
pediatricians during the childhood period and later on to general practitioners when these indi-
viduals grow up as adults. Congenital hypothyroidism is a potentially serious disease that we
need to emphasize on early detection, using proper diagnostic tools and early and planned
therapeutic approach.

Introduction associated with some genetically deter-

Congenital hypothyroidism (CH), defined as thyroid
hormone deficiency presenting at birth is the com-
monest preventable cause of mental retardation in
pediatric age group having a global incidence of
1:2000 to 1:4000 newborns [1].
CH in the majority of cases is due defected thyroid
gland embryological development (dysgenesis) or less
commonly due to defect in thyroid hormone synthesis
(dyshormonogenesis), collectively both etiologies lead
to the major type; primary congenital hypothyroidism.
Central congenital hypothyroidism; secondary CH is
caused by pituitary defected thyroid stimulating hor-
mone (TSH), mostly it is associated with defects in the
other pituitary hormones, termed as congenital hypo-
pituitarism [1]. The third etiology is called peripheral
hypothyroidism in which, the defect is related to thy-
roid hormone transport, metabolism, or its action.
If the thyroid hormone deficiency is persistent and
mandates life-long treatment it is classified as perman-
ent CH, while temporary deficiency of thyroid hor-
mone that is recovering to normal in the first couple
months or years of life is classified as transient CH.
Syndromic hypothyroidism is another entity that is
mined syndromes.
Due to some residual thyroid function and or
incomplete trans-placental maternal thyroid hormone
that protect neonates’ tissues clinical manifestations of
CH usually appear beyond age of 3 months, during
that period effects of thyroid hormone deficiency on
the developing brain tissue might be irreversible.
Since mid-1970s Thyroid function tests had been
incorporated in the newborn screening (NBS) pro-
grams which helped in early detection and manage-
ment of neonates with CH.
The main scope of this review article is to cover the
primary CH and to some extent the secondary (pituit-
ary) and tertiary (hypothalamic) CH. Although the
exact etiologies of the CH are not well determined,
yet early diagnosis and management of this serious
hypothyroid disorder of the neonate to prevent the
permanent damage is the major target of this topic.
Epidemiology
Before the start of newborn screening programs, the
incidence of clinical diagnosis of congenital hypothy-
roidism was in the range of 1: 7000 to 1:10,000 and
after implementing the screening programs, the

CONTACT Mohammad Al-Qahtani mhqahtani@iau.edu.sa Consultant of Pediatrics and Pediatric Endocrinology at King Fahd Hospital of the
University, P.O. Box 2208, Alkhobar, 31952, Kingdom of Saudi Arabia
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 M. AL-QAHTANI
Figure 1. The incidence of congenital hypothyroidism; dysgenetic vs euotopic. Statistics from reference [40].
incidence is in the range of 1:3000 to 1:4000 [2].
However the incidence varies according to geographic
location, racial and ethnic populations. The French
newborn screening program estimated the incidence
of permanent hypothyroidism to be 1:10,000 [3],
whereas the incidence in the Greek Cypriot population
was around 1:800 [4]. A recent study in the United
States showed increased incidence from 1:4094 in
1987 to 1:2372 in 2002 [5]. The increased incidence is
possibly explained by a change in testing strategy.
Saudi population incidence has been reported in the
range of 1:2666 to 1:3417 [6].
Recently there is doubling of the incidence of con-
genital hypothyroidism reported from multiple coun-
tries in the range of 1/1400 and 1/2800. This increased
rate has been attributed to different reasons, the
major factor is due to lowering of TSH screening cut-
offs in many newborn screening programs [7] the
other factor is due to improved survival of preterm
and low birth weight (LBW) infants achieved by the
improvement of the neonatal intensive care services
[8]. Figure 1 shows an example of the increasing inci-
dence of the eutopic thyroid (normal thyroid anatomy
with abnormal function) vs. the static incidence of the
dysgenetic thyroid diseases in live births.
