A prospective cohort study on the effect of epidural labor analgesia on syndecan-1 in patients with preeclampsia

SUN Shen, TIAN Fu-bo, HUANG Shao-qiang, YUAN Hong-bin

(1Department of Anesthesiology,Changzheng Hospital,Second Military Medical University,Shanghai 200003,China;2Department of Anesthesiology,Obstetrics and Gynecology Hospital,Fudan University,Shanghai 200090,China)

【Abstract】 Objective To evaluate the treatment effects of epidural labor analgesia on syndecan-1 in patients with preeclampsia. Methods During Jan.,2016 and Dec.,2017,150 unipara females with preeclampsia and gestational age>37 weeks were enrolled in the prospective cohort study.They were devided into intervention and control group (n=75 in each group) with and without epidural labor analgesia,based on whether epidural labor analgesia applications were made by the patients at the first examination of cervical dilation of 2 cm.The primary outcomes were mean change and change rate of syndecan-1 from baseline to 2 h post-treatment,and the secondary outcomes were visual analogue scale (VAS),IL-6 level and mean arterial pressure (MAP). Results Absolute change of syndecan-1 from baseline to 2 h post-baseline was (-11.49±82.80) ng/mL in the intervention group and (45.09±55.14) ng/mL in the control group,respectively.There was a significant difference in mean change of syndecan-1 between the two groups (P<0.001).Similarly,the intervention group exhibited a greater reduction in change rate of syndecan-1 compared with the control group (P<0.001).Moreover,the intervention group had greater reduction in VAS and MAP compared with the control group (P<0.001 for both).There was no significant difference in IL-6 level between the two groups. ConclusionsEpidural labor analgesia was associated with greater reduction in syndecan-1,VAS and MAP compared with the control condition.In contrast,administration of epidural analgesia did not significantly change IL-6 level.

【Key words】 epidural labor analgesia; preeclampsia; syndecan-1; IL-6

Preeclampsia is diagnosed in 3%-5% of all pregnancies,and characterized by newly-onset hypertension and end organ damage after 20 weeks of gestation[1].Progression of preeclampsia is multifactorial,and the disease includes several subtypes[2].Early-onset preeclampsia affects placental development,while late-onset preeclampsia can affect the interaction between the placenta and damaged maternal microvasculature[3].A previous study examined preeclampsia in females during their first pregnancies[4]and found that maternal immune reactions against paternal antigens expressed in the placenta could affect defective trophoblast invasion and placental dysfunction,even causing preeclampsia progression.This mechanism might explain the lower risk of preeclampsia among multiparous women.

Epidural labor analgesia has increasingly become popular with patients:reducing the degree of pain during the labor,improving material well-being,and facilitating early bonding between mother and child[5].

The expression of endothelial glycocalyx can be evaluated through sydencan-1,heparin sulfate,hyaluronic acid shedding,and changes in calyx thickness observed under microscopy.The endothelial glycocalyx helps regulating vascular permeability,mediating shear force responses,and maintaining functional vascular homeostasis,which is an important prognostic factor of circulatory status during the perioperative period.This effect of the endothelial glycocalyx may play more important role in patients with preeclampsia than that in common patients.By enhancing vagus nerve activity through cholinergic anti-inflammatory pathways,epidural labor analgesia can suppress systemic inflammation and sympathetic nervous system impairment which can damage the endothelial glycocalyx[6].However,to the best of our knowledge,few studies have evaluated the treatment effects of epidural labor analgesia on the endothelial glycocalyx in unipara females with preeclampsia.

Materials and Methods

Study PopulationThe prospective cohort study was approved by the medical ethics committee of Obstetrics and Gynecology Hospital,Fudan University.This study examined monotocous unipara with preeclampsia from Jan.,2016 to Dec.,2017 in Obstetrics and Gynecology Hospital.The inclusion criteria included monotocous unipara with preeclampsia,older than 18 years,gestational week>37 weeks,and fetal cephalic presentation.We excluded patients with diabetes mellitus,coronary artery disease,abnormal liver function,a history of chronic opioid use,ahistoryof headache or other neurological symptoms,or contraindications for epidural labor analgesia.Patients with preeclampsia were divided into epidural labor analgesia group (intervention group) and no epidural labor analgesia (control group) based on whether epidural labor analgesia applications were made by the patients at the first examination of cervical dilation of 2 cm,and 75 patients were enrolled in each group.All participating patients provided written informed consent.According to disease conditions,labetalol for hypertension and magnesium sulphate for spasm were managed by obstetricians.

Anesthetic TechniquesAfter baseline sydencan-1 level measurement,patients in epidural labor analgesia group were placed with left lateral position for L3-L4 interstitial epidural catheterization.A loss of resistance technique was used with a 17G Tuohy needle to identify the epidural space.A single orifice 19G epidural catheter (Flex Tip Plus,Arrow International,Inc.,USA) was threaded and secured 4-5 cm in the epidural space and an epidural test dose (1.5% lidocaine with 5 μg/mL epinephrine,3 mL) was injected.The loading dose was 8 mL boluses of 0.1% ropivacaine and 0.3 μg/mL sufentanil.An unblinded research nurse programmed the epidural pump.

