Neonatal Neurology in the Low-Resource Setting for the Term and Preterm Newborn

Introduction

Prominent identified causes of brain injury in the low-resource setting (LRS) include hypoxic-ischemic encephalopathy (HIE)/neonatal encephalopathy (NE), germinal matrix–intraventricular hemorrhage (GMH-IVH) in the premature infant, prolonged neonatal seizures, neonatal hypoglycemia, and hyperbilirubinemia (kernicterus). The magnitude of the contributions of these individual conditions to brain injury is underestimated in the LRS because of the lack of consistent standardized and repeated neurological assessments; neuroimaging (cranial ultrasound [CUS] scans, computed tomography [CT], and magnetic resonance imaging [MRI]); electroencephalographic (EEG) monitoring; and routine glucose or bilirubin monitoring/screening. Even in countries where some facilities for diagnosis and treatment are available in a tertiary hospital, this availability does not extend to almost all other hospitals in the health care system. For this review, we will focus on HIE/NE in the term-born newborn infant and IVH in the premature infant.

HIE/NE IN THE TERM-BORN NEWBORN

Magnitude of the Problem of Neonatal Death and Brain Injury Secondary to Birth Asphyxia in the LRS and Globally

The burden of neonatal brain injury secondary to intrapartum hypoxia-ischemia, particularly in the term infant in the LRS, is not entirely clear but is likely to be enormous. The most common precursor to such injury, termed birth asphyxia (BA), is defined as failure to initiate or establish spontaneous respirations at birth. The term is imprecise, nonspecific, and no longer recommended. However, given the longevity of its use, including many studies defining BA as a 5-minute Apgar score (AS) less than 7, it is critical to place into context the current understanding and implication of the term BA in the LRS, and specifically how it relates to subsequent neonatal death (ND) and HIE/NE.

Approximately 4 million NDs occur every year, with developing countries, especially those within Asia and sub-Saharan Africa, disproportionately affected. BA, as defined earlier, is thought to be responsible for 23% to 25% of NDs globally and 26% of the 1 million intrapartum stillbirths observed annually . The first day and especially the first hour are critical to newborn survival, with the highest risk of intrapartum-related ND (60% to 70%) occurring within 24 hours of birth . In previous Global Burden of Disease estimates, BA accounted for one of the highest numbers of disability-adjusted life years for any single condition. Importantly, over 90% of the disease burden occurs in low- to middle-income countries (LMICs) (5 to 20 per 1000 live births [LBs]), an incidence that is 5 to 20 times higher than that of high-income countries (1 to 2 per 1000 LBs). This higher risk in LMICs may be explained in part by the fact that approximately 50 million births take place at homes without a skilled birth attendant and where emergency obstetrical care is inaccessible .

Importance of BA in HIE/NE in the LRS

Perinatal hypoxic-ischemic brain injury constitutes the major portion of newborn brain injury in term infants in the LRS. The clinical expression of such injury has been referred to as HIE, but more recently the nonspecific term NE has been suggested. However, as has been noted, numerous MRI studies of term infants, within the clinical context of presumed hypoxia-ischemia proximate to the time of delivery, have delineated a topography of lesions highly correlated with that defined by human and animal models of hypoxia-ischemia. These imaging findings, coupled with clinical features characteristic of perinatal hypoxic-ischemic insult(s), warrant the specific designation of neonatal HIE. This designation is complicated in the LRS, where clinical features and neuroimaging (e.g., MRI findings), are very often lacking or absent. In this chapter we will refer to HIE/NE interchangeably. In addition, it is important to recognize that not all cases of NE are related to hypoxia-ischemia and that both antepartum and postpartum disorders (particularly infectious but also metabolic and genetic causes) may lead to encephalopathy. Because of the frequent lack of documentation of pertinent history and/or the inability to obtain concurrent testing, there is likely a marked underrepresentation of the magnitude of NE in the LRS .

