Assessment of Risk Factors and Prognosis in Asphyxiated Infants

1. Background

Perinatal asphyxia is a significant cause of neonatal mortality and neurological complications (1). Although the majority of these disorders are transient, the long-term consequences of asphyxia may affect the central nervous system (CNS), which can ultimately lead to cerebral palsy, epilepsy, and learning disabilities (2, 3).

There is considerable controversy over the definition and diagnosis of asphyxia. Apgar score, arterial blood gas, and signs of hypoxic-ischemic encephalopathy (HIE) are among the current criteria for the diagnosis of severe asphyxia. However, there is no correlation between patients’ prognosis and the diagnostic criteria for asphyxia. About 25% of surviving asphyxiated newborns is likely to present with neurological problems. Annually, 4,000,000 babies are born with asphyxia, of whom 800,000 die and 800,000 suffer from the associated complications (2, 4, 5).

The incidence of asphyxia is 1 - 6 per 1000 births in developed countries and 5 - 10 per 1000 births in developing countries (6). According to statistics by world health organization (WHO), in developing countries 3% of infants (3.6 million people) suffer from moderate to severe asphyxia, of whom 23% (840,000) die, and almost the same number suffer from the associated consequences (2). Examination of the causes of neonatal mortality in Bushehr revealed that 22% of deaths are due to perinatal asphyxia (7).

Apgar score can be helpful in identifying newborns with fetal distress, intrauterine asphyxia, airway obstruction, CNS depression, and impaired airways. However, low Apgar score does not necessarily indicate fetal asphyxia, since other factors (e.g. prematurity, use of narcotics and sedatives) are also associated with reduced Apgar scores. Thus, Apgar score is not a predictive factor for consequent cerebral palsy in infants (5).

Klinger et al. (8) in a 5-year study on 244 children with HIE reported 64 deaths and 63 cases of severe neurodevelopmental disorders. Moreover, a retrospective study (1999 - 2000), which aimed to examine the risk factors for neonatal HIE in 17,706 Thai patients, showed that 84 infants were born with asphyxia. As the results indicated, 1- and 5-minute Apgar scores, male gender, umbilical cord prolapse, post mature birth, and instrumental delivery were among the risk factors for HIE, although only 5-minute Apgar score was statistically correlated with HIE (9).

Parents of surviving asphyxiated infants are greatly concerned about the future of their newborns. Despite the vast advances in the pathophysiology of asphyxia, no definite criteria have been determined for identifying the long-term prognosis in these patients. Despite the extensive worldwide research on this condition, less attention has been paid to the long-term prognosis of asphyxiated infants in Iran.

2. Objectives

Considering the high incidence of asphyxia and its adverse consequences, we aimed to perform a cohort study to evaluate the risk factors and prognosis in asphyxiated infants.

4. Results

Of approximately 11,347 infants born during the study period, 110 infants presented with asphyxia, which accounted for about 1% of births. Overall, 260 infants were divided into control (150 healthy infants, 56.90%) and case (110 asphyxiated infants, 43.10%) groups.

Statistical analysis showed that 41.96% of asphyxiated infants with normal outcome were male and 58.04% female. Also, 64.40% of asphyxiated infants with abnormal outcome were male and 35.60% female.

There was a significant difference between the two groups in terms of first-hour pH (P = 0.000), 1-minute Apgar score (P = 0.000), 5-minute Apgar score (P = 0.000), and BE (P = 0.000); the values were lower in infants with asphyxia.

t-test results showed that 1-minute Apgar score (P = 0.008), 5-minute Apgar score (P = 0.000), urea level (P = 0.016), and serum creatinine level (P = 0.032) were significantly different between asphyxiated neonates with normal and abnormal outcome. There was no statistically significant difference between these two groups in terms of maternal age (P = 0.095) (Table 1).

Regarding the arterial blood gas changes in asphyxiated infants, the results showed no significant difference between the two groups in terms of 24-hour pH (P = 0.346), 48-hour pH (P = 0.117), 24-hour BE (P = 0.511), 48-hour BE (P = 0.131), 48-hour HCO₃ (P = 0.117), partial pressure of carbon dioxide during the first hour (PCO₂) (P = 0.087), 24-hour PCO₂ (P=0.325), or 48-hour PCO₂ (P = 0.806).

However, there was a significant difference between the two groups of asphyxiated infants regarding first-hour pH (P = 0.000), first-hour BE (P = 0.000), first-hour HCO₃ (P = 0.013), and 24-hour HCO₃ (P = 0.040); these variables had lower values in asphyxiated infants with consequent abnormal outcomes (Table 2).