The initial settings for PCEA were a basal infusion rate of 8 mL/h,patient-administered epidural boluses of 6 mL with a lock-out interval of 15 min and a 1-h infusion limit of 18 mL(ropivacaine 0.1% and sufentanil 0.3 μg/mL).Breakthrough pain was managed by the anesthesia provider using manually administered boluses of 10 mL 0.125% bupivacaine with 5 μg sufentanil.

Thirty minutes after the loading dose,we measured bilateral upper sensory block level to cold using alcohol swabs and obtained a modified Bromage score (0:no motor paralysis;1:inability to raise extended leg,but able to move knee and foot;2:inability to raise extended leg and to move knee,but able to move foot;3:inability to raise extended leg or to move knee and foot).

Biomarker MeasurementBaselinesydencan-1 levels were measured in both groups right after enrollment,and 2 h post-baseline sydencan-1 levels were measured at 2 h after baseline in both groups.Collected blood was left at room temperature for 1 h,and then centrifuged at 434×gand 4 ℃ for 10 min.After this,sydencan-1,and IL-6 levels were measured using ELISA.We also collected mean arterial pressure (MAP) and visual analogscale (VAS) of analgesia before and 2 h post-baseline.

Statistical AnalysisThe primary efficacy endpoint was the absolute and percent change in syndecan-1 from baseline to 2 h post-baseline.Secondary efficacy endpoints included the absolute and percent change in VAS,and absolute change in IL-6 levels and MAP between baseline and 2 h post-baseline.All available variables were continuous in nature,and means (standard deviation) or medians (quartile) were used to characterize unipara with preeclampsia.LSM-t and pairedttests were employed to compare the treatment effectiveness of the intervention between and within groups,respectively (if the data were normally distributed).All analyses were two sided,andP<0.05 was considered statistically significant.All statistical analyses were conducted using SAS version 9.2.

We calculated the sample size for sydencan-1 using GPower 3.1 software.In a preliminary trial with 30 primiparas,the SD of change ratio in syndecan-1 from baseline to 2 h post-baseline was 10%.With a one-tailed α of 0.05,to detect a difference of ≥5% in percent of change in syndecan-1 from baseline to 2 h post-baseline between epidural labor analgesia group and the control group,we planned to enroll 69 patients in each group to acquire the desired power of 90%.After accounting for potential exclusions,we enrolled 75 patients in each group.

Results

Baseline Characteristics of patients with preeclampsiaA total of 150 unipara patients with preeclampsia were examined in this study,with 75 cases in each group.There was no significant difference in gestational age,age,height,weight,body mass index (BMI) and the severity of preeclampsia between the two groups (Tab 1).

Tab 1 Baseline characteristics of patients with preeclampsia

Primary OutcomeSyndecan-1 levels in both groups at baseline and 2 h post-baseline were shown in Tab 2 and Fig 1.Baseline syndecan-1 levels were significantly higher in the intervention group compared with the control group (P<0.001).After 2 h,there was no significant difference in syndecan-1 level between the intervention group and the control group (P=0.090).There were significant differences in absolute change and change rate from baseline to 2 h post-baseline in syndecan-1 levels between the two groups (P<0.001 for both).Finally,thePvalue for covariance indicated significant differences between the two groups (P=0.018).

Syndecan-1(ng/mL)Interventiongroup(n=75)Controlgroup(n=75)PBaseline607.84±99.53546.76±74.61<0.001a2hpost-baseline596.35±61.38591.85±43.800.090bAbsolutechange-11.49±82.8045.09±55.140.734c,<0.001d,eChangerate(%)-2.06±13.567.75±9.490.880c,<0.001d,e0.018f

aBetween groups before treatment;bBetween groups after treatment;cWithin groups before treatment;dWithin groups after treatment;eBetween groups;fCovariance.

A:Control group;B:Epidural labor analgesia group;T1:Baseline;T2:2 h post-baseline.(1)P<0.001.

Fig 1 Syndecan-1 level of patients before and 2 h afterimplementation of labor analgesia

There was no significant change in syndecan-1 levels between baseline and 2 h post-baseline in the intervention group (P=0.734,0.880).However,there were significant changes within the control group (P<0.001 for both).

Secondary OutcomesThe VAS at baseline and 2 h post-baseline in both groups were shown in Tab 3 and Fig 2.There were significant differences between the two groups in baseline VAS and VAS obtained at 2 h post-baseline (P<0.001 for both).There were also significant differences between the two groups in absolute change and change rate in VAS (P<0.001).Analysis for covariance reported similar results (P<0.001).

