
==== Front
BMC Pediatr
BMC Pediatr
BMC Pediatrics
1471-2431
BioMed Central London

5041
10.1186/s12887-024-05041-1
Research
Correlation between anesthetic concentration and low Apgar scores in neonates born via Cesarean sections under general anesthesia
Gao Yang 1
Song Yun 1
Miao Jingkun 2
Lei Xiaofeng 1
Liu Hao 2
Gan Lin 1
Cai Meng 1
http://orcid.org/0000-0001-8568-9166
Yu Jin dodoes@qq.com

1
1 https://ror.org/05pz4ws32 grid.488412.3 Department of Anesthesiology, Chongqing Health Center for Women and Children, Women and Children’s Hospital of Chongqing Medical University, No. 120, Longshan Road, Yubei District, Chongqing, 401147 China
2 https://ror.org/05pz4ws32 grid.488412.3 Department of Pediatrics, Chongqing Health Center for Women and Children, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China
7 9 2024
7 9 2024
2024
24 57119 1 2024
29 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Objectives

This study aimed to compare plasma concentrations of anesthetic drugs administered during Cesarean section with low Apgar score in neonates deliveried under general anesthesia and analyze associated risk factors.

Methods

Data from 76 neonates undergoing Cesarean section under general anesthesia with blood concentrations of anesthetic drugs were analyzed. A low Apgar score was defined as ≤ 7. Perioperative maternal and neonatal data were collected and analyzed. Neonates were divided into a control group (Group CON, n = 65) and a low Apgar score group (Group LAS, n = 11) based on Apgar score.

Results

There were no significant differences in the plasma concentrations of anesthetic drugs in maternal artery, umbilical vein or umbilical artery blood between the two groups. Risk factors for neonatal low Apgar scores during Cesarean section under general anesthesia were premature delivery (aOR 10.2, 95% CI = 1.8–56.9) and preoperative fetal distress (aOR 9.6, 95% CI = 1.3–69.0). The prediction model was: probability = 1/(e‑Y), Y= -4.607 + 2.318× (premature delivery) + 2.261× (fetal distress) (yes = 1, no = 0). The Hosmer–Lemeshow test showed χ²= 9.587, P = 0.213, and the area under the curve (AUC) was 0.850 (0.670 ~ 1.000). With a cutoff value of 0.695, sensitivity and specificity were 81.8% and 87.7%, respectively.

Conclusions

There was no correlation between blood concentration of general anesthetic drugs and Apgar score or occurrence of neonatal low Apgar scores. Premature delivery and preoperative fetal distress were identified as independent risk factors for neonatal low Apgar scores after Cesarean section under general anesthesia.

Keywords

General anesthesia
Cesarean section
Neonatal outcome
Apgar score
Anesthetics
Correlation analysis
Natural Science Foundation of Chongqing of Chinacstc2021jcyj-msxmX0763 National Key Clinical Speciality Construction ProjectObstetrics and Gynecology issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Approximately one million neonates die annually worldwide from intrapartum-related complications, such as birth asphyxia [1]. Two million neonates suffer from hypoxic ischemic encephalopathy(HIE), and 1.2 million experience developmental delays [2]. Various antepartum or intrapartum factors contribute to birth asphyxia, including primipara mother, placental abruption, intrauterine growth restriction, prolonged second-stage labor, meconium-stained or bloody amniotic fluid, and abnormal fetal heart rate (FHR) tracings [3]. Multivariate analysis of 1200 neonates identified maternal factors (gestational hypertension, gestational diabetes, placenta previa, meconium stained amniotic fluid, intrauterine infection, anemia, educational level and age), fetal factors (twins, gestational age, breech position, umbilical cord around the neck and fetal distress), and other factors (Cesarean section and prolonged labor) as risk factors for neonatal asphyxia [4].