BA worldwide is considered to represent the most important precursor for HIE and is responsible for approximately 25% of ND. The initial hour (the so-called Golden Hour) and the first 24 hours in general are critical to newborn survival, with the highest risk of intrapartum-related NDs (60% to 70%) occurring within this time frame. The timing of BA-related ND does not differ greatly between Asia and Africa.

The burden of HIE/NE across the globe is high with a wide discordancy between the incidence in the LRS (i.e., 8.5 to 10/1000 LBs) and the incidence in the resource-replete setting (RRS) , where estimates range from 1 to 2 per 1000 LB. In 2010, globally there were an estimated 1.15 million (range 0.89 to 1.60 million) new cases of HIE/NE associated with intrapartum-related events (male-to-female ratio 1.47:1), yielding an incidence of 8.5/1000 LBs. The authors estimated that 439,000 (29%) cases were mild, 438,000 (29%) cases were moderate and 273,000 (18%) were severe. Furthermore, it was estimated that 287,000 (26%) (range 181,000 to 440,000) infants with HIE/NE died during the first month of life. These data likely underestimate the magnitude of the problem in LMIC, where access to neonatal intensive care is limited. Moreover, these numbers do not account for intrapartum-related deaths in newborns who die shortly after birth and before the clinical onset of HIE/NE, or in countries where home deliveries predominate (e.g., Nepal, Nigeria, Ethiopia). The highest regional incidence of NE is in sub-Saharan Africa (14.9 per 1000 LB), followed by South Asia (10.4 per 1000 LB).

It is estimated that at least 30% of cases of NE in developed populations and 60% to 70% in developing populations have some evidence of intrapartum hypoxic ischemia. Mathematical modeling by Lee and colleagues on data from 184 countries over 20 years from 1990 to 2010 reported that the incidence of NE has decreased from 11.7 to 8.5 per 1000 LBs because of increased institutionalized deliveries and improved intrapartum care.

A major focus must be directed toward identifying those events/factors during labor that are important precursors to HIE/NE. The inability to consistently identify high-risk cases in labor and to intervene in a timely manner are two of the most important factors underlying the increased incidence of BA and resulting HIE/NE in the LRS .

The following sections will focus on the current definition of BA in the LRS and its relationship to early ND and subsequent HIE/NE; methods of identifying high-risk infants during labor; the importance of early resuscitation, including bag mask ventilation (BMV) in the nonbreathing infant; neuroimaging studies to evaluate the extent of brain injury; management of the newborn with evolving HIE/NE; and outcome of affected infants.

Neonatal Encephalopathy

Definition of BA in the LRS

BA in the LRS, as defined by the World Health Organization (WHO), is the failure to initiate or sustain spontaneous breathing at birth. A more recent report suggests that noncrying is an important additional sign in characterizing respiratory transition at birth with a 100% sensitivity of identifying nonbreathing infants at birth. This broad definition would be greatly enhanced if the description of nonbreathing included the intervention(s) implemented in the delivery room (DR) to restore cardiorespiratory status (i.e., stimulation, BMV) (see later). BA as currently defined accounts for an estimated 1 million NDs each year and is one of the primary causes of HIE/NE and early ND in the LRS. studies indicate that up to 60% to 70% of cases of “BA” in the LRS have some evidence of intrapartum hypoxic ischemia .

Defining BA Using Noninitiation of Breathing and/or 5-Minute AS Less Than 7

The burden of BA using the definition of the noninitiation of breathing and/or 5-minute AS less than 7 appears to be the highest reported in sub-Saharan Africa. In Ethiopia, a meta-study reviewing 12,249 LBs revealed an overall pooled prevalence of BA of 24% (95% confidence interval [CI] 18.11 to 30.01). In a review of data from eight countries (sub-Saharan Africa [ n = 7] and Nepal [ n = 1]), the incidence of BA was 16.1% (range 6% to 33%), and the case fatality rate was 26.7% (range 14% to 47%). However, challenges exist in the manner in which BA is defined in the LRS, whether by noninitiation of breathing and/or a 5-minute AS.

