The Egyptian Journal of Radiology and Nuclear Medicine (2012) 43, 265–274

Egyptian Society of Radiology and Nuclear Medicine

The Egyptian Journal of Radiology andNuclearMedicine

www.elsevier.com/locate/ejrnmwww.sciencedirect.com

ORIGINAL ARTICLE

Transcranial US of preterm neonates: High risk gestational

age and birth weight for perinatal asphyxia

Mahmoud Agha a,c,*, Gehad Selmi b,c, Mohamed Ezzat c

a Medical Research Institute, Alexandria University, Egyptb Suez Canal University, Egyptc AGH, Hufuf, Saudi Arabia

Received 25 July 2011; accepted 8 February 2012Available online 6 March 2012

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KEYWORDS

TCUS;

Perinatal asphyxia;

Preterm neonates;

Hypoxic encephalopathy;

IVH;

Gestational age and body

weight

Corresponding author. Addr

l Najah St., Al Ahsa, Hofu

87000, 5893413, 5893491; fax

mail address: dr.mahmoudag

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uclear Medicine.

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Abstract Objective: The study aims to determine the high risk gestational week (GW) and/or birth

weight (BW) of the preterm neonate, belowwhich perinatal hypoxic cerebral injuries are expected to occur.

Material and methods: Eighty preterm neonates, born at or before 37 GW, were included. Twenty-three of

themwere<32GW and 57>32GW. Also, 28 of them were<1500 g and 52>1500 g. Imaging was done

by transcranial ultrasound with 4–9MHz curvilinear probe. CT scan was additionally performed for only 18

candidates. The study protocol was approved by the ethics committee in Al-ManaGeneral Hospital (AGH).

Results: Intraventricular hemorrhage (IVH) was diagnosed in six preterm neonates<32GW and two>32

GW.Three<32GWandone>32GWpresentedwithhypoxic ischemic encephalopathy (HIE)withnohem-

orrhage. Two preterm neonates <32 GW had both IVH &HIE. All positive cases were below 1500 g BW.

Conclusion: Preterm neonates<32GW and/or<1500 g are highly susceptible for HIE and/or IVH. Thus,

specialmedical care, including post-labor hospitalization inwell equipped special baby care units (SCBU) and

routine transcranial ultrasound (TCUS) screening is recommended for those preterm neonates.� 2012 Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier B.V.

Open access under CC BY-NC-ND license.

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il.com (M. Agha).

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Table 1 Grading of IVH (6).

Grade Definition Prognosis

I Subependymal/germinal

matrix in caudothalamic groove

Overall good

II IVH with normal sized ventricles Relatively good

III IVH with hydrocephalus Mortality 20%

IV G III & parenchymal hemorrhage Mortality 90%

Table 2 Grading of PVL (7).

Grade Definition

I Transient periventricular hyperechogenecity lasting

II Periventricular hyperechogenecity with small locali

III Extensive periventricular cystic lesions

IV Involvement of the deep and subcortical white ma

Figure 1 Normal TCUS of preterm neonate. Anterior fontanel appro

and (B) coronal at level of third ventricle showing normal caliber of th

and cerebellum (notched arrow). (C) Midline sagittal anterior fontanel v

overlying cingulated gyrus (dashed arrow). (D) Trans-temporal axial

266 M. Agha et al.

1. Introduction

Preterm neonates are more susceptible to cerebrovascular in-sults compared to full term ones, due to immaturity of their

cerebral physiologic autoregulation. Perinatal asphyxia is theleading cause of cerebrovascular accidents (CVA) in prematureneonates. It is associated with high mortality and morbidity

scores, including permanent neuropsychiatric disorders e.g.,

Prognosis

for 7 days or longer Overall Good

zed frontoparietal cystic lesions Developmental delay

Spastic diplegia

tter with extensive cystic lesions Spastic quadriplegia

ach (A) oblique coronal at the level of the body of lateral ventricle

e lateral ventricles (dashed arrow), choroid plexus (straight arrow)

iew showing lateral ventricle (notched arrow) corpus callosum and

approach showing cerebral peduncles (curved arrow).

Figure 2 Preterm neonate with cerebral hemorrhage, that was excluded from the study due to associated hydranencephaly (A) Anterior

fontanel oblique coronal at the level of the body of the lateral ventricle and (B) coronal more posterior oblique TCUS showing absence of

cerebral tissues with extensive CSF accumulation, intact falx (notched arrow) and organized hematoma (arrow).