For Cesarean sections, regional anesthesia is preferred due to its adequate analgesic efficacy and minimal adverse effects on both mother and neonate [5]. General anesthesia may be necessary in cases where regional anesthesia is ineffective, contraindicated, or for emergency deliveries [6]. General anesthesia is typically reserved for emergency cesarean deliveries or situations where neuraxial anesthesia is not feasible.

Concerns have been raised about the potential impact of general anesthesia during Cesarean section on neonatal outcomes, including the risk of neonatal low Apgar scores. However, the relationship between plasma anesthetic drug concentrations during Cesarean sections under general anesthesia and neonatal Apgar scores remains unclear. This study aims to compare plasma anesthetic drug concentrations in neonates with and without low Apgar scores and to analyze the potential risk factors associated with low Apgar scores during Cesarean sections under general anesthesia.

Methods

Objects and grouping

This study was approved by the Medical Ethics Committee of Chongqing Health Center for Women and Children (reference number: 2021-011),and registered at the Chinese Clinical Trial Registry (ChiCTR) (www.chictr.org) with registration ID ChiCTR2100046547. Informed consent was obtained from all participants. The data of neonates delivered via Cesarean section under general anesthesia and maternal perioperative data from April 15, 2021, to April 10, 2022, were reviewed and analyzed. The general inclusion criteria were neonates delivered via Cesarean section, the use of the same general anesthesia scheme, and the measurement and recording of anesthetic drug concentrations. Neonates with congenital malformations were excluded. The enrolled participants were divided into a control group (Group CON, n = 65) and a low Apgar scores group (Group LAS, n = 11) based on the Apgar score. Neonates with an Apgar score < 8 at 1, 5, or 10 min after birth were classified as having neonatal low Apgar score. A total score of 0–3 points, 4–7 points and 8–10 points indicated severe asphyxia, mild asphyxia and normal, respectively [7].

The concentrations of anesthetic drugs in the included subjects were measured using liquid chromatography-tandem mass spectrometry. Maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood samples were collected after umbilical cord ligation for analysis of drug concentrations. The samples were centrifuged in sodium citrate-coated anticoagulant tubes at 3000 rpm at 4 °C for 10 min. The plasma was isolated and stored at -80 °C for later analysis. The anesthetic drugs tested included etomidate, remifentanil and rocuronium bromide in MA, UV, and UA blood samples.

General anesthesia scheme

General anesthesia for the Cesarean section was administered using a combination of intravenous and inhalation induction. The detailed procedure included inducing anesthesia with sevoflurane inhalation at 5% and a remifentanil infusion at 5 ng/ml using target-controlled infusion (TCI) mode. Additionally, etomidate (0.25 mg/kg) and rocuronium bromide (0.6 mg/kg) were administered as single injections. Sevoflurane was stopped once the eyelash reflex was lost, and tracheal intubation was performed after the muscle relaxants took effect. Anesthesia was maintained with remifentanil (5 ng/ml) and propofol (3.5 µg/ml) in TCI mode after the neonatal umbilical cord was disconnected.

Data collection

Maternal and fetal characteristics, blood concentrations of anesthetic drugs, time from induction to skin incision (I-S), time from induction to delivery (I-D), and time from uterine incision to delivery (U-D) were recorded and analyzed. Apgar scores at 1, 5, and 10 min were collected retrospectively. Maternal indicators included age, body weight, height, body mass index (BMI), gestational age, gestational hypertension, gestational diabetes, scar uterus (previous Cesarean section), hemoglobin, hematocrit, leukocytes, platelets, plasma prothrombin time (PT), activated partial thrombin time (APTT), D-dimer, plasma fibrinogen, thrombin time (TT), premature rupture of membranes, placental abruption and polyhydramnios or oligohydramnios. Fetal-related indicators included fetal sex, twin pregnancy, premature delivery, abnormal umbilical cord (such as the umbilical cord around the neck or first exposed umbilical cord), and fetal distress.