Recent studies suggest that these definitions are quite broad and not ideal for identifying infants with the poorest outcomes. In a 1-year retrospective study of liveborn newborns with a birth weight (BW) of at least 2000 g, the incidence of BA based on the absence of noninitiation of breathing at birth coupled with use of BMV was 15.2 per 1000 LBs. By comparison, when using a combination of a 5-minute AS less than 7, base deficit greater than 12 mmol/L and BMV, the incidence of BA was 8.7 per 1000 LB (49% fewer newborns). Similar differences in incidences of NE/ HIE were noted (i.e., 13.3 vs. 8.5 per 1000 LBs), based on the preceding comparisons. With specific regard to HIE/NE, 53% of newborns needing BMV and 59% of those with a 5-minute AS less than 7 and a base deficit greater than 12 mmol/L exhibited moderate to severe encephalopathy. Twenty-eight (10%) newborns who needed BMV evolved to Stage 3 encephalopathy, and 16 (58%) died. Of those with an AS less than 7 and base deficit greater than 12 mmol/L, 24 (13.1%; see Table 43.1 ) evolved to Stage 3, and 15 (62.5%) died ( Table 43.1 ). Importantly, both markers of BA identified a comparable percentage of infants who progressed to Stage 3, the group of infants with substantial mortality ( Table 43.2 ).

TABLE 43.1

The Relationship Between the Stages of Encephalopathy and Mortality in Infants Who Needed BMV as Compared With Infants With Apgar Score Less Than 7 and Base Deficit Greater Than 12 mmol/L

Adapted from Bruckmann EK, Velaphi S. Intrapartum asphyxia and hypoxic ischaemic encephalopathy in a public hospital: Incidence and predictors of poor outcome. S Afr Med J . 2015;105(4):298–303.

Category	Total	Need for BMV Incidence/1000 Live Births	Died n (%)	AS < 7 + BD > 12 mmol/L		Died n (%)
Category	Total	Need for BMV Incidence/1000 Live Births	Died n (%)	Total	Incidence/1000 Live Births	Died n (%)
No HIE	40 (12%)	–	0 (0%)	4 (2.2%)	–	0 (0%)
Stage 1	131 (46%)	6.2	2 (1.5%)	71 (38.8%)	3.4	1 (1.4%)
Stage 2	122 (43%)	5.8	7 (5.7%)	84 (45.9%)	4	6 (7.1%)
Stage 3	28 (10%)	1.3	16 (57%)	24 (13.1%)	1.1	15 (62.5%)
All HIE	281 (100%)	13.5	25 (8.9%)	179 (98%)	8.5	22 (12%)

AS , Apgar score; BD , base deficit; BMV , bag mask ventilation; HIE , hypoxic-ischemic encephalopathy.

TABLE 43.2

Predictors of the Development of Severe HIE and/or Death as a Function of a 10-Minute Apgar Score Less Than 5, the Need for Intensive Resuscitation, Time to Spontaneous Respirations, and pH

From Bruckmann EK, Velaphi S. Intrapartum asphyxia and hypoxic ischaemic encephalopathy in a public hospital: Incidence and predictors of poor outcome. S Afr Med J . 2015;105(4):298–303.

VARIABLE	OR (95% CI)
Apgar Score at 10 minutes
>7	Reference
5–7	3.05 (1.08–8.62)
<5	19.13 (5.66–66.89)
Resuscitation
BMV Only	Reference
Chest Compressions	4.51 (1.06–17.98)
Adrenaline	81.2 (13.1–647)
Time to Spontaneous Respiration (minutes)
<5	Reference
>20	27 (6.89–117.3)
pH
>7.25	Reference
<7.00	5.33 (1.31–25.16)

BMV , Bag mask ventilation; CI , confidence interval; HIE , hypoxic-ischemic encephalopathy; OR , odds ratio.