Because of the highly sensitive and accurate TSH
assays, many programs around the world have shifted
from the primary T4-follow-up TSH approached, to the
primary TSH test approach. All screening programs
documented the female preponderance, of about 2:1
and a higher incidence among Down syndrome babies
with 35 times more than the normal babies [9]. The
United States Screening programs showed a higher
incidence in the Asian, Native American, and Hispanic
populations and lower among black American popula-
tion compared to the Whites. It was found two times
higher in twin births (1:876) compared to singletons
(1:1765). Babies born to older mothers (>39 years) had
higher incidence as well as preterm compared to term
infants [5].
Clinical manifestations
The rarity of clinical signs in affected newborns is due
to the presence of maternal thyroid hormone in
umbilical cord serum estimated to be 25–50% of nor-
mal, if the mother is hypothyroid and her fetus is hav-
ing CH as in case of severe iodine deficiency, there is
a prominent defect in neuro-intellectual development
despite early and appropriate treatment immediately
after birth. The clinical presentations of CH are often
subtle and most babies will not have any at birth,
which will delay their diagnosis [10,11]. The small
amount of maternal thyroid hormone is protective to

CONGENITAL HYPOTHYROIDISM
Permanent
(Fetal Origin)
Sporadic Inherited
Dyshormonogenesis
(14%)
Ectopic Athyrotic Hypoplastic
(32%) (31%) (22%)
TRBAbs, Thyrotropin blocking anbodies
Figure 2. Types and etiologies of Congenital Hypothyroidism.
the fetus brain [12]. Furthermore, the some moder-
ately functioning thyroid tissue in dysgenetic types of
CH might ameliorate the effect on the brain tissue
[13]. Nonspecific and slow development of clinical
symptoms of CH, in addition to the value of earlier
treatment, mandates the implementation of newborn
screening programs for this disorder. Since the new-
born screening for CH is only implemented in about
1/3 of the world countries [1], it is crucial for the clini-
cians to be able to recognize and treat this potentially
serious disorder. One of the common presentations is
prolonged indirect hyperbilirubinemia for more than
3 weeks due to immaturity of hepatic glucuronyl trans-
ferase [10], less commonly there might be history of
late gestation, maternal autoimmune thyroiditis, very
quiet babies with prolonged sleeping, hoarse cry and
constipation.
One third of the affected babies have larger birth
weight more than the 90th percentile [10].
The commonest clinical signs are umbilical hernia,
macroglossia and cold or mottled skin [14]. Because
thyroid hormone is essential for the ossification of the
fetal bones [15] this explains the finding of wide pos-
terior fontanel and radiological absent femoral epiphy-
ses in 54% of affected newborns [4]. Very few infants
with CH have palpable goiters, usually found in thy-
roid dyshormonogenesis or Pendred syndrome if it is
associated with deafness; other findings include flat
nasal bridge, hypertelorism and open mouth due to
macroglossia. Some babies might show bradycardia.
Abnormal neurological features include hypotonia and
delayed deep tendon reflexes [16].
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
Transient
(Maternal Origin)
Iodine Iodine anthyroid
TRBAbs
deficiency Excess medicaons
In 1420 infants with CH, associated congenital mal-
formations found in 8.4% of them, the cardiac malfor-
mations was the commonest [17] Saudi study showed
prevalence of 19.8%, about half of them were cardiac
anomalies [6].
A distinct clinical phenotype, Pendred’s syndrome,
caused by gene mutation in Pendrin; a chloride-iodide
transporter found in thyroid and inner ear tissues [10],
these babies have sensorineural deafness, congenital
hypothyroidism and goiter. Bamforth-Lazarus syn-
drome constitutes of thyroid dysgenesis, choanal atre-
sia, cleft palate and spiky hair [18].