Table 3 Epidemiology of the included newborns.

Sex Age Weight

Male Female <32 GW >32 GW <1500 g >1500 g

32 48 23 57 28 52

Total 80

GW: gestational weeks.

Transcranial US of preterm neonates: High risk gestational age and birth weight for perinatal asphyxia 267

cerebral palsy, cognitive and behavioral deficits. Global hy-poxia mainly affects the watershed zones, which differ accord-

ing to the degree of cerebral maturity, so the most vulnerablesites change with the gestational age. Germinal matrix andperiventricular white matter are the watershed zones in the pre-

term neonate (1,2).Perinatal asphyxia leads to hypoxemia and hypercapnea

that initiate cerebral sequential biochemical insults, mediated

through acidosis and release of inflammatory mediators. Thisresults in loss of vascular autoregulation and interruptions in

Table 4 Findings in different age groups.

Age Normal Hge Isch.

<32 GW 12 6 3

>32 GW 54 2 1

Hge: hemorrhage. Ich.: ischemia. GW: gestational weeks.* Fisher’s exact test.

Table 5 Findings in different weight groups.

Weight Normal Hge Isch.

<1500 GM 14 8 4

>1500 GM 52 0 0

Hge: hemorrhage. Ich.: ischemia. GW: gestational weeks.* Fisher’s exact test.

cellular metabolism, followed by re-perfusion prior to neuro-

nal cell death. Intrauterine asphyxia occurs when placentalblood flow and gas exchange are interrupted. This may becaused by fetal factors (e.g., fetal bradycardia) and/ or mater-

nal factors e.g., inadequate placental perfusion (commonlyassociates with maternal hypotension, preeclampsia or abrup-tio placenta), impaired maternal oxygenation (e.g., pulmonary

embolism, carbon monoxide poisoning), or disrupted umbili-cal circulation (e.g., cord prolapse). Postnatal asphyxia mayoccur due to severe hyaline membrane disease, meconium aspi-ration or congenital heart diseases. Regardless of the etiology,

asphyxia may end in neuronal cell death, if there is delayedand/or inadequate re-perfusion (3–5).

Severity and duration of hypoxia determine the pattern of

cerebral insult. Transient hypoxia with generous re-perfusionusually causes venous congestion that may lead to IVHwith dif-ferent degrees of severity, graded according to Burstein et al.

grading scores (Table 1) (6). Prolonged hypoxia-withoutadequate re-perfusion– usually leads to periventricular white

Hge & Isch. Total P value*

2 23 0.002

0 57

Hge & Isch. Total P value*

2 28 0.001

0 52

268 M. Agha et al.

matter ischemia (periventricular leukomalacia (PVLM)).PVLM is reported with different degrees of severity accordingto de Vries et al. grading scores (Table 2) (7).

Due to lack of specific clinical signs of hypoxic cerebralinjuries in preterm neonates, brain imaging is an essential diag-nostic tool for such injuries. Different imaging modalities can

be used for the evaluation of preterm neonatal hypoxicencephalopathy e.g., TCUS, CT scan and MRI. TCUS wasfirst introduced in neonatology in the late 1970s. As neonatal

fontanels and multiple skull sutures are still patent, they canbe used as acoustic windows to image the brain for assessingdifferent neurologic insults in this age group. Being fast, cheap,widely available, bedside and safe (non-ionizing radiation), it is

a preferred imaging modality of preterm and critically ill full-term neonates (8,9).

Doppler examination of the intracranial arteries, with

assessment of resistive indices (RI) can provide informationabout cerebral perfusion. Abnormal decrease inRI value, whichoccurs at the start of hypoxic status, denotes a decrease in cere-

brovascular resistance secondary to impaired vascular autoreg-ulation. Prolonged asphyxia, with a subsequent development of

Figure 3 Preterm neonate (<32 GW & <1500gm) with grade II IV

coronal at level of the body of the lateral ventricles (B), posterior fonta

(D) axial non-contrast CT scan brain. All show IVH (dashed arrows

ambient cistern (short arrows in C).

intracranial hemorrhage or hypoxic ischemic encephalopathyand the resultant loss of forward diastolic flow can lead toabnormal increase in RI, which is indicative of poor outcome.

Being age dependent, there are available charts of the normalRI values of different gestational ages (10,11).

