Although TH is an effective intervention to enhance survival without neurological deficit for infants with moderate to severe HIE, whether this therapeutic strategy should become the standard of care in middle-income countries remains problematic, because the treatment effect varies in high- versus low-resource settings [7, 10]. Reported incidences of HIE, associated demographics, and outcomes stem mostly from robust clinical trials conducted in either high-income countries or heterogeneous studies executed in LMIC settings, with recognized confounders. Data particularly from least developed or LMIC SEA countries that include Thailand, is limited.
The true national incidence, severity, and outcomes of infants with perinatal asphyxia is uncertain due to the lack of a uniform reporting system in Thailand and continuous immigration into the country. The ICD-10 definition identifies the status of infants at 1-minute but majority of the infants rapidly improve following resuscitation and achieve clinical stability. Our data shows that 12% of infants with an Apgar score of ≤7 at 1-minute remained at ≤5 at 5 minutes. Since we wanted to evaluate only infants at high-risk for HIE that were potential candidates for TH, we chose an Apgar score of ≤5 at 5 minutes for our definition of perinatal asphyxia and as a flag for the chart review [34]. Comparing incidences of perinatal asphyxia among regions is challenging because of inconsistent definitions and reports on pre-specified GA-groups [12]. In our study, the incidence of perinatal asphyxia ranged from 2.6 to 6.7 per 1000 live births with regional variation. The average incidence of 3.8 per 1000 live births is marginally higher than 2.6 per 1000 livebirths reported in Malaysia [15] but lies within the range reported by developed countries (1 to 8 per 1000 live births),[12] and is 4-fold lower than lower-income and developing countries (16%) [35, 36]. However, our hospital-based incidence using both inborn and outborn infants as a denominator, is potentially higher than the true population-based incidence due to selective bias since we only included referral hospitals and 35% of the subjects were outborn.
Twenty-one percent of the infants were born to immigrant SEA mothers but racial disparity did not influence management. Ninety-seven percent of the mothers had antenatal care and only 31% had complications. Overall demographic characteristics of the enrolled subjects were similar to many clinical trials of TH in developed countries. Our rates of major complications were comparable to the control group of the National Institute of Child Health and Human Development trial [21]; mean maternal age (27.9 vs. 27 years), maternal hypertension (11% vs. 13%), diabetes (11% vs. 8%), and antepartum hemorrhage (7% vs. 10-19%). Our rate of maternal fever was 2.2% which was also similar to clinical trials of TH (range:1.8% -12%) [18, 21, 28]. Meconium-stained amniotic fluid occurred in 19% of our study subjects while it was reported up to 29% in the neo.nEURO network randomized trial [29]. In the present study, a total of 54% of the subjects were born by cesarean section compared to reports of clinical trials from developed countries which varied from 46% to 75% [18, 21].
Apart from maternal factors, the mean birthweight of infants in the group ≥35-weeks GA was 3009 g (10% were small for GA) which is slightly lower than approximately 3300g in several studies [18, 21, 29]. Pertinent demographic characteristics were similar except for the number of inborn infants which is one of the interesting factors related to outcome.[37] Overall, 65% of the infants in our study were inborn and 59% were ≥35-weeks GA which was similar to the ICE and neo-nEURO network trials. The mean time to NICU admission was 2.8 hours and 91% were admitted to the referral hospitals within 6 hours of life. This is well within the golden, recommended period of 6 hours to initiate TH and positively influence outcomes [37, 38]. Although it is difficult to accurately compare the incidence of risk factors associated with perinatal asphyxia due to variable study definitions, gestational age categories selected apriore, and type and quality of included data, the overall baseline maternal and infant characteristics relating to outcomes show a similar trend between high- versus middle-income countries (Table 3).
Fifty-eight percent (136/235) of infants in the ≥35-week GA with perinatal asphyxia had HIE. Only 85 (62.5%) met eligibility criteria for TH and 48 (35.3%) received treatment (62.5% of eligible infants). The reasons that 27.2% did not receive therapy was due to the unavailability of TH at the referral center at the time of birth, inability to refer to the cooling center within 6 hours of age, and non-familiarity with referral hospitals that performed TH. More than 90% of the enrolled subjects were clinically evaluated for TH based on Apgar scores, prolonged ventilation, or sentinel events. Umbilical cord or early blood gas analysis was performed in 77.9% of our cohort, and the availability of both have improved in rural Thai regions over time. We propose that the criteria for TH in LMIC settings should include intrapartum sentinel events as described and simpler HIE classification based on Apgar scores and clinically documented encephalopathy without mandatory blood gas analysis, which is inconsistently available.
To our knowledge, the true incidence of perinatal asphyxia in SEA countries remains undetermined. Our average frequency of HIE across the 4 institutions is similar to the Malaysian registry and high-income countries. However, the range suggests that in parts of Thailand the incidence is likely higher and the availability of TH could alter long-term adverse sequelae. Individual chart review by neonatologists using specific definitions for each variable relevant to current practice, ensures internal validity of our results. Moreover, we included major referral hospitals in different parts of Thailand to minimize selective bias and afford country-wide generalizability of the findings.
Nevertheless, some limitations related to the retrospective chart review merit consideration. First, complete chart data may not have been assembled, and we were unable to identify maternal socioeconomic and nutritional status which are reported risk factors for neonatal encephalopathy [24]. Hence, we utilized standard antenatal care as a proxy for the surveillance of good maternal health in 97% of the pregnancies. Second some variables were missing particular for infants who were outborn, such as maternal temperature and complete details of birth resuscitation. Third, as previously addressed, an umbilical cord gas or arterial blood gas analysis within the first few hours of life was either unavailable in some rural hospitals, or not considered part of standard practice in most hospitals during the study period. However, the total number of recruited infants should partially compensate for these limitations and maintain the validity of our results.
In summary, maternal and infant demographic characteristics and intrapartum risk factors for perinatal HIE in Thailand were comparable to published reports from high-income countries. Sixty-three percent of eligible infants received TH treatment. To improve access to country-wide TH, strategies need to be implemented to raise awareness of the eligibility criteria for therapy among obstetricians and allied perinatal health-care providers. Simplifying the criteria for TH in low-middle income countries may enhance accessibility to TH where transport of potential candidates can be expedited in a timely manner.