Permanent primary congenital hypothyroidism
The commonest type of CH is due to primary defect
in the thyroid gland its self is called primary CH and is
mainly caused by thyroid gland maldevelopment (dys-
genesis) in 85% of cases or less commonly by
defected thyroid hormone synthesis (dyshormonogen-
esis) in 10–15% of the cases, or the least common
cause; defected TSH receptor or its subsequent trans-
duction [19]. Figure 2 shows the etiological classifica-
tion of all the types of congenital hypothyroidism.
CH due to thyroid dysgenesis
Thyroid dysgenesis, is sporadic although, recent stud-
ies suggest some genetic participation. Castanet et al.
found 2% of all the dysgenetic congenital hypothy-
roidism was familial in origin [20]. In one study 7.9%
of first degree relatives to babies with CH had
4 M. AL-QAHTANI
spectrum of thyroid embryological development
defects [21].
Thyroid dysgenesis includes three major forms: first
is the ectopic thyroid; an ectopic location of the thy-
roid gland, it constitutes 60% of all congenital dysge-
netic hypothyroidism and it is two times more
common in female [22]. In these cases, the thyroid
gland is round and not bilobed, found along the thy-
roglossal duct, which is the normal path through
which the developing thyroid descends to the final
position in the neck [22,23]. Second most common is
athyreosis; indicating total absence of thyroid tissue,
forming about 30%, the third and least common form-
ing 5% is thyroid hypoplasia, which is a small gland,
developed in the normal anatomical place [24].
Investigators suggested Some genetic basis as a cause
of thyroid dysgenesis, which includes mutations in
transcriptional factors of the thyroid gland develop-
ment, such as thyroid transcription factor 2 (TTF-2),
NKX2.1 (TTF-1) and paired box gene 8 (PAX-8) [25],
however only 2–9% of all the dysgenetic hypothyroid
cases were proved to have such genetic mutations
[25–29], because these transcription factors are
expressed in different fetal tissues, their mutations
might lead to distinct phenotypic syndromes [30].
CH due to thyroid dyshormonogenesis
Autosomal recessive inherited defects of thyroid hor-
mone biosynthesis are responsible for 10-15% of all
the cases of permanent congenital hypothyroidism.
Dyshormonogenesis causes goitrous congenital hypo-
thyroidism; which is a rare clinical finding in babies
diagnosed by newborn screening [31]. Deficiency of
thyroid peroxidase (TPO) enzyme is considered the
commonest cause of dyshormonogenesis [32], as it
engages hydrogen peroxide to couple iodine to thyro-
globulin in the thyroid cells, producing both T3 and
T4. If it is severely defected it will lead to total defect
in the iodide organification which can be diagnosed
radiologically by high radioactive iodine (RAI) uptake
followed by >90% release post sodium perchlorate
administration [33]. Loss of function genetic mutation
of the transmembrane protein (pendrin) (ch7q31),
leads to a Pendred’s syndrome; triad of hypothyroid-
ism, goiter and deafness [17]. Another rare gene muta-
tions discovered recently include mutations in the
enzyme dual oxidase 2 which lead to deficient produc-
tion of hydrogen peroxide and iodide organification, it
is thought to be autosomal dominant [34]. Other rare
genetic causes of dyshormonogenesis include defects
in sodium/iodide transporter, thyroglobulin action
defect [35] and ineffective peripheral conversion of T4
to the active form T3 due to iodotyrosine deiodinase
deficiency [36].
Permanent Central (secondary) congenital
hypothyroidism
Deficiency of thyroid stimulating hormone (TSH) pro-
duction; most commonly, as part of congenital hypo-
pituitarism is associated clinically with any midline
defects such as septo-optic dysplasia or cleft lip and/
or palate or as component of genetic syndrome due
to pituitary gland development gene mutations, like
PROP1, HESX1, LHX3, LHX4 and PIT1, in central hypo-
thyroidism other pituitary hormones might be affected
together with TSH, like growth hormone, gonado-
tropin, adrenocorticotrophin and antidiuretic hor-
mone [37].
