J. Perinat. Med. 2015; aop

Avraham Sarit, Amit Sokolov and Ariel Many*

Is epidural analgesia during labor related to retained placenta? Abstract Objectives: To explore the influence of epidural analgesia on the course of the third stage of labor and on the incidence of the complete retained placenta as well as retained parts of the placenta. Study design: This is a population-based cohort study in a tertiary medical center. We collected data from all 4227 spontaneous singleton vaginal deliveries during 6 months and compared the incidence of retained placenta in deliveries with epidural analgesia with those without analgesia. Multivariable logistic regression was used to control for possible confounders. Results: More than two-thirds of the women (69.25%) used epidural analgesia during their delivery. A need for intervention due to placental disorder during the third stage of labor was noted in 4.2% of all deliveries. Epidural analgesia appeared to be significantly (P = 0.028) related to placental disorders compared with no analgesia: 4.8% vs. 3%, respectively. Deliveries with manual interventions during the third stage, for either complete retained placenta or suspected retained parts of the placenta, were associated with the use of epidural analgesia (P = 0.008), oxytocin (P = 0.002) and older age at delivery (P = 0.000), but when including all factors in a multivariable analysis, using a stepwise logistic regression, the factors that were independently associated with interventions for placental disruption during the third stage of delivery were previous cesarean section, oxytocin use and, marginally, older age. Conclusions: Complete retained placenta and retained parts of the placenta share the same risk factors. Epidural analgesia does not directly influence the incidence of complete retained placenta or retained parts, though clinically linked through increased oxytocin use. The factors that were independently associated with interventions

*Corresponding author: Ariel Many, Tel Aviv Sourasky Medical Center, Lis Maternity Hospital, 6 Weizman St, Tel Aviv 64239, Israel, Tel.: +97252371126, E-mail: [email protected] Avraham Sarit: Tel Aviv Sourasky Medical Center, Lis Maternity Hospital, Tel Aviv, Israel Amit Sokolov: Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

for placental disruption during the third stage of delivery were previous cesarean section, oxytocin use and older age. Keywords: Oxytocin; post-partum hemorrhage; retained placenta. DOI 10.1515/jpm-2014-0359 Received November 21, 2014. Accepted January 23, 2015.

Introduction Retained placenta (RP) is a major risk factor for postpartum hemorrhage (PPH) and was reported in up to 3% of vaginal deliveries, with higher rates in developed countries [1, 2]. Contributing factors were suggested to be related to disruption of placental-myometrial interface, as in cases of previous abortion or previous uterine injury, and to augmented or induced labor [1]. Accepted steps for active management of the third stage of labor are oxytocin administration and uterine massage. With failure of these actions, manual removal of the placenta (MROP) is usually applied, soon enough to avoid PPH but adequate to allow spontaneous separation of the placenta [3]. The cut-off time for MROP changes according to different protocols and guidelines. According to the World Health Organization (WHO) guidelines, MROP can be delayed up to an hour following the delivery in the absence of hemorrhage [4]. A recent case-control study from a single center [5] suggested that, among other risk factors, epidural analgesia was related to increased risk of retained placenta in a multivariable logistic regression analysis. This finding was attributed to depressed myometrial contraction, as a result of the regional analgesia. However, a cohort study on 386,607 women with singleton vaginal deliveries failed to show a significant association of epidural on retained placenta [6]. To our current knowledge, no study directly explored the influence of epidural analgesia on the risk of retained placenta or prolonged third stage [7]. In this study, we aimed to explore the influence of epidural analgesia on the course of the third stage of labor

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2      Sarit et al., Epidural analgesia related to retained placenta

and the incidence of retained placenta. As retained placenta is a term used to describe the non-separated complete placenta, as well as retained placental parts after delivery of the placenta, we also described the prevalence of both situations separately in order to allow a more accurate analysis.

compare continuous variables with and without normal distribution between the groups, respectively. The chi-square and Fisher’s exact tests were used for categorical variables. Differences were considered significant when the P-value was   2  h without for nulliparous, and  > 2  h or  > 1  h for multiparous women, respectively [8]. All women with previous cesarean section (CS) in this study had only one CS prior to delivery, as the trial of labor after CS is restricted to a previous single CS in our institute.

Statistics Data analysis was performed with the SPSS v18.0 package (Chicago, IL, USA). Student’s t-test and Mann-Whitney U-test were used to

Mean maternal age (years) Previous abortions  0  1   ≥ 2 Previous CS Parity  Primipara (n = 1774)  Multipara (n = 2453) Mean pregnancy length (weeks) CS = cesarean section.

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Epidural analgesia (n = 2927)

No analgesia (n = 1300)

31.92±4.85

32.81±4.94

2093 (71.5%) 574 (19.6%) 260 (8.9%) 128 (4.4%)

911 (70.3%) 252 (19.5%) 132 (10.2%) 47 (3.6%)

1423 (48.6%) 1504 (51.4%) 39.38±1.13

351 (27%) 949 (73%) 39.26±1.086

P-value

0.000 NS (0.399)

NS (0.277) 0.000

0.001

Sarit et al., Epidural analgesia related to retained placenta      3

Table 2: Third-stage course of all deliveries.