Statistical analysis

Normally distributed measurement data are presented as mean ± standard deviation, while count data are expressed as numbers. T-tests were used to compare measurement data between groups, and the chi-square test was used for count data comparison. Pearson correlation analysis was conducted to evaluate the correlation between blood concentrations of anesthetic drugs and Apgar scores at 1, 5, and 10 min. A significance level of P < 0.05 was considered statistically significant. Logistic regression analysis was performed to assess the relationship between potential factors and neonatal low Apgar scores, calculating both crude odds ratio (OR) and adjusted odds ratio (adjusted OR). Binary logistic regression was used to analyze risk factors, and receiver operating characteristic (ROC) analysis was conducted to evaluate factors influencing prognosis. An area under the curve (AUC) > 0.5 indicated predictive value. Independent risk factors were identified, and regression equations were constructed as follows: probability = 1/(e‑Y) and Y = A + B1 × 1 + B2 × 2, where “A” is a constant, “B” is the regression coefficient of each risk factor, “X” is the risk factor, and the probability represents the risk value of neonatal birth asphyxia under general anesthesia.

Results

Preoperative maternal and fetal characteristics

Neonatal low Apgar scores were observed in 11 out of 76 neonates delivered via Cesarean section under general anesthesia, resulting in an incidence rate of 14.47%. There were no significant differences in preoperative maternal or fetal indicators except for gestational age, D-dimer concentration and fetal distress between the low Apgar score (LAS) group and the control (CON) group. The incidence of fetal distress in the CON group was 6.15% (4 out of 65), while in the LAS group, it was significantly higher at 36.36% (4 out of 11) (P < 0.05) (Table 1).

Table 1 Preoperative maternal and fetal characteristics

	Group CON(n = 65)	Group LAS(n = 11)	P value	
Age, years	31.82 ± 3.8	30.91 ± 6.4	0.659	
Body weight, kg	71.06 ± 9.7	66.06 ± 12.9	0.243	
Height, cm	157.80 ± 4.9	155.18 ± 7.3	0.275	
BMI	28.55 ± 3.8	27.43 ± 5.5	0.396	
Gestation, weeks	37.58 ± 1.9	34.36 ± 3.5	0.012*	
Gestational hypertension(Yes/No)	5/60	2/9	0.266	
Gestational diabetes (Yes/No)	13/52	4/7	0.228	
Scar uterus(previous CS) (Yes/No)	17/46	2/9	0.537	
Hemoglobin, g/L	123.06 ± 13.4	118.82 ± 17.9	0.359	
Hematocrit, %	35.66 ± 4.3	34.70 ± 3.7	0.485	
Leukocyte, 109/L	8.01 ± 2.2	7.85 ± 2.1	0.820	
Platelet, 109/L	146.26 ± 60.7	166.55 ± 66.3	0.359	
PT, second	10.25 ± 1.1	10.36 ± 0.7	0.740	
APTT, second	26.50 ± 2.0	26.90 ± 1.9	0.547	
FIB, g/L	4.49 ± 0.9	4.84 ± 1.4	0.274	
TT, second	17.77 ± 1.8	17.82 ± 1.1	0.903	
D-Dimer, mg/L FEU	2.79 ± 1.7	4.11 ± 2.5	0.032*	
Fetal sex(female/male)	29/34	6/5	0.602	
Premature rupture of membranes	7/56	0/11	0.585	
Twin pregnancy (Yes/No)	19/44	5/6	0.317	
Premature delivery (Yes/No)	16/47	9/2	0.001*	
Placental abruption (Yes/No)	3/60	2/9	0.102	
Polyhydramnios or oligohydramnios (Yes/No)	6/57	2/9	0.394	
Abnormal umbilical cord

(umbilical cord around neck, umbilical cord exposed first)

	13/50	2/9	0.852	
Fetal distress (Yes/No)	4/59	4/7	0.003*	
BMI: body mass index, TT: thrombin time, PT: plasma prothrombin time, FIB: plasma fibrinogen, APTT: activated partial thrombin time

*Compared with the control group

Blood concentrations of anesthetic drugs

There were no significant differences in the plasma concentrations of anesthetic drugs (remifentanil, etomidate, or rocuronium bromide) between the two groups in maternal artery blood (MA), umbilical vein (UV), or umbilical artery (UA) blood (P > 0.05) (Table 2; Figs. 1, 2 and 3).