Permanent CH due to thyroid hormone
metabolism defects
Mutated gene responsible for monocarboxylase trans-
porter 8 (MCT8); the main thyroid hormone trans-
porter has been reported in five males diagnosed with
Allan-Herndon-Dudley syndrome; an X-linked hypothy-
roidism, mental retardation and quadriplegia, they
have normal TSH with low T4 and high T3 levels [38].
Autosomal dominant mutations in thyroid hormone
receptor b (TR b) leads to resistance of thyroid hor-
mone the action in 90% of cases, T3 and T4 are mildly
elevated yet not able to decrease TSH, these labora-
tory findings might explain missing the diagnosis in
these babies in the neonatal screening programs [39].
Transient congenital hypothyroidism (TCH)
If the state of congenital hypothyroidism lasts for
3–6 months it is called transient congenital hypothy-
roidism, another clinical definition of TCH is resolution
of the hypothyroidism by age of 3 years [40]. TCH is
less common in the United States (1:50,000) compared
to Europe (1:100) [3], because it is caused mainly by
Iodine deficiency secondary to maternal iodine defi-
cient diets which is common in European countries,
especially in preterm infants [3,13], Iodine is the major
functional and structural component of the maternal
as well as the fetal thyroid hormone. Maternal Iodine
requirement is increased during pregnancy due to
increased thyroid hormone production, increased renal
iodine excretion, and fetal thyroid iodine require-
ments [41].

Iodine deficiency can cause fetal and maternal goi-
ter and increased rates of miscarriage, stillbirth, and
possibly higher mortality. Infants of Iodine-deficiency
mothers are prone to have cretinism, with
significant mental retardation and musculoskeletal
manifestations.
Globally, iodine deficiency is the commonest cause
of transient hypothyroidism, especially in the prema-
ture newborns. It is diagnosed by eutopic thyroid with
high uptake of 123I in the radioisotope scan. It is
treated with iodine replacement until normal iodine
level is achieved [42].
Because of iodine deficiency serious consequences
on mother and her fetus, WHO recommended total
dietary intake of iodine is 250 lg/day [43].
International Federation of Gynecology and Obstetrics
(FIGO) recently has recommended the iodine supple-
mentation for iodine-deficient women to decrease its
adverse effects and the supplement should be initi-
ated as early as possible since the first trimester is the
critical period for the fetal development [44].
Iodine excess on the other hand passes freely
through placenta and breast milk to suppress fetal
thyroxine synthesis which is called Wolff–Chaikoff
effect. This effect lasts for about 10 days, and usually
caused by the use of iodine-containing anti- septics,
contrast agents, and amiodarone. The newborn will
have low T4 and high TSH concentrations, after
2–3 days of age. Excess iodine will block the 123I
uptake by the thyroid in the isotopic scanning, how-
ever ultrasonography will detect euotpic gland with or
without goiter [45].
The other cause is trans-placental maternal blocking
antibodies which block the TSH receptor in the thyroid
tissue of the newborns thereafter maternal antibodies
decline [46]. Another cause of TCH is maternal anti-
thyroid medications that decrease fetal thyroid hor-
mone production and lasting up to two weeks after
birth, also maternal use of amiodarone can cause TCH
in their infants and may continue till the age of
5 months and may lead to significant neurological
complications [47]. When newborns, especially pre-
term infants are exposed to large amount of iodine
they might have TCH [48]. Reported cases of congeni-
tal liver hemangiomas secretes huge amounts of type
3 iodothyronine deiodinase which produces high lev-
els ineffective reverse T3 requiring large doses of thy-
roxin for its treatment, however the surgical
management is curative [49].
Performing ultrasonography and 123I scintigraphy of
the thyroid gland is an efficient strategy to detect the
dygenetic thyroid causes and can help to differentiate
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
them from the transient congenital hypothyroid
causes [45].
Newborn thyroid screening tests
Since the clinical symptoms and signs of CH are late
and nonspecific, the well-trusted and specific early
diagnostic method is the neonatal screening.