Normal placenta Manual removal of retained placenta (MROP) Revision of uterine cavity

Table 4: Pregnancy and delivery characteristics in regard to the third stage of labor.

Epidural analgesia (n = 2927)

No analgesia (n = 1300)

Total

2787 (95.2%) 65 (2.2%)

1261 (97%) 17 (1.3%)

4048 (95.8%) 82 (1.9%)

75 (2.6%)

22 (1.7%)

97 (2.3%)

P-value = 0.028.

probably lack clinical significance. Oxytocin use was recorded in 35% of all deliveries, significantly more likely to be administered in deliveries with epidural analgesia compared with no analgesia (48% vs. 5.8%, P = 0.000). Delivery characteristics are presented in Table 3. In order to identify factors that potentially relate to placental disorders, we analyzed pregnancy and delivery characteristics concerning third stage of labor (Table 4), and then used a multivariable stepwise logistic regression to control for possible confounders (Table 5). Deliveries with manual interventions during the third stage, for either complete retained placenta or suspected retained parts of the placenta, were associated with the use of epidural analgesia (P = 0.008), oxytocin (P = 0.002) and older age at delivery (P = 0.000) (Table 4), but when including all factors in a multivariable analysis, using stepwise logistic regression (Table 5), the factors that were independently associated with interventions for placental disruption during the third stage of delivery were previous CS, oxytocin use and, marginally, older age. After controlling for possible confounders, epidural analgesia was not significantly associated with disrupted third stage (P = 0.12). These findings were similar when only cases of MROP were analyzed compared with normal third stage.

Table 3: Delivery characteristics. Epidural No analgesia P-value (n = 1300) analgesia (n = 2927) Stage 2 length mean (min) Primipara Multipara Stage 3 length mean Oxytocin use during delivery (n)

68.44±67.28 21.90±32.54 107.43±67.35 45.96±47.29 30.27±39.66 12.19±16.02 14.71±10.07 13.69±8.51 1406 (48%) 75 (5.8%)

0.000 0.000 0.000 0.002 0.000

Previous CS  Yes (n = 175)  No (n = 4048) Parity  Primipara (n = 1774)  Multipara (n = 2454) Oxytocin use  No (n = 2747)  Yes (n = 1481) Epidural analgesia  No (n = 1300)  Yes (n = 2927) Previous abortions  None (n = 3004)  1 (n = 826)   ≥ 2 (n = 393) Prolonged 2nd stage  Normal (n = 3866)  Prolonged (n = 146) Age (years) Pregnancy length (weeks) 2nd stage duration (min)

Normal 3rd stage

Disrupted 3rd stage

P-value

93% 96%

7% 4%

0.084

95.4% 96%

4.6% 4%

0.314

96.5% 94.4%

3.5% 5.6%

0.002

97% 95.2%

3% 4.8%

0.008

95.7% 96.4% 94.9%

4.3% 3.6% 5.1%

0.479

95.9% 93.8% 32.1±4.8 39.3±1.1 54.4±62.7

4.1% 6.2% 33.7±4.8 39.3±1.2 65.7±68.2

0.21 0.000 0.74 0.01

CS = cesarean section.

Table 5: Factors associated with placental disorders after multivariable forward stepwise logistic regression analysis. P-value

Previous CS Age Oxytocin

0.041 0.000 0.000

OR

1.970 1.068 1.854

95% CI for OR Lower

Upper

1.027 1.033 1.348

3.779 1.103 2.551

CS = cesarean section, OR = odds ratio, CI = confidence interval.

Discussion This study is, to the best of our knowledge, the first study that directly explored the influence of epidural analgesia on the course of the third stage of labor. We found that although epidural analgesia seemed to cause disturbances in placental separation, it was actually a confounder and was not related directly to retained placenta by a multivariate analysis. The strongest predictors of retained placenta were oxytocin use during labor and previous CS. Endler et al. [6] did not find an association between epidural analgesia and retained placenta. In contrast, Ashwal and colleagues [5] described a correlation of epidural analgesia to