Table 2 Blood concentrations of anesthetic drugs

	Group CON (n = 65)	Group LAS (n = 11)	P value	
Remifentanil MA, ng/ml	3.87 ± 1.3	4.15 ± 1.5	0.545	
Remifentanil UV, ng/ml	1.86 ± 0.9	1.78 ± 0.5	0.772	
Remifentanil UA, ng/ml	0.94 ± 0.8	0.77 ± 0.7	0.499	
Remifentanil UV / MA	0.49 ± 0.2	0.47 ± 0.1	0.725	
Remifentanil UA / MA	0.24 ± 0.2	0.19 ± 0.2	0.369	
Etomidate MA, ng/ml	477.17 ± 154.0	446.16 ± 238.7	0.662	
Etomidate UV, ng/ml	322.25 ± 129.0	276.65 ± 129.3	0.321	
Etomidate UA, ng/ml	180.14 ± 66.6	183.11 ± 118.5	0.910	
Etomidate UV / MA	0.70 ± 0.2	0.70 ± 0.3	0.985	
Etomidate UA / MA	0.40 ± 0.1	0.45 ± 0.2	0.373	
Rocuronium bromide MA, ug/ml	5.98 ± 2.5	6.07 ± 2.9	0.916	
Rocuronium bromide UV, ug/ml	0.80 ± 0.5	0.84 ± 0.4	0.786	
Rocuronium bromide UA, ug/ml	0.47 ± 0.3	0.42 ± 0.2	0.627	
Rocuronium bromide UV / MA	0.15 ± 0.1	0.18 ± 0.1	0.452	
Rocuronium bromide UA / MA	0.09 ± 0.1	0.08 ± 0.1	0.755	

Fig. 1 The concentrations of remifentanil in the MA, UV and UA blood samples

Fig. 2 The concentrations of etomidate in MA, UV and UA blood samples

Fig. 3 The concentrations of rocuronium bromide in MA, UV and UA blood samples

Correlation analysis

There was no correlation found between the blood concentrations of anesthetic drugs in MA, UV, UA blood and Apgar scores at 1, 5, and 10 min. The specific correlation coefficients and P-values are detailed in Table 3.

Table 3 Correlation coefficients and P-values between blood concentrations of anesthetic drugs and apgar scores at 1, 5, and 10 min

	Apgar score
at 1 min	Apgar score
at 5 min	Apgar score
at 10 min	
Remifentanil MA	r = -0.021, p = 0.863	r = -0.033, p = 0.786	r = -0.013, p = 0.786	
Remifentanil UV	r = 0.071, p = 0.555	r = 0.011, p = 0.925	r = 0.014, p = 0.905	
Remifentanil UA	r = 0.176, p = 0.140	r = 0.106, p = 0.378	r = 0.120, p = 0.316	
Etomidate MA	r = -0.114, p = 0.339	r = 0.081, p = 0.501	r = 0.073, p = 0.543	
Etomidate UV	r = 0.177, p = 0.136	r = 0.196, p = 0.098	r = 0.164, p = 0.168	
Etomidate UA	r = 0.041, p = 0.731	r = 0.114, p = 0.339	r = 0.045, p = 0.706	
Rocuronium bromide MA	r = 0.036, p = 0.766	r = 0.151, p = 0.204	r = 0.128, p = 0.283	
Rocuronium bromide UV	r = -0.035, p = 0.768	r = -0.064, p = 0.592	r = -0.078, p = 0.512	
Rocuronium bromide UA	r = 0.011, p = 0.927	r = -0.046, p = 0.702	r =-0.088, p = 0.464	
MA: maternal artery blood, UV: umbilical vein blood, UA: umbilical artery blood

Procedure duration-related factors

There was no significant difference between the two groups in term of I-S, I-D, or U-D time (P > 0.05) (Table 4).