The relation of these two definitions to the severity of subsequent HIE was addressed in eight studies. Moderate encephalopathy was noted in approximately 46% of cases, with a 20% mortality rate (range 14% to 54%). Severe encephalopathy was noted in approximately 20% of cases, with an overall mortality of 60% (50% to 70%), clinical seizures complicated approximately 40% of cases ( Box 43.1 ). We interpret these findings to indicate that both definitions are very broad for identifying infants at risk for NE/ HIE and lack precision in identifying those infants who progress to severe encephalopathy and subsequent mortality. The ability to identify the newborn early at highest risk for abnormal outcome may be enhanced by using a more detailed definition (see Table 43.2 ). For example, an AS less than 5 at 10 minutes increased the likelihood of severe HIE/NE death 19-fold, adrenaline use increased the likelihood of abnormal outcome 81-fold, a cord pH less than 7.0 increased the likelihood fivefold, and absent spontaneous respirations greater than 20 minutes increased the likelihood of abnormal outcome 27-fold. Since HIE developed on the first day in all reported cases, consistent with an intrapartum etiology, detection of the fetus at greatest risk for developing HIE secondary to hypoxia-ischemia during labor must be a major priority for the clinician .

BOX 43.1

Apgar Score Less Than 7 at 5 Minutes and/or Noninitiation of Breathing

HIE , Hypoxic-ischemic encephalopathy.

Overall Summary

Approximately one-third of newborns with Apgar score less than 7 at 5 minutes developed HIE
HIE developed on the first day, consistent with an intrapartum etiology in all cases
Seizures were noted in approximately 40% of cases
Moderate encephalopathy was noted in 46% (range 24% to 75%) and mortality in 20% (range 14% to 54%) ( n = 7)
Severe encephalopathy was noted in 21% (range 1.7% to 73%) and mortality in 60% (range 50% to 70%) ( n = 7)

Challenges in the Assessment of the Fetus During Labor in LRS

Assessing the fetus during labor and identifying those at highest risk for compromise are critical if a reduction in HIE/NE in the term infant is to be achieved. The standard methods of evaluating the fetus in labor in RRS are reviewed in Chapter 21 and include assessment of fetal movements, fetal heart rate (FHRT) monitoring, and intrapartum monitoring of progress of labor (partogram) and contractions in relation to the patterns of the FHRT. These assessments aim to identify the fetus at potential risk for circulatory compromise or adverse outcome.

Partogram

The WHO has recommended use of the partograph as an effective tool for the detection of maternal and fetal progress during childbirth. The aim of the partogram is to provide a pictorial overview of labor that analyzes cervical change, uterine contractions and fetal presentation in relation to time, for the purpose of alerting midwives and obstetricians to deviations in maternal or fetal well-being and labor progress (see Fig. 43.1 ).

Is There Evidence Supporting the Use of the Partogram During Labor?

In a review of six studies involving 7706 women, there was no difference between partogram use and no partogram use as it relates to cesarean section (CS) rates or instrumental deliveries. In contrast, a systematic review of 37 studies on the use of the partogram in conjunction with FHRT monitoring for intrapartum fetal surveillance in low- and middle-income countries showed improved perinatal outcomes with a reduction in the rates of fresh still birth (FSB). Inadequate use of the partogram has been associated with increased FSB rates. Thus use of the partogram during labor in the LRS appears beneficial.

FHRT Monitoring During Labor

Intermittent Detection of FHRT With a Fetal Stethoscope

The second major assessment of the fetus during labor involves the assessment of the FHRT to identify the fetus at potential risk. Several barriers to successful implementation of FHRT monitoring in the LRS have been recognized ( Box 43.2 ). Cardiotocography is the gold standard for identifying fetuses at high risk for fetal compromise in RRS, but this device is neither available nor feasible in LRS. Thus intermittent FHRT monitoring with a fetal acoustic stethoscope is the most frequent and recommended method used in these areas.