The neonatal outcomes were re-evaluated 6, 12, 18, and 24 months after birth. Of 110 asphyxiated cases, 50 (45.5%) had normal development, 29 (26.3%) passed away, and 31 (28%) presented with developmental delay including 13 (8.11%) patients with mild, 7 (4.6%) with moderate, and 11 (10%) with severe developmental delay.

In this study, a statistically significant association was observed between HIE severity and patients’ prognosis; i.e., with increased severity of HIE, incidence of developmental delay increased. In the control group, 14 (32.55%) cases had no HIE, 26 (40.46%) presented with HIE grade I, and 3 (6.97%) were identified with HIE grade II. In the case group, 1 (1.69%) case had no HIE, 7 (11.86%) cases presented with HIE grade I, 27 (45.76%) were identified with HIE grade II, and 25 (42.37%) had HIE grade III.

Overall, 38 infants with poor and 5 infants with good prognosis were ventilated (P < 0.001). Dystocia was identified in 35 with poor and in 5 infants with good prognosis, (P < 0.001). Chi-square test results showed a significant difference in terms of sex (P = 0.003) and obstetric complications (P = 0.000) between asphyxiated neonates with normal and abnormal outcomes. However, mode of delivery (P = 0.161) and pregnancy-related complications (P = 0.081) were not significantly different between these two groups (Table 3).

According to data analysis by regression models, variables such as 5-minute Apgar score (P = 0.015), use of ventilators (P = 0.000), and first-hour pH (P = 0.001) were important factors for determining prognosis in infants with asphyxia. One-minute Apgar score (P = 0.929) was not a reliable criterion for determining prognosis in patients. Moreover, 5-minute Apgar score was not associated with first-hour pH (P = 0.000) (Table 4).

In 89.9% of cases, the risk of developmental delay can be determined based on variables such as severity of HIE, ventilation, one-minute Apgar score, and 5-minute Apgar score (Table 5).

5. Discussion

In this study, approximately 26% of infants with asphyxia died and 28% presented with developmental delay during a 2-year follow-up. The severity of HIE, need for ventilators, first-hour pH, and 5-minute Apgar score were important predictive factors for long-term neonatal complications. Our results showed that about a quarter of infants died from asphyxia and a larger number suffered from developmental delays. Overall, the mortality rate associated with asphyxia varies between 16% and 72%, according to previously conducted studies (6, 7). In a study by Klinger et al. (8) on 244 children with HIE, 26% of the subjects died, and 25% presented with neuro-motor dysfunctions, results which are almost similar to the present findings.

HIE is seen as an important cause of morbidity and mortality in infants. Given the fact that Ghaem Hospital, affiliated to Mashhad University of Medical Sciences, is one of the two main centers for high-risk pregnancies in Mashhad city, increased incidence of birth asphyxia can be related to the increased number of high-risk pregnancies, women’s late referral to hospital, and poor surveillance, resuscitation, and tranfer systems. Prenatal and childbirth care, proper monitoring during labor, presence of a resuscitation team in the delivery room, appropriate resuscitation and stabilization, and proper transfer of the infant to the ward can reduce the associated infant mortality (11).

In our study, higher incidence of asphyxia in infants with dystocia indicates the significance of maternal complications during pregnancy and childbirth. Therefore, the severity of consequent complications can be reduced by proper interventions, appropriate monitoring during labor, the presence of a pediatric specialist at the mother’s bedside before delivery, and preparedness for a risky childbirth.

Based on the results, 1- and 5-minute Apgar scores in the control group were significantly lower than those reported in patients with asphyxia. However, comparison between the two subgroups with normal development and developmental delay showed that 5-minute Apgar score is significantly helpful in predicting children’s development (P = 0.015) and can be among the most important prognostic factors for asphyxiated infants.

Furthermore, a statistically significant association was found between 1- and 5-minute Apgar scores and first-hour pH (P = 0.000). Similarly, In Toh’s study (12), low 5-minute Apgar score, use of adrenaline, and low initial arterial pH were significant risk factors for asphyxia. Kaveh et al. (13) showed a significant correlation between Apgar score and arterial blood gas within the first hour of life, i.e. arterial pH in infants with low Apgar score was lower. There was also a direct correlation between low Apgar score and asphyxia. Hence, infants born with low Apgar scores may suffer from acidosis, alkaline deficiency, asphyxia, and require special treatment. On the other hand, in other studies, Apgar score in infants with consequent cerebral palsy was shown to be normal, and incidence of cerebral palsy was low in infants with low Apgar score (5-minute Apgar score: 0 - 3) (13, 14). Therefore, Apgar score cannot be the sole criterion for the identification of infants with birth hypoxia and asphyxia.

