Long-term neurodevelopmental effects of exclusively high cord lactate levels in term newborn

Abstract Introduction Cord arterial blood gas analysis (ABGA) results are used as diagnostic criteria for hypoxic-ischemic encephalopathy in newborns with suspected perinatal asphyxia. This study evaluated the effect of cord ABGA lactate level on the long-term neurodevelopment of newborns without any clinical signs of perinatal asphyxia. Methods This clinical observation study was designed among term babies born between 2018 and 2019 in our unit. Cases with a 5-min Apgar score <7 and signs of fetal distress in their antenatal follow-up were excluded. The cases (n = 1438) were divided into two groups those with high cord lactate levels (above 5 mmol/L, n = 92) and those with low lactate levels (below 2 mmol/L, n = 255). An Ages and Stages Questionnaire, Third Edition (ASQ-3) developmental screening questionnaire was sent to all parents. Patients with a chronological age between 24 and 42 months and for whom the parents fulfilled the questionnaire (low lactate group, n = 29, and high lactate group, n = 45) were evaluated. Results No difference was observed between the two groups in terms of demographic characteristics such as age (p = .1669), male gender (p = .906), mother’s working situation (p = .948), mother’s education level (p = .828), father’s education level (p = .507), and family’s total income (p = .642). Mean ACQ-3 developmental screening test scores were significantly lower in the high lactate group compared to the low lactate group concerning; fine motor (40 vs. 60, p = .001), problem-solving (50 vs. 60, p = .002), and personal social development (45 vs. 60, p = .003). No difference was observed in terms of communication and gross motor total scores. Discussion In general practice, routine cord ABGA is not generally recommended for patients with normal Apgar scores and no suspected hypoxia. However, in this study, we observed that cases with a normal 5-min Apgar score, no suspected perinatal asphyxia, and a cord lactate value of ≥5 fell behind their peers when evaluated with the ACQ-3 developmental screening questionnaire.


Introduction
Apgar score and cord arterial blood gas analysis (ABGA) are the two main parameters used to evaluate a baby's well-being after birth [1].The cord ABGA is routinely recommended in newborns with suspected asphyxia, especially in cases with a 5-min Apgar score below 5.It has been reported that primarily 5-and 10-min Apgar scores below 7 increase the risk of hypoxic-ischemic encephalopathy (HIE) [2,3].According to the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics, low cord arterial blood pH <7.0 and/or actual base excess (BE) < −12 mmol/L are the generally accepted threshold values for pathological acidosis and are considered to increase the risk of seizures, HIE and cerebral palsy [4].
Metabolic acidosis develops in the late stage of fetal hypoxia when the fetal oxygen supply is insufficient, and the anaerobic metabolism of carbohydrates increases lactic acid production.As the lactate concentration rises, the actual BE levels decrease.Therefore, lactate appears to be the most direct parameter to express the severity of metabolic acidosis [5].As a rule, the strength of lactate as acid is similar to that of bicarbonate, which is a base, so lactate elevations cause a one-to-one decrease in the bicarbonate level.Therefore, acidosis typically becomes apparent at lactate levels of about 45 mg/dL (5.0 mmol/L) [6].It has also been reported that the lactate level measured from the fetal scalp may be an earlier marker than pH in the hypoxic process [7,8].
The Canadian Pediatric Association supports developmental screening of all children at 18 months using an approved screening tool, and the American Academy of Pediatrics recommends developmental screening at 9, 18, and 24 or 30 months [9,10].Some recent studies have shown that neurodevelopment tests can be applied in preterm infants and at earlier ages [11,12].An experienced healthcare professional can detect development delay by age two, but many children are only diagnosed after age four [13,14].A parent-completed screening tool such as the Ages and Stages Questionnaire (ASQ) has become popular since it is a low-cost screening tool that parents can easily apply in a home setting with a short completion time.The ASQ, Third Edition (ASQ-3) has been shown to perform well in children with biological risk factors (gestation age, birth weight, and gender) or certain environmental risk factors [15,16].
This study aimed to evaluate the effect of cord ABGA lactate levels on the long-term development of term newborns who did not experience any perinatal asphyxia (5-min Apgar score of 7 and above and no fetal distress detected in antenatal follow-up).Therefore, the cases were divided into two groups according to their cord ABGA lactate levels, and their development was compared with the ACQ-3 Screening Questionnaire.

