Epidural Analgesia and Neutrophil-to-lymphocyte Ratio in Nulliparous Women Undergoing Vaginal Delivery.

Editor, Labour is an inflammatory process associated with leukocytosis.1 Granulocytes are activated during labour, and the number of neutrophils in the circulation of women who undergo labour is higher than that of women who do not.2 The stress of labour pain is also associated with maternal inflammatory responses.3 Epidural analgesia, an effective method of reducing labour pain, has been found to partly prevent the labour-induced changes in cellmediated immunity.4 However, it is not clear whether epidural analgesia is involved in the modulation of inflammatory process during labour. We hypothesised that the use of labour epidural analgesia might attenuate the maternal inflammatory response. The neutrophil-to-lymphocyte ratio (NLR) has been recognised as a new marker to indicate systemic inflammatory status.5 In this prospective cohort study, we aimed to evaluate the association of labour epidural analgesia and the maternal inflammatory response, by investigating the NLR in nulliparous women undergoing vaginal delivery. Ethical approval for this study (GKLW2019-15) was provided by the Ethics Committee of the International Peace Maternity and Child Health Hospital, Shanghai, China on 4 November 2019. Written informed consent was obtained from all participants. The protocol was registered at http://www.chictr.org.cn (ChiCTR20000 34900). A total of 1421 women gave birth to a live foetus from January 2018 to January 2019 and were eligible for inclusion. Exclusion criteria were parturients who were parous (n = 354), preterm labour (n = 41), fever on admission (n = 174), lack of blood test data (n = 426) and parturients with pregnancy complications (n = 162), leaving only 264 women in the final analyses. At the first request for pain relief, all women received 100 mg of intramuscular pethidine. Subsequently half (132) of the women received epidural analgesia with the remainder requiring no further analgesia, after 3 cm cervical dilatation (Fig. 1). In the epidural group, the catheter was placed at either the L2-3 or L3-4 epidural space. An initial dose of 8 ml ropivacaine 0.1% with sufentanil 0.4 μg cml−1 was given, and the catheter was subsequently connected to a patient-contro ed epidura ana gesia pump. The epidura solution was 0.1% ropivacaine with sufentanil 0.4 μg ml−1 and the pump program was a 6 ml patient-controlled bolus with a 20 min lockout and a background infusion of 7 ml per hour. A nurse monitored the sensory level with an alcohol-soaked swab and adjusted the pump to maintain a total loss of cold sensation at the T10 level. During the first half hour, sensory testing was undertaken frequently, and then every 2 h.Fig. 1: Participant flowchart.The blood tests for leukocyte screening were performed on admission and the first day after delivery in all women. The NLR value was calculated by dividing the number of neutrophils by the number of lymphocytes. The primary outcome of this study was the change in NLR in women undergoing vaginal delivery. The sample size was calculated from women in a preliminary study, indicating a minimum of 120 eligible parturients per group would be adequate to detect a difference of 4 in the NLR, with a power of 0.80 at a significance level of 0.05 (two-sided). To allow for 10% loss during the study period, recruitment of 260 parturients was intended. Data of the preliminary women were not included in the study. The baseline patient characteristics were not statistically different between the two groups. Baseline antepartum neutrophil and lymphocyte counts were not statistically different between the two groups. On the day after delivery, the lymphocyte count was greater in the women who had used epidural analgesia compared with women not using epidural analgesia (1.1 [0.9 to 1.6] versus 0.9 [0.7 to 1.4] 109 l−1, P< 0.001). In contrast, the neutrophil count was lower in the epidural group than in the nonepidural group (13.1 [9.6 to 15.2] versus 13.4 [11.0 to 16.8] 109 l−1, P = 0.043). In the same way, the lymphocyte percentage (8.1 [5.7 to 11.6] versus 5.8 [4.0 to 9.9]%, P< 0.001) and neutrophil percentage (86.7 [81.7 to 89.5] versus 89.7 [84.5 to 92.2]%, P < 0.001) showed consistent changes (Table 1). Table 1 - White cell counts before and after delivery Epidural group (n = 132) Nonepidural group (n = 132) P value Antepartum WBC count (109 l−1) 8.0 [7.0 to 9.5] 8.0 [6.29 to 9.2] 0.675 Lymphocyte count (109 l−1) 1.5 [1.3 to 1.8] 1.6 [1.2 to 2.0] 0.543 Lymphocyte% 18.8 [15.9 to 23.1] 19.9 [15.6 to 24.1] 0.340 Neutrophil count (109 l−1) 5.8 [4.9 to 7.1] 5.6 [4.8 to 6.7] 0.727 Neutrophil% 72.8 [68.3 to 76.6] 71.4 [67.3 to 76.4] 0.197 Postpartum WBC count (109 l−1) 14.8 [12.0 to 17.3] 15.0 [12.5 to 18.4] 0.126 Lymphocyte count (109 l−1) 1.1 [0.9 to 1.6] 0.9 [0.7 to 1.4] <0.001 Lymphocyte% 8.1 [5.7 to 11.6] 5.8 [4.0 to 9.9] <0.001 Neutrophil count (109 l−1) 13.1 [9.6 to 15.2] 13.4 [11.0 to 16.8] 0.043 Neutrophil% 86.7 [81.7 to 89.5] 89.7 [84.5 to 92.2] <0.001 Data are presented as median [interquartile range]. WBC, white blood cell. The NLR was calculated from the antepartum and post-partum white blood cell (WBC) counts. The antepartum NLR was comparable between the epidural and nonepidural groups: 3.9 [2.9 to 4.7] versus 3.6 [2.8 to 5.1], P = 0.520 (Fig. 2a). However, on the first postpartum day, the NLR was significantly lower in the epidural group than that in the nonepidural group: 10.5 (6.9 to 15.4) versus 15.6 (8.6 to 23.3), P less than 0.001 (Fig. 2b). Delivery outcomes, including haemorrhage, assisted delivery rates, episiotomy, perineal trauma, neonatal 1 and 5 min Apgar scores, were not significantly different between the two groups.Fig. 2: The neutrophil-to-lymphocyte ratio before and after delivery.Systemic inflammation results in lymphopenia and neutrophilia. The NLR based on the neutrophil and lymphocyte counts has been well established to reveal a systemic inflammatory state.5 However, there are insufficient NLR data in obstetric patients, particularly in women who have epidural analgesia in labour. Our findings indicate that the postpartum NLR was lower in women using labour epidural analgesia, suggesting that epidural analgesia was associated with a milder inflammatory response during labour. Acute pain changes the immunological process and the NLR value is, therefore, associated with the degree of pain.6 Epidural analgesia with its associated sympathetic nervous system block is a technique that could suppress neuroendocrine stress, and modulate inflammatory cytokines.7 Consistent with previous studies, the lower post-partum NLR in this study suggests that labour epidural analgesia not only relieves labour pain but also is associated with a blunting of the maternal inflammatory response during labour, which may be of benefit for outcomes associated with maternal inflammatory responses. Although there were no differences in shortterm pregnancy outcomes between the groups, one of the limitations of this study is that we did not investigate long-term maternal or neonatal outcomes, particularly those outcomes associated with systemic inflammation. In addition, because of a possible difference in the immune status of women with fever, women with fever from any cause, including epidural-related maternal fever, were excluded from this study. In conclusion, this study demonstrates that the postpartum NLR was lower in the parturients receiving epidural analgesia compared with women not receiving epidural analgesia, suggesting the use of labour epidural analgesia is associated with a blunting of the maternal inflammatory response during labour. Further studies are needed to understand potential mechanisms for this, as well as longterm outcomes associated with lower NLR.