CT scan is a sensitive tool for the diagnosis of hemorrhagic

encephalopathy and has the advantage that it can be done with-out sedation. It also helps in the diagnosis of other associatedabnormalities e.g., hydranencephaly, craniosynostosis or other

congenital cerebral anomalies. However, it is less sensitive fornon-hemorrhagic HIE, as high water content of the neonatalbrain limits the soft tissue contrast resolution and clear identifi-cation of the cytotoxic edema. Also, CT has the disadvantage of

ionizing radiation exposure together with a relative high cost, soit is not recommended for multiple follow up examinations (12).

MRI is the most sensitive imaging modality for the diagno-

sis of HIE, especially diffusion-weighted imaging (DWI). Itclearly demonstrates restricted water diffusion of cytotoxicedema within 30 min of the start of ischemic insult. Also, it

is not affected by the normal neonatal high cerebral watercontent, so DWI is the fastest and most accurate sequence

H and subarachnoid hemorrhage. (A) Anterior fontanel oblique

nel sagittal left paramedian, (C) axial temporal window TCUS and

) and subarachnoid hemorrhage abundantly demonstrated in the

Transcranial US of preterm neonates: High risk gestational age and birth weight for perinatal asphyxia 269

for HIE diagnosis (13,14). MR spectroscopy (MRS) can pro-vide analysis of the different metabolic structures of the cere-bral tissues, that change according to the type of cerebral

insult. In HIE, it usually shows decrease in N-acetyl aspartate(NAA) and elevated lactate in the affected areas. Despite accu-racy and sensitivity of MRI, the transport of neonates (some-

times with life supporting measures) from intensive care units,high cost of the examination and needs for anesthesia limit itsfrequent application for follow up (15).

The study was done to identify the high risk gestational age(GW) and/ or low birth weight (LBW) of preterm neonatesassociated with high susceptibility of perinatal asphyxia.

2. Patients and methods

2.1. Study population

This is a prospective descriptive screening study including 80preterm neonates, born at the obstetric department of Almana

Figure 4 Preterm neonate (<32 GW & <1500 g) with IVH. (A) A

sagittal left paramedian and (C) anterior fontanel coronal TCUS show

hemorrhage (arrows), more severe on the right with moderate hydro

TCUS at the level of the body of the lateral ventricle showing or

hydrocephalus (GIII IVH).

General Hospital (AGH) or other hospitals in Hufuf- KSA andthen referred to the special care baby unit (SCBU) of AGH. Thestudy protocol was approved by the scientific and ethics com-

mittee in Al-Mana General Hospital (AGH). A written signedconsent was obtained from all study candidates’ parents. Itwas conducted fromAugust 2009 to January 2011 and designed

to include all neonates, born at or before 37 GW, regardless theclinical presentation of perinatal asphyxia. The candidates weredivided into groups, according to the birth gestational age and

weight. Twenty-three neonates were<32GWand 57>32GW.Twenty-eight neonates were <1500 g and 52 >1500 g.

2.2. Technique of TCUS

Bedside TCUS examinations were done in SCBU, by one ofthe two author radiologists. Examinations were performedthrough multiple acoustic windows; the anterior and posterior

fontanel as well as the temporal and mastoid windows. Ante-rior fontanel is the commonly used acoustic window, however

nterior fontanel sagittal right paramedian, (B) anterior fontanel

ing sizable lateral and third ventricular subependymal hyperechoic

cephalus. (D) 2WK follow up coronal oblique anterior fontanel

ganized intraventricular hematoma (dashed arrows) with severe

270 M. Agha et al.

it can miss far sites as posterior fossa, brainstem, basal cisternsand fourth ventricle. The posterior, temporal and mastoid fon-tanels are additional helpful windows for these far sites (8,9).

Initially, classic anterior fontanel window was used. Imageswere recorded in at least six standard coronal planes and fivestandard sagittal planes on each side, together with real life

sonographic mapping. The other supplemental acoustic win-dows were applied in coronal and transverse planes, in anattempt to maximize the spatial resolution to image the whole

surface of the brain (9).All patients were examined by portable transcranial US

(Sonoace X8 Medison, Seoul, South Korea) with high resolu-tion multifrequency 4–9 MHz curvilinear transducer. The re-

corded images were transferred to the reporting roomworkstation, through the picture archiving and communica-tion system (PACS). All reports were approved and released

after evaluation and combined discussion of the two radiologyauthors.