Table 4 Procedure duration-related factors between the two groups

	Group CON(n = 65)	Group LAS(n = 11)	P value	
I-S, min	2.58 ± 0.6	2.58 ± 0.6	0.990	
I-D, min	5.98 ± 2.9	6.49 ± 2.4	0.513	
U-D, second	59.69 ± 25.2	61.00 ± 23.6	0.873	
I-S represents the time from induction to skin incision; I-D represents the time from induction to delivery; and U-D represents the time from uterine incision to delivery

Logistic regression analysis

Univariate analysis revealed that premature delivery, fetal distress and increased D-dimer levels were associated with neonatal low Apgar scores compared to the CON group (P < 0.05). The logistic regression analysis results showed that the crude odds ratio (OR) for premature delivery was 13.8 (95% CI, 2.7–70.5; p = 0.002), for fetal distress it was 8.7 (95% CI, 1.8–42.7; p = 0.041), and for D-dimer it was 1.4 (95% CI, 1.0–1.9; p = 0.041). In the multivariate analysis, the adjusted ORs were 10.2 for premature delivery (95% CI = 1.8–56.9; p = 0.008), 9.6 for fetal distress (95% CI = 1.3–69.0; p = 0.025) and 1.4 for D-dimer (95% CI = 1.0–2.0; p = 0.073) (Fig. 4).

Fig. 4 The adjusted odds ratios (ORs) for premature delivery, fetal distress and D-dimer levels from multivariate analysis

Premature delivery and fetal distress were identified as independent risk factors for neonatal low Apgar scores. The risk prediction model yielded a probability of 1/(e‑Y), where Y=-4.607 + 2.318×(premature delivery) + 2.261×(fetal distress). The Hosmer–Lemeshow test showed χ²= 9.587, P = 0.213, indicating a good model fit. The risk index for low Apgar scores under general anesthesia was calculated using the model prediction index, and ROC analysis was conducted with various risk factors. The AUC was 0.850 (0.670 ~ 1.000), with a sensitivity of 81.8% and specificity of 87.7% at a cutoff value of 0.695 (Fig. 5).

Fig. 5 The receiver operating characteristic (ROC) curve of the prediction model

Discussion

Birth asphyxia can occur during childbirth, potentially leading to conditions such as cerebral palsy and affecting cognitive, behavioral, and motor development later in life if there is a restriction in oxygen flow to the brain and compromised cerebral blood circulation [8]. The central nervous system can sustain irreversible damage from hypoxic insult due to birth asphyxia, resulting in long-term consequences [9]. Asphyxia during childbirth is often accompanied by a low Apgar score. Therefore, identifying and preventing risk factors associated with neonatal low Apgar scores can help reduce neonatal asphyxia.

Neuraxial anesthesia is a commonly used and safe anesthesia technique for Cesarean section deliveries, recommended by anesthesia guidelines. However, some patients may have contraindications to neuraxial anesthesia or may refuse it due to fear or anxiety [5]. Consequently, a percentage of Cesarean sections are performed under general anesthesia.

Traditionally, Cesarean sections under general anesthesia were believed to increase the risk of neonatal low Apgar score due to the placenta transmission of general anesthetic drugs. This study aimed to compare anesthetic drug concentrations in the umbilical artery, umbilical vein, and maternal arterial tract between neonates with and without low Apgar scores and identify specific risk factors associated with low Apgar scores in patients undergoing Cesarean sections under general anesthesia. The study found that the incidence of low Apgar scores was 14.47% in infants delivered via Cesarean section under general anesthesia (4.08% in full-term deliveries and 36% in premature deliveries). There was no significant correlation between neonatal low Apgar scores and blood concentration of general anesthetic drugs or the I-S, I-D or U-D duration. Low Apgar scores were independently associated with premature delivery and preoperative fetal distress.