BOX 43.2

Barrier to Successful Implementation of FHRT Monitoring in the LRS

Overall Key Points

High demand for services in the face of low midwife-to-mother staffing ratios
Lack of fetal monitoring equipment
Lack of trained staff and obstetrical resources (i.e., competent providers) and lack of operating rooms
Delay in identification of fetal jeopardy
Delays in providing rapid obstetrical intervention during labor when indicated
Effective leadership, targeted resource allocation, enhanced human resources, and a well-organized health care system could save many lives

The value of intermittent detection of FHRT using an acoustic stethoscope during labor was demonstrated in a study involving 10,271 infants in the LRS. The objective was to determine the value of routine intermittent FHRT monitoring in the detection of FHRT abnormalities and the relationship of such abnormalities to subsequent FSB, BA, need for neonatal BMV, and ND within 24 hours. Abnormal FHRT was associated with a 31-fold increase in labor complications, a 7.8-fold increased need for BMV, a 21-fold increased likelihood of BA, almost a 10-fold increased likelihood of ND, a 35-fold increased likelihood of an FSB, and a 1983-fold increased likelihood of FSB with an undetected FHR. These data point to the value of intermittent detection of abnormal FHRT using a fetal stethoscope to identify abnormal outcomes in the LRS .

The Minimal Criteria Necessary to Define BA and Link It to Subsequent HIE/NE in the LRS

To address the relationship of BA to subsequent HIE/NE in the LRS, minimal criteria to define BA should be generated. Three consensus statements addressing the terminology and diagnosis of BA have been released since 1996. All three statements recommended that terms such as birth asphyxia, perinatal asphyxia, fetal distress, hypoxic-ischemic encephalopathy , or postasphyxial encephalopathy should not be used unless a series of minimal criteria are met. We suggest the following minimal criteria necessary for establishing a link between an acute intrapartum event and subsequent NE in the LRS:

Evidence of a sentinel event (e.g., abruptio placentae, fetal bradycardia)
Evidence of nonbreathing at birth with or without absent cry
Resuscitation that includes BMV
Subsequent evolution of NE (HIE)
No other cause to explain the encephalopathy

Intrapartum Risk Factors and Their Relationship to BA, ND, and HIE/NE

As noted earlier, complications during the intrapartum period have the strongest association with perinatal mortality in the LRS. Obstructed or prolonged labor is the most common preventable cause of fetal/neonatal mortality (NM), affecting 3% to 6% of LBs, and accounts for approximately 43,000 maternal deaths annually. The incidence is particularly high in settings with no skilled personnel attending the birth and frequently results in hypoxic events that can eventually lead to HIE/NE. Other studies also point to the “important contribution of intrapartum complications” to the subsequent development of neonatal respiratory depression or a 5-minute AS less than 7 at birth.

These factors are illustrated in several important studies. Thus in a hospital-based unmatched case-control study of newborns, factors associated with BA (5-minute AS < 7) included prolonged labor (fourfold increased risk), breech delivery (fivefold increased risk), cesarean delivery (threefold increased risk), vaginal assisted delivery (fivefold increased risk), and lack of use of the partogram (threefold increased risk).

A second unmatched case-control study from Uganda added several independent risk factors for HIE/NE. NE was defined as a Thompson score greater than 5 within 12 hours of birth. Neurological assessment was performed at recruitment for cases ( n = 210) and controls ( n = 409) and then daily for 5 days. Encephalopathy was graded using the Sarnat classification. Independent risk factors for HIE/NE included increased risk in acute intrapartum events (ninefold), obstructed labor (fourfold), lack of fetal monitoring (threefold), augmentation of labor (twofold), noncephalic presentation (fivefold), neonatal bacteremia (eightfold), and histological funisitis (11-fold), but not chorioamnionitis (placental pathology, n = 60).

A third report from Nepal comprising 131 infants with NE and 635 unmatched infants recruited over 12 months added several other important risk factors for NE. Intrapartum risk factors included noncephalic presentation (odds ratio [OR] 3.4), particulate meconium (OR 18), and oxytocin administration (OR 5.7). Overall, 60% of affected infants, compared with 6% controls, either had evidence of intrapartum compromise or were born after intrapartum difficulty likely to result in fetal compromise.

Finally, a recent systematic review involving a total of 23,383 term deliveries in LMIC reported a twofold increased incidence of NE with intrapartum oxytocin use.

Taken together, these findings reinforce the importance of intrapartum risk factors (e.g., obstructed or prolonged labor, FTHR abnormalities in the genesis of BA, ND, and HIE/NE) in the LRS .

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