Participants
The cases whose cord ABGA results were evaluated (n ¼ 1781) from babies born (n ¼ 2262) at Istanbul University Cerrahpas ¸a-Cerrahpas ¸a Medical Faculty between 1 January 2018 and 31 December 2019, were included in the study.First, unfollowed pregnancies, newborns with fetal distress, congenital anomalies, severe and moderate metabolic acidosis (pH �7.1 at cord ABGA), neonates requiring cardiopulmonary resuscitation in the delivery room, pre-and post-term newborns were excluded from this study.Second, according to the cord ABGA lactate levels, the cases were classified into two groups, high and low lactate levels, above 5 mmol/L levels and below 2 mmol/L, respectively.Their parents could not be contacted and did not agree to fill out the questionnaire, cases aged below 24 months and over 42 months when the study was conducted, some cases had a neurologic disorder and known or suspected neurological disorder, and if the parents could not adequately complete questionnaires, they were excluded.The parents of these cases were contacted via phone, and the ACQ-3 developmental screening questionnaire online was sent to their mobile phones after informing them in detail.Patients with a chronological age between 24 and 42 months and for whom the parents fulfilled the questionnaire (low lactate group, n ¼ 29, and high lactate group, n ¼ 45) were evaluated.
Parents were divided into five groups according to their education level as they needed to be literate, primary school, secondary school, high school, and university graduates.The economic income of the family was evaluated as high and low income (over 10,000 TL and below 10,000 TL) based on the current poverty line in Turkey [17].

Ages and Stages Questionnaire
The ACQ-3 was used in this study.The ACQ is a standard parent-filled questionnaire that screens children's developmental delays using 19 separate age-specific developmental questionnaires beginning at 4 months and ending at 60 months [15].There are five fields in the ACQ-3 questionnaire; fine motor, gross motor, communication, problem-solving, and personal-social.Each field contains six questions; scoring is determined according to the answers given as follows; yes (10 points), sometimes (5 points), or not yet (0 points) [18].

Statistics
SPSS v21.0 (SPSS Inc., Chicago, IL) was used for statistical analysis.The variables were investigated using visual (histograms, probability plot) and analytical methods (Shapiro-Wilk's test) to determine whether or not they are normally distributed.Continuous variables were given as medians (25th-75th percentile), and categorical variables as frequency and percentage.Where appropriate, the Chi-square test or Fisher's exact test was used to analyze categorical variables.Comparing two groups that were non-normally distributed was performed with the Mann-Whitney's U-test.A p value <.05 was considered for statistical significance.

Demographic characteristics of the cases
In the high lactate (>5 mmol/L) group, 92 cases were detected, and 55 were reached, but 30 were accepted to participate in the questionnaire.One case was excluded from the study because he needed help to fill out the questionnaire appropriately.Thus remaining 29 cases were evaluated.In the low lactate (<2 mmol/L) group, 255 cases were detected, and 95 were reached, but 46 of them agreed to participate in the survey.One case was excluded from the study because it was diagnosed with autism, and the results of the remaining 45 cases were evaluated (Figure 1).None of the cases in the high and low lactate groups were admitted to the neonatal intensive care unit and were alive without any treatment.When median (25-75%) age (35 (28.5-39.5)months vs. 41 (29-41.5)months, p ¼ .166),gender (p ¼ .906),employment status of mothers (27.6% vs. 31.1%,p ¼ .948),mothers' education level (p ¼ .828),fathers' education level (p ¼ .507),and the economic status of the family (p < .642)were compared, no difference was observed between the two groups (Table 1).