Figure 5 Preterm neonate (>32 GW & <1500 g) with evolving IVH

ventricle showing right subependymal (grade I) IVH (arrow), 5 days lat

ventricles (B) and at slightly higher level (C) showing IVH & mild hy

2.3. Timing of examinations

First TCUS was done within first two days after birth and re-peated in the fourth and seventh day for all candidates. IfTCUS was still negative until the seventh day, the candidate

was considered free and excluded from further follow upschedules (Fig. 1). If positive, multiple sequential repeatedTCUS examinations were done, at least twice a week, for grad-ing and follow up until discharged from SCBU or referred to

neurosurgery department. Grading of IVH and PVL was doneaccording to Burstein et al. (Table 1) (6) and de Vries et al.(Table 2) (7), respectively.

Neonates with other neurological abnormalities or majorcongenital anomalies e.g., Dandy Walker syndrome or hydran-encephaly, were discarded, i.e. not included in the study in an

attempt to specify the susceptibility of hypoxic cerebral insultsto the premature birth age and/ or low birth weight withoutsuperadded pathology (Fig. 2).

. Anterior fontanel TCUS (A) coronal view at the level of third

er posterior coronal oblique views at the level of the body of lateral

drocephalus (grade III) with subarachnoid tracking (arrows).

Transcranial US of preterm neonates: High risk gestational age and birth weight for perinatal asphyxia 271

2.4. CT scan

Complementary non-contrast CT scans were applied to allTCUS positive candidates (14 neonates) to confirm the USfindings of IVH or to assure the non-hemorrhagic nature of

HIE. They were also done for four sonographically freecandidates, presented with suspected clinical signs. CT scanswere done without sedation using CT Neusoft C 3000 (dualslice), Shenyang, Liaoning, China.

2.5. Management

HIE and IVH were initially managed conservatively and mon-

itored by multiple close follow up TCUS examinations.Uncontrolled high grade intraventricular hemorrhage (III orIV) was managed through repeated lumbar puncture and the-

cal tapping. Only three patients were referred for ventriculo-peritoneal (VP) shunting.

Figure 6 Preterm neonate (>32 GW & <1500 g) with HIE. Ante

supraventricular level and (B) coronal at the level of the third ventric

mater hyperechogenicity consistent with grade I encephalomalacia (

cerebral edema with complete attenuation of the lateral ventricles.

2.6. Statistics

Data analysis was done through the on line web site (http://www.graphpad.com/quickcalcs/contingency2.cfm), with appli-cation of Fisher’s exact test to estimate P-values that reflect the

susceptibility difference of the study groups. P values less than0.05 are consistent with statistically significant difference.

3. Results

The study included 80 preterm neonates (32 males and 48 fe-males), with gestational age ranged from 26 to 37 GW, 23(28.75%) were delivered at or before 32 GW, while 57

(71.25%) after 32 GW. Birth weight of 28 (35%) of them wasequal to or below 1500 g (VLBW), while 52 (65%) of them wereabove 1500 g (Table 3). Three neonates <32 GW (13%) and

only one >32 GW (1.5%) were presented with hypoxicischemic encephalopathy (HIE) with no hemorrhage. TCUSdiagnosed intracerebral hemorrhage in six preterm neonates

rior fontanel coronal oblique TCUS (A) oblique coronal at the

le showing intense basal ganglia, peri-and supraventricular white

arrows). (C) Axial non-contrast CT scan showing severe diffuse

272 M. Agha et al.

<32GW (26.6%) and two>32GW (3.5%). Two preterm neo-nates <32 GW (8.6%) had both IVH & HIE (Table 4). All po-sitive cases were below 1500 g BW (50%). This means that, out

of 14 positive cases, 11 were below 32 GW (84.6%) and all werebelow 1500 g (Table 5). P value equals 0.02 as regards compar-ative statistics of the two different age groups, while it equals

0.01 as regards the two different gestational weight groups,i.e. consistent with significant susceptibility difference.

All positive TCUS (14 patients) were confirmed by non-

contrast CT scan. Another four clinically suspected candidateswith negative TCUS were confirmed to be free by CT scan.

4. Discussion

This study was conducted to determine the crucial gestationalage and weight, below which hypoxic encephalopathy is

considerably expected to occur. For such high risk preterm

Figure 7 Preterm neonate (<32 GW & <1500 g) with mixed IVH an

the level of the lateral ventricles and (B) at the supraventricular level sh

cystic leukomalacia (arrow heads).

neonates, plans for intensive care should be arranged andimmediately applied after birth, in an attempt to limit severityand long term complications as lowest as possible. TCUS is a

sensitive imaging tool for the diagnosis of IVH or HIE. It iseven reported to be more sensitive than CT scan in some re-cently published studies (16).