VASInterventiongroup(n=75)Controlgroup(n=75)PBaseline5.15±0.803.36±0.88<0.001a2hpost-baseline2.80±0.723.56±0.76<0.001bAbsolutechange-2.35±1.020.20±0.49<0.001c,d,eChangerate(%)-95.78±59.255.56±13.86<0.001c,e,0.002d<0.001f

aBetween groups before treatment;bBetween groups after treatment;cWithin groups before treatment;dWithin groups after treatment;eBetween groups;fCovariance.

A:Control group;B:Epidural labor analgesia group;T1:Baseline;T2:2 h post-baseline.(1)P<0.001.

Fig 2 VAS level of patients before and 2 h afterimplementation of labor analgesia

IL-6 levels and MAP at baseline and after 2 h were shown in Tab 4.There was no significant difference in IL-6 levels at baseline,after 2 h and mean change between the two groups.There was also no significant difference in MAP at baseline between the two groups.However,MAP after 2 h and its mean change from baseline exhibited statistical differences between the two groups (P<0.05).

VariableInterventiongroup(n=75)Controlgroup(n=75)IL-6(pg/mL) Baseline20.1±4.219.7±4.5 2h20.4±4.619.9±5.0 Meanchange0.3±4.40.2±4.8MAP(mmHg) Baseline115±4.5116±4.8 2h102±5.1115±4.6(1) Meanchange-13±4.8-1±4.7(1)

(1)P<0.05.MAP:Mean arterial pressure.

Discussion

This prospective cohort study involved pregnant,unipara females,gestational age>37 weeks,with preeclampsia.We evaluated the effectiveness of epidural labor analgesia treatment versus control on syndecan-1,VAS of analgesia,IL-6 level and MAP.Our results indicated that epidural labor analgesia was associated with greater reduction in syndecan-1,VAS and MAP compared with the control condition.There was no significant differences between the groups in levels of baseline IL-6,IL-6 after 2 h,and absolute change in IL-6.

Reasons for lower syndecan-1 levels at baseline in the control group compared with the epidural labor analgesia group could relate to lower baseline VAS in the control group.Higher VAS could reflect sympathetic nervous system activation,associated with higher level in syndecan-1[7-8].After 2 h,syndecan-1 levels were significantly higher than baseline levels in the control group.This could indicate that syndecan-1 shedding tends to increase as preeclampsia and labor progress[9-11].Moreover,there was no significant change between baseline and 2 h in syndecan-1 levels in the epidural analgesia group.

Our results revealed that in control group,both the sydencan-1 and VAS at 2 h were significantly higher than those at baseline,indicating that pregnancy process and pain could lead to glycocalyx injury.Our results also suggests labor analgesia prevents syndecan-1 loss from endothelial to blood in women with preeclampsia,following labor onset.This may help lessen changes in syndecan-1 levels over time[12].The possible mechanism may be that by enhancing vagus nerve activity through cholinergic anti-inflammatory pathways,epidural labor analgesia can suppress sympathetic nervous system activation induced by pregnancy process and pain which can damage the glycocalyx.Syndecan-1 shedding in patients with preeclampsia is more frequent than that in common patients,which may be associated with the up-regulation of inflammatory media in patients with preeclampsia[13].This effect of the endothelial glycocalyx may play more important role in patients with preeclampsia than that in common patients.Labor analgesia can not only effectively decrease the labor pain and stabilize blood pressure among patients with preeclampsia,but can also reduce endothelial glycocalyx shedding,which then may improve vascular permeability,maintain vascular function,reduce inflammatory reaction,and better obstetric outcomes.

There were significant differences between the groups in absolute levels and percent change insyndecan-1 levels.This could be attributable to different baseline VAS scores,preeclampsia and labor progression,and use of epidural labor analgesia.

As expected,there were significant differences between the groups in mean and percent change in VAS.The results of covariance analysis were similar after adjustment for baseline VAS values[14-16].IL-6 is an important cytokine that promotes inflammation and significantly correlates with the pathological processes and severity of preeclampsia[17-19].There was no significant differences between the groups in IL-6 levels.This might because inflammatory changes take longer than 2 h to completely manifest.

Several limitations of this study should be highlighted:(1) Participants were not randomly assigned to groups,and the additional differences between the groups might induce potential confounders;(2) We only examined dependent variables at baseline and after 2 h,a longer follow-up duration may produce different results;(3) Our outcome variables were limited to syndecan-1,VAS,IL-6 level,and MAP,while the results of neonate and parturient outcomes were not reported;(4) Speculated mechanisms of action require further verification using bothinvitroand animal studies.

In conclusion,there were significant differences between the epidural labor analgesia and control groups in change in syndecan-1,VAS and MAP.There was no significant differences between the two groups in IL-6 levels.Further prospective studies should be conducted to verify these results and evaluate the long-term effectiveness of epidural labor analgesia treatment on neonatal and patient outcomes.