Discussion
The Apgar score, developed by Dr. Virginia Apgar and used to evaluate the postnatal well-being of newborn babies, maintains its current value but is affected by differences between observers [19].Cord ABGA provides a more objective and detailed evaluation.Using both the Apgar score and cord ABGA in newborns with suspected HIE is recommended [20,21].However, there is no well-defined cutoff value for newborns with moderate and mild acidemia, and there are little data on the long-term neurological outcomes of these babies [4].A recent study by Malak et al. showed that cord blood gas was associated with low pH, sucking reflex, tonic neck reflex, attention deficit, and general motor development according to the development score [22].We aimed to conduct a study concerning the developmental outcomes of term newborns with normal 5-min Apgar scores and no signs of hypoxia in the antenatal follow-up but with a high lactate level in the cord gas.In this study, we did not evaluate patients' cord ABGA pH results.However, we could not reach a significant number of cases in both groups; we found that the high lactate group fell behind in fine motor, problem-solving, and personalsocial development compared to the normal lactate group in the ACQ-3 developmental screening questionnaire.
The frequency of neurodevelopmental retardation in children has been reported to be between 5 and 9% [23][24][25].Delays in neurological development mean failure to reach developmental milestones for children under five, resulting in poor long-term health problems and reduced quality of life, creating higher health and social costs in the future [26][27][28][29].In recent years, ACQ-3 and Parents' Evaluation of Developmental Status has been the most widely used developmental test in pediatrics [30].In a recent study, the ACQ-3 test was found to be 85% specific in children under 42 months, and it was reported to offer advantages for detecting developmental delays [31].In another recent study, the high specificity and negative predictive value of the ACQ-3 test were demonstrated, and it was shown to be particularly effective at the age of 24 months [32].Because of these reasons, our study group was selected from term infants aged 2-3.5 years, and the ASQ-3 questionnaire was used to evaluate the development of the cases.
Few studies evaluated the neurological outcomes of patients with mild acidemia in the cord blood gas analysis.In a prospective study by Mousa et al., when the short-term results of cases with cord blood pH above and below 7.2 were compared, the need for resuscitation, convulsions, hypoxic encephalopathy, hospitalization, and more extended hospital stay concerned low pH [22].It was also shown that high lactate values were closely associated with metabolic acidosis, mortality, and morbidity and could be used as a predictive marker of end-tissue oxygenation [6].It had been reported in previous studies that a high lactate value could be regarded as a poor prognostic factor, but a definite cutoff value was not given [33,34].A review of recent cross-sectional randomized controlled studies reported that umbilical cord lactate was an effective, feasible, and inexpensive method that could be used to determine acidemia and hypoxic ischemic encephalopathy [34].A recent large-scale study showed that cord lactate value was as reliable as pH and BE in detecting hypoxic-ischemic infants.The most sensitive blood gas parameter was reported to be the lactate level when it was adjusted for the gestational week in the same survey [35].In another large-scale study, the combination of umbilical arterial lactate level and neonatal resuscitation need was the highest predictor for detecting moderate to severe HIE [36].Our study found a developmental delay in the group with high cord blood lactate value compared to the group with low lactate.Even if antenatal hypoxia is not severe enough to develop signs of HIE, high lactate levels above 5 may affect long-term neurological development.
The main limitation of this study is the inability to reach a significant amount of cases in low and high lactate groups.Another limiting factor was that most cases were in the low-income group.To our knowledge, it is the only study that performed the longterm neurologic evaluation of a group with no perinatal asphyxia findings, a normal 5-min Apgar score, but a high lactate level in the umbilical cord analysis.
Although the reliability of the Apgar score is still generally accepted today, we propose that cord ABGA evaluation should be performed routinely even if there is no suspicion of perinatal asphyxia.In the cord ABGA, patients with high lactate levels should be followed closely regarding neurological development.Isolated cord lactate elevation may cause long-term neurological developmental delay.

Table 2 .
Comparison of the group with low and high umbilical cord lactate levels with an ACQ-3 development test.Mann-Whitney's U-test, bold values indicate statistically significant (p < .05). 1

Table 1 .
Demographic data of umbilical cord lactate level cases.