According to the statistics in our study, the incidence ofIVH (Figs. 3–5), HIE (Fig. 6) or mixed IVH & HIE (Fig. 7)was significantly high in preterm neonates 632 GW and/ or

VLBW 61500 g. These results support the fact that 32 GWand 1500 g BW should be considered alarming values, belowwhich perinatal hypoxic insults are highly expected. Almostsimilar results were reported by Waldemar et al. (17) and

Lee et al. (18) who stated that, the perinatal morbidity andmortality scores for preterm less than 32 GW or with verylow birth weight (VLBW) are relatively high.

Perinatal asphyxia (HIE & IVH) is a devastating event thatcan lead to permanent motor, cognitive, visual, hearing,

d HIE. Anterior fontanel coronal oblique TCUS views (A & C) at

owing hydrocephalus, IVH (arrows) and extensive periventricular

Transcranial US of preterm neonates: High risk gestational age and birth weight for perinatal asphyxia 273

behavioral, social-emotional, health, and growth problems.Treatment of HIE is expected to do little, if not started inthe few hours immediately following the causative insult, hence

the importance of early diagnosis. For the six (6) neonatespresented with HIE in our study (4 ischemic and 2 mixed ische-mia and IVH), neuroprotective strategies including hypother-

mia and administration of excitatory amino acid antagonistsand calcium channel blocker with adequate perfusion andventilation, were applied. Successful arrest of progress was

achieved in the four patients (19).All neonates with IVH (8 IVH & two mixed with HIE) were

managed by variable mixture of the previously mentioned sup-portive measures with successful response in the eight patients

with only IVH. The other two patients (mixed IVH & HIE)showed uncontrolled hydrocephalus and cystic myelomalacia(unresponsive to frequent thecal tapping and transfusion of

packed red blood cells and platelets in an attempt to restorethe homeostasis and normal hematocrit level). They were re-ferred to the neurosurgical department for VP shunting (20).

This deterioration may be partly explained by relative delayeddiagnosis with TCUS done after 24 h of the insult as well as theseverity of mixed IVH and HIE. Although significant advance

had been achieved in obstetrics, there is no concomitant de-crease in the incidence of preterm labor, which is still consid-ered the major cause of neonatal morbidity and mortalityeven in developed countries. This may be due to lack of full

neonatal physiological maturity with poor underdevelopeddefense mechanisms. Many maternal conditions may lead topreterm labor e.g., hypertension, diabetes, smoking, collagen

vascular disease, bronchial asthma and restrictive lung disease,obesity, family history of spontaneous preterm birth, short in-ter-pregnancy interval and infertility treatments. Obstetricians

usually try to avoid preterm labors by recommending bed rest,describing contraction inhibitor drugs, vitamin K and proges-terone for high risk pregnancy (21–23). The valuable result of

the study was the early diagnosis of these serious cerebral in-sults that helped limiting their severity and evolution as wellas restoring the normal cerebral hemodynamics with promis-ing long term outcome. Also TCUS has the advantage of being

low cost non-ionizing radiation, so, it can be frequently ap-plied. Also being a bedside examination, it can be done forcritical patients with difficult issues, like those in need of life

supporting measures and ventilators (24).

4.1. Limitations of TCUS and future plans

As TCUS is currently performed using standard 2D probe,sensitivity is mainly based on real life interpretation, which isoperator dependent. Recently, 3D and 4D sonography areprocessed retrospectively to obtain custom imaging planes,

improving spatial resolution, approximating cross-sectionalmodalities (CT and MRI) and enabling post-processing groupdiscussion.

5. Conclusion

Preterm neonates less than 32 GW and /or 1500 g are more

prone to perinatal asphyxia. TCUS is a sensitive imaging toolfor the diagnosis of perinatal asphyxia. TCUS should be usedfor routine screening of all preterm neonates less than 32 GW

and/or VLB <1500 g BW, as early as possible. Expected

preterm labors are recommended to be conducted in wellequipped maternal hospitals with special baby care units.

Acknowledgments

Valuable regards to all SCBU medical and paramedical staff,considering their efforts and special care for all preterm neo-nates who were and were not candidates in this study.

References

(1) Grant PE, Yu D. Acute injury to the immature brain with

hypoxia with or without hypoperfusion. Radiol Clin North Am

2006;44:63–77.