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4      Sarit et al., Epidural analgesia related to retained placenta

retained placenta, but their study was not controlled for oxytocin use during labor. Oxytocin was previously shown to be an independent risk factor for retained placenta [9] and is administered more frequently, as was found in our study and others, in deliveries that involve epidural analgesia [7]. We believe that the apparent correlation of retained placenta to epidural analgesia was mediated mainly through oxytocin use. Epidural analgesia was shown to elongate the second stage of labor, as was known from previous multiple studies [10, 11]. This effect was more prominent in primiparas that significantly required more use of epidural analgesia. We found that previous CS, and less extensively advanced maternal age, were both significantly related to retained placenta, as was shown in other studies [12–14]. As the rate of both CS and maternal age rose consistently in the last few decades [15, 16] the rate of retained placenta is also expected to increase. Women undergoing vaginal birth after cesarean section (VBAC) should be informed about the risk of future retained placenta. Parity was not shown to be related to placental disruption in our study. Reports in the literature range from protective effect [6, 9], through no effect [14], to increased risk in the parity of 5 five deliveries or more [13, 17]. As mentioned previously, no relation between parity and retained placenta was demonstrated in our cohort, but we could not discuss the effect of grand multiparity due to extremely low number of women in their fifth delivery or more (0.03%). Previous abortions, specifically dilation and curettage, were recognized by several studies as a risk factor for retained placenta [5, 6, 17]. We failed to show this relation in our study. It may be explained by lack of details concerning the mode of abortion in the computerized file, and the fact that previous abortion could relate to spontaneous resolution, medical abortion or surgical abortion. In this research, we distinguished for the first time between two different settings that require manual intervention and demonstrated that they share the same risk factors. The large sample size allowed us to identify the common risk factors that were attributed to retained placenta. Our study does not support the suggestion raised in a previous study [5] in regard to that epidural analgesia as an independent risk factor for retained placenta, although a causative relation exists due to increased use of oxytocin in deliveries under epidural analgesia. Our study has few limitations. This is a retrospective study in nature and lacked details such as the mode of

previous abortions. Nevertheless, the real-time computerized data is validated periodically for the quality of data. In conclusion, we found that the complete retained placenta and retained parts of the placenta share the same risk factors. We also found that epidural analgesia does not directly influence the incidence of complete retained placenta or retained parts during the third stage of labor. Future studies are needed to further explore the pathophysiology of the retained placenta.

References [1] Weeks AD. The retained placenta. Best Pract Res Clin Obstet Gynaecol. 2008;22:1103–17. [2] Cheung WM, Hawkes A, Ibish S, Weeks AD. The retained placena: histrorical and geographical rate variations. J Obstet Gynaecol. 2011;31:37–42. [3] Urner F, Zimmermann R, Krafft A. Manual removal of the placenta after vaginal delivery: an unsolved problem in obstetrics. J Pregnancy. 2014; doi:10.1155/2014/274651. [4] WHO recommendations for the prevention and treatment of postpartum hemorrhage. Geneva: World Health Organization; 2012:ISBN-13: 978-92-4-154850-2. [5] Ashwal E, Melamed N, Hirrsch L, Wiznitzer A, Yogev Y, Peled Y. The incidience and risk factors for retained placenta after vaginal delivery – a single center experience. J Matern Fetal Neonatal Med. 2014;27:1897–900. [6] Endler M, Saltvedt S, Cnattinquis S, Stephansson O, Wikstrom AK. Retained placenta is associated with pre-eclampsia, stillbirth, giving birth to a small-for-gestational-age infants, and spontaneous preterm birth: a national register-based study. BJOG. 2014;121:1462–70. [7] Anim-Somuah M, Smyth RM, Jones L. Epidural versus nonepidural or no analgesia in Labour. Cochrane Database Syst Rev. 2011;7:CD000331. [8] Laughon SK, Berghella V, Reddy UM, Sundaram R, Lu Z, Hoffman MK. Neonatal and maternal outcomes with prolonged second stage of labor. Obstet Gynecol. 2014;124: 56–67. [9] Endler M, Grunewald C, Saltvedt S. Epidemiology of retained placenta: oxytocin as an independent risk factor. Obstet Gynecol. 2012;119:801–9. [10] Halpern SH, Muir H, Breen TW, Campbell DC, Barrett J, Liston R, et al. A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor. Anesth Analg. 2004;99:1532–8. [11] Halpern SH, Abdallah FW. Effect of labor analgesia on labor outcome. Curr Opin Anaeshesiol. 2010;23:317–22. [12] Belachew J, Cnattingius S, Mulic-Lutvica A, Eurenius K, Axelsson O, Wikstrom AK. Risk of retained placenta in women previously delivered by cesarean section: a population-based cohort study. BJOG. 2014;121:224–9. [13] Soltan MH, Khashoggi T. Retained placenta and associated risk factors. J Obstet Gynaecol. 1997;17:245–7.

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[14] Panpaprai P, Boriboonhirunsarn D. Risk factors of retained placenta in Siriraj hospital. J Med Assoc Thai. 2007;90:1293–7. [15] Montan S. Increased risk in the elderly parturient. Curr Opin Obstet Gynecol. 2007;19:110–2. [16] Rozenberg P. Evaluation of cesarean rate: a necessary progress in modern obstetrics. J Gynecol Obstet Biol Reprod. 2004;33:279–89.

[17] Owolabi AT, Dare FO, Fasubaa OB, Ogunlola IO, Kuti O, Bisiriyu LA. Risk factors for retained placenta in southwestern Nigeria. Singapore Med J. 2008;49:532–7.

The authors stated that there are no conflicts of interest regarding the publication of this article.

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