Implementing newborn screening programs, detects
almost all babies affected by CH. Screening programs
have been implemented in all the developed countries
and some of the developing countries. Only one quar-
ter of 127 million worldwide births undergo screening
for congenital hypothyroidism. Blood sample taken by
heel-prick is collected on special filter paper cards
between the 2nd and 5th day of life or at early dis-
charge are sent to a central laboratory for hormonal
testing [2].
The commonest and popular programs initially test
for TSH due to its high accuracy to detect cases of
congenital hypothyroidism. Generally every program
should have its own T4 and TSH cutoff levels for test
results using normal distribution curve with low T4
defined as less than 10th centile and other programs
define the upper TSH cutoff > 97th percentile, this
approaches detects most cases of primary congenital
hypothyroidism. However, the primary t4-follow-up
TSH test approach detects cases of secondary or ter-
tiary hypothyroidism as well as cases with delayed
TSH rise. These two testing approach are not able to
detect cases of thyroid hormone transport defects, or
action defects. Recent screening programs are measur-
ing both T4 and TSH, which enabled them to find
higher incidence of congenital hypothyroidism [50].
Hypothalamic-Pituitary-Thyroid axis gets full activation
of around 27 weeks of gestation that is why the pre-
term babies will have this axis immature and non-
reactive [51]. The cutoff filter paper screening TSH is
approximately 30mU/L in the first few days of life as a
result of the TSH surge that occurs immediately after
birth. To confirm the diagnosis the serum levels
should be collected one to two weeks of age, when
the upper TSH level falls to approximately 10 mU/L.
Table 1 shows the normal ranges for serum FT4 and
TSH in the first month of age [52]. Although levels of
all hormones are higher at 1–4 days of age, by
Table 1. Reference ranges for TSH and FT4 in the first
4 weeks of life.
Age TSH (mU/L) Free T4 (pmol/L)
1–4 Days <39 25–64
2–4 Weeks <10 10–26
6 M. AL-QAHTANI
Table 2. Interpretation of the thyroid function tests.
TSH Total T4/FT4
High Low
High Normal
Normal Low
Low/Normal Low
2–4 weeks of age they have fallen closer to the levels
typically seen in infancy.
In some countries with early newborn discharge
like Saudi Arabia, they depend initially on the Cord
TSH screening system with cut point of 30 mU/L
recently have been lowered to 20.0 mU/L which is
comparative to other studies using more sensitive
assays [53]. Adding FT4 level measurement in the
newborn screening is useful for earlier detection of
the transient and permanent central cases of congeni-
tal hypothyroidism [54].
Confirming the diagnosis
All infants having abnormal thyroid screening tests
should be called immediately for thorough physical
examination and confirmatory laboratory testing for
serum TSH and FT4 checking the results to the normal
corresponding age levels [55].
After birth there is a physiological surge of TSH
which can be as high as 39mU/L lasting up to 4 days,
reaching the normal infant levels by 2–4 weeks. So the
confirmatory serum tests should be obtained within
1–2 weeks of age, at that time the highest TSH level is
expected to fall to approximately 10mU/liter. Table 2
gives the general interpretation of the thyroid hor-
mone levels in the different situations.
Radiological diagnostic methods
To determine the anatomy, size and location of the
thyroid tissue, thyroid radionuclide uptake and scan is
the best radiological study of choice. The preferred
radioactive tracer in neonate is iodine123 (I123) or
sodium pertechnetate tc99m. If no radionuclide
uptake found this might indicate thyroid aplasia, how-
ever it may also indicate gene mutation in TSHb or
TSH receptor. Other possible diagnoses include
defected iodide trapping process or effect OF maternal
thyrotropin receptor blocking antibodies (TRB-Ab). If
the uptake is decreased and the size is small this indi-
cates hypoplastic gland or ectopic gland.