Advancements in general anesthesia techniques and the use of short-acting anesthetics have not shown conclusive evidence that general anesthesia during Cesarean sections increases the risk of neonatal birth asphyxia [10]. Studies have reported a better fetal oxygen supply, higher umbilical cord blood pH and smaller base deficit in Cesarean sections under general anesthesia compared to vaginal delivery with epidural anesthesia or Cesarean sections under subarachnoid block [11]. Randomized controlled trials have consistently shown similar results, indicating that neonatal Apgar scores and outcomes are not affected by the choice of anesthetic technique [12, 13].

Among pregnant patients with severe thrombocytopenia, there were no cases of birth asphyxia in the group that underwent Cesarean section under general anesthesia. In contrast, two cases of birth asphyxia were reported in the local anesthesia group [14]. Therefore, the use of general anesthetic drugs or the choice of general anesthesia modality does not increase the risk of incidence of low Apgar scores, as indicated by the results of this study. Anesthetic drug concentration was not found to be a risk factor for neonatal asphyxia. While prolonged infusion times (I-S, I-D or U-D) may lead to increased accumulation of anesthetic drugs, they were not identified as risk factors for neonatal low Apgar scores in this study.

Several studies have assessed the intrapartum factors and obstetric and fetal conditions associated with birth asphyxia [15–20]. These studies have identified various risk factors for birth asphyxia, such as preterm birth and fetal distress. However, there is a lack of research specifically investigating the risk factors for neonatal asphyxia resulting from Cesarean section under general anesthesia. In this study, univariate analysis indicated that premature delivery, preoperative fetal distress, and elevated D-dimer levels are associated with an increased risk of neonatal low Apgar scores under general anesthesia. However, only premature delivery and preoperative fetal distress remained significant in the multifactor analysis.

Delivery with fetal distress is typically urgent, necessitating emergent anesthesia [21]. General anesthesia is often preferred for these patients due to its rapid onset and concerns about hemodynamic complications associated with regional techniques. Preterm birth is a multifactorial condition, with prematurity being a major factor contributing to birth asphyxia due to alveolar hypoplasia [22, 23]. According to the study findings, the risk of neonatal low Apgar scores is approximately ten times higher when one or both of the these risk factors are present during general anesthesia.

This study has two limitations. Firstly, the sample size was relatively small, although it met the minimum requirement for multifactor regression analysis. Secondly, the participants included were receiving general anesthesia and agreed to blood collection for drug concentration measurements, which may have introduced bias into the analysis.

Conclusions

In conclusion, there was no correlation found between the blood concentration of general anesthetic drugs and the occurrence of neonatal low Apgar scores. Premature delivery and preoperative fetal distress were identified as independent risk factors for neonatal low Apgar scores under general anesthesia.

Acknowledgements

We are grateful to Prof. Yongchun Su at Chongqing Youyoubaobei Women and Children’s Hospital for his manuscript preparation assistance.

Author contributions

JY and XL contributed to the conception and the work design; YG and YS contributed to the analysis and interpretation of data for the work; YG and MC drafted the work and revised it critically for important intellectual content; HL and LG contributed to the drug concentration test. JM supervised the test procedure. All authors have read and approved the manuscript.

Funding

This study was sponsored by Natural Science Foundation of Chongqing of China (No. cstc2021jcyj-msxmX0763), National Key Clinical Speciality Construction Project (Obstetrics and Gynecology).

Data availability

The data presented in this study are available on request from the corresponding author.

Declarations

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of Chongqing Health Center for Women and Children (reference number: 2021-011). And was performed in accordance with International Conference on Harmonization - Guidelines for Good Clinical Practice (ICH-GCP) and Declaration of Helsinki. Informed consents were obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yang Gao and Yun Song contributed equally to this work.
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