The present study indicated a statistically significant association between HIE severity and long-term prognosis in infants, i.e. with increasing severity of HIE, incidence of developmental delay increases. In fact, 19% of infants with HIE grade I, 58% with HIE grade II, and 100% with HIE Grade III had developmental disorders. Shireen et al. (6) also indicated that the incidence of developmental delay in infants with asphyxia increases with problems such as prematurity, low birth weight, and increased severity of HIE. In this regard, Soleimani and colleagues (15) indicated a relationship between delayed motor development and asphyxia.

Hatami et al. (7) examined the impact of moderate to severe HIE in neonates in Bushehr, Iran during five years. They showed that among 17 surviving infants, 5 (30.4%) cases suffered from developmental disorders (2 and 3 patients developed mild and severe cerebral palsy, respectively) and 12 (6.70%) cases were healthy. Thus, a surviving infant with moderate to severe asphyxia needs proper planning and care. Overall, evaluation of nutritional status, vision and hearing examinations, treatment of seizures, cognitive skill assessment, and language development evaluation are required for these patients (16).

In terms of sex, there was a statistically significant difference between asphyxiated infants with normal development and those with developmental delays (P = 0.003), i.e. 64% of infants with developmental delay were male. In a study by Mohamed and Aly (17), African-American ethnicity and male gender were significantly correlated with neonatal asphyxia. Moreover, Hussein et al. (18) evaluated the relationship between sex and cerebrospinal fluid levels of interleukin-8 (IL-8) and antioxidants in 32 asphyxiated neonates (19 boys and 13 girls). They found that male infants were more vulnerable to brain damage, compared to female newborns, since IL-8 and antioxidant levels and pro-oxidant-antioxidant balance in cerebrospinal fluid of female infants are higher (18).

In the current study, delivery-related complications were important risk factors for birth asphyxia. Majeed et al. (19) found that lack of prenatal care, poor nutritional status, prenatal bleeding, and maternal toxemia increased the incidence of asphyxia.

Utomo (3) found that prepartum hemorrhage, preeclampsia, preterm birth, post term birth, and low birth weight were among the risk factors for neonatal asphyxia. Hence, understanding the risk factors and promoting prenatal care can reduce the incidence of neonatal asphyxia and mortality rates.

Mode of delivery was among the evaluated variables in the present study. The results showed that this factor plays no major role in the incidence of birth asphyxia. However, Onyearugha and Ugboma (20) showed the (7.3 times) increased risk of neonatal asphyxia by cesarean section. In addition, Utomo (3) showed that cesarean section was a risk factor for asphyxia. Lack of association between mode of delivery and neonatal outcomes in our study may be related to delayed referral of women with obstetric complications and improper monitoring during labor.

In our study, neonatal asphyxia had no association with maternal age, which was consistent with findings of Shireen et al. (6). The results showed that pH, BE, and HCO₃ within the first hour and 24 hours after birth were different between asphyxiated newborns with normal development and those with developmental delays. In other words, the values of these variables in asphyxiated neonates with developmental delay were lower than those reported in infants with normal development. Therefore, pH, BE, and HCO₃ changes during the first hour increase the possibility of poor prognosis in infants. Additionally, in case changes of HCO₃ persist into the next day, possibility of future complications increases. Kaveh et al. (13) also emphasized the relationship between arterial blood gas (including pH and BE) and Apgar score and showed that 90% of infants with Apgar scores < 7 had BE < -10, while 75% of newborns with Apgar scores > 7 had the same amount of BE. Fetal asphyxia is a condition in which blood gas variations lead to hypoxia, hypercapnia, and metabolic acidosis. Thus, detection of this condition during labor is needed to assess blood gas and blood’s acid-base (21). Long-term follow up of infants, not checking the CT scan results and also lack of motivation in some parents of neonates were the limitations of this study.

Based on our findings, incidence of long-term complications in newborns with HIE is high and is directly associated with the severity of asphyxia. Risk factors for developmental delay in surviving asphyxiated infants included the severity of asphyxia, need for mechanical ventilation, severity of acidosis at birth, dystocia and obstetric labor complications, and low 5-minute Apgar score. Therefore, it seems that with proper care during pregnancy, fetal control and surveillance during labor, and proper resuscitation and stabilization, the associated adverse outcomes can be reduced. Finally, special attention should be paid to the prognosis of infants with moderate or severe HIE, metabolic acidosis, and those requiring mechanical ventilation.