(2) Arti M, Arun G, Rajiv A, et al.. Incidence of periventricular

leucomalacia among a cohort of very low birth weight neonates

(<1500 g). Indian Pediatric 2006;43:210–6.

(3) Felderhoff-Mueser U, Rutherford MA, Squier WV, et al..

Relationship between MR imaging and histopathologic findings

of the brain in extremely sick preterm infants. AJNR Am J

Neuroradiol 1999;20:1349–57.

(4) Hoppy PS. Advances in postnatal neuroimaging: relevance to

pathogenesis and treatment of brain injury. Clin Perinatol

2002;29:827–56.

(5) Barkovich AJ. Pediatric neuroimaging. 3rd ed. New York, NY:

Lippincott Williams & Wilkins; 2000, pp. 162–208.

(6) Burstein J, Papile LA, Burstein R. Intraventricular hemorrhage

and hydrocephalus in premature neonate: a prospective study

with CT. AJR Am J Roentgenol 1979;132:631–5.

(7) De Vries LS, Eken P, Dubowitz LMS. The spectrum of

leukomalacia using cranial ultrasound. Behav Brain Res

1992;49:1–6.

(8) G van WM. Neonatal cranial ultrasonography. 1st ed. Berlin,

Heidelberg: Springer-Verlag; 2007, p. 10–1.

(9) Di Salvo DN. A new view of the neonatal brain: clinical utility of

supplemental neurologic US imaging windows. Radiographics

2001;21:943–55.

(10) Gabriel ML, Piatto VB, Souza AS. Clinical application of

transcranial Doppler ultrasonography in premature, very-low-

birth weight neonates. Radiol Bras 2010;43(4):213–8.

(11) Nayara A, Ines L, Suely R. Cranial Doppler resistance index

measurement in preterm neonates with cerebral white matter

lesion. J Pediatr (Rio J) 2006;82(3):221–6.

(12) Barkovich AJ. The encephalopathic neonate: choosing the

proper imaging technique. Am J Neuroradiol

1997;18:1816–20.

(13) Robertson RL, Ben-Sira L, Barnes PD, et al.. MR line-scan

diffusion-weighted imaging of term neonates with perinatal brain

ischemia. AJNR Am J Neuroradiol 1999;20:1658–70.

(14) Forbes KP, Pipe JG, Bird R. Neonatal hypoxicischemic enceph-

alopathy: detection with diffusion-weighted MR imaging. AJNR

Am J Neuroradiol 2000;21:1490–6.

(15) Barkovich AJ, Baranski K, Vigneron D, et al.. Proton MR

spectroscopy for the evaluation of brain injury in asphyxiated,

term neonates. AJNR Am J Neuroradiol 1999;20:1399–405.

(16) Imran AK, Shagufta W, Rizwan AK, et al.. Neonatal Intracra-

nial Ischemia and Hemorrhage: Role of Cranial Sonography and

CT Scanning. J Korean Neurosurg Soc 2010;47(2):89–94.

(17) Carlo WA, Gr SS, Imtiaz J, et al.. High mortality rates for very

low birth weight infants in developing countries despite training.

Pediatrics 2010;126:e1072–80.

(18) Lee ACC, Mullany LC, Tielsch JM, et al.. Risk factors for

neonatal mortality due to birth asphyxia in Southern Nepal: a

prospective, community-based cohort study. Pediatrics May

2008;121:e1381–11390.

274 M. Agha et al.

(19) Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-

ischemic encephalopathy. Pediatrics 1997;100:1004–14.

(20) Dani C, Poggi C, Ceciarini F, et al.. Transfusion practice.

Coagulopathy screening and early plasma treatment for the

prevention of intraventricular hemorrhage in preterm infants.

Transfusion 2009 Dec;49(12):2637–44.

(21) Goldenberg RL, Culhane JF, Iams JD, et al.. Epidemiology and

causes of preterm birth. Lancet 2008 Jan 5;371(9606):75–84.

(22) Lt Col GS, Capt RC, Maj KS. Maternal factors for low birth

weight babies. MJAFI 2009;65:10–2.

(23) Crowther CA, Henderson-Smart DJ. Vitamin K prior to preterm

birth for preventing neonatal periventricular haemorrhage. Coch-

rane Database Syst Rev 2001;CD000229.

(24) Salerno CC, Pretorius DH, Hilton SW, et al.. Three-dimensional

ultrasonographic imaging of the neonatal brain in high-risk

neonates preliminary study. J UltrasoundMed 2000;19(8):549–55.