Diagnosis
 Primary congenital hypothyroidism
 Persistent congenital hypothyroidism
 Transient congenital hypothyroidism
 Delayed maturation of the hypothalamic-pituitary axis
 Subclinical hypothyroidism
 Pituitary hypothyroidism
 Hypothalamic immaturity in infants
 Hypothalamic hypothyroidism
Congenital hypothyroidism due to dyshormonogen-
eses in the other hand will be manifested as large
gland with increased uptake; its diagnosis is confirmed
by a perchlorate discharge test [56].
In case of absent radionuclide uptake, thyroid apla-
sia is confirmed by thyroid ultrasound, however,
Normally positioned thyroid gland absent radionuclide
uptake is suggestive of either TSHb gene mutations,
TSH receptor inactivating mutation, defected iodide
trapping or maternal TRB-Ab. The large normal-anat-
omy thyroid gland in ultrasound is suggestive of dys-
hormonogenesis, Ohnishi H et al. showed that using
thyroid ultrasound with color Doppler flow can detect
up to 90% of cases of ectopic thyroid [57].
Treatment and prognosis of congenital
hypothyroidism
Immediate treatment should be started once the diag-
nosis of congenital hypothyroidism is confirmed and
preferably within the first 2 weeks of age. The drug of
choice is Levothyroxine and the recommended start-
ing dose is 10–15 mcg/kg, given as a single daily dose.
Since late treatment is having to poor outcome on the
infant neurodevelopment [58–61].
Levothyroxine should be given as a crushed tablet
mixed with few drops of water, breast milk or the
regular formula, and it is not recommended at all to
use the liquid formulations since they are not homo-
geneous solutions and because of the different prepa-
rations they are not consistent. Since soy-based
formula reduces the levothyroxine absorption, it is not
recommended solvent for the crushed tablet causing
undertreated congenital hypothyroidism cases [62].
The main target of early treatment is rapid achieve-
ment of laboratory euthyroidism status then to keep it
maintained all through. Improved cognitive functions
outcome is accomplished by normalizing serum TSH
and FT4 within 2 weeks of starting the treatment [61].
On the other hand the overtreatment with levothyr-
oxine could be harmful as they might cause attention
and over activity problems at the school age [63,64].
The recommended monitoring strategy for patients

with congenital hypothyroidism is to perform clinical
assessment of thyroid status, growth parameters and
development milestones to ensure optimal dosage
and compliance of levothyroxine.
Serum TSH and FT4 to be done after 2–4 weeks
after the starting dose and then every 1–2 months in
the first 6 months of age, then every 3–4 months till
age of 3 years, then every 6–12 months till the end of
physical growth process. Four weeks after each levo-
thyroxine dose adjustment thyroid function tests
should be repeated [58].
The target of this strategy is to maintain clinical
and biochemical euthyroidism, specifically in the first
3 years of life when brain development is mostly
dependent on thyroid hormone. Biochemical target is
to keep Serum TSH in the age- specific normal range
and serum FT4 in the upper half of the age-specific
normal range [58,65–67]. It is so importance to explain
to parents the importance of the treatment and
the possible dangerous outcomes in case of
noncompliance.
Prognosis
Generally, the developmental outcome in early treated
patients with congenital hypothyroidism is excellent,
as it prevents severe neurocognitive deficits and nor-
malizes intelligence quotient. Few studies found
babies with low birth FT4 level to have mild deficits in
motor development, verbal skills, attention, and mem-
ory despite optimal treatment [68–71].
Lifelong treatment is mandatory for proven cases
with thyroid dysgenesis. On the other hand, transient
treatment is more likely in cases due to maternal ant
thyroid medications or maternally-derived TSH recep-
tor-blocking antibodies. Most patients with other etiol-
ogies can undergo the challenge test where the
treatment is stopped after the age of three years to
decide if congenital hypothyroidism has resolved.
LOW levothyroxine dose requirement less than 2 mcg/
kg/day at age of 3 years is considered a very good
indicator for successful discontinuation of the treat-
ment [72].
Disclosure statement
No potential conflict of interest was reported
the author(s).
ORCID
Mohammad Al-Qahtani http://orcid.org/0000-0003-
2655-7459
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 7
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