Arch Gynecol Obstet DOI 10.1007/s00404-013-3101-8
MATERNAL-FETAL MEDICINE
Do uterotonic drugs increase risk of abruptio placentae and eclampsia? Mamoru Morikawa • Kazutoshi Cho • Takahiro Yamada Takashi Yamada • Shoji Sato • Hisanori Minakami
•
Received: 5 January 2013 / Accepted: 18 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To determine whether the use of uterotonics, including oxytocin and prostaglandins, increases the risk of abruptio placentae and eclampsia. Materials and methods A retrospective analysis was conducted among 260,174 Japanese women at term. Demographic characteristics were studied as possible candidates for risk factors of abruptio placentae and eclampsia using multivariate logistic regression analyses. Results A total of 1,058 (0.41 %) and 147 (0.06 %) women developed abruptio placentae and eclampsia, respectively. Abruptio placentae and eclampsia occurred in 177 (0.29 %) and 42 (0.07 %) of the 61,857 women treated with uterotonics, respectively. Multivariate regression analyses indicated that uterotonics did not increase risk of developing either abruptio placentae or eclampsia. Primiparity [odds ratio (95 % confidence interval) 1.41 (1.24–1.60)], age C35 years [1.17 (1.03–1.33)], and presence of hypertension [2.42 (1.93–3.03)] were significant independent risk factors for abruptio placentae, while advancing gestation [0.67 (0.63–0.71)] decreased risk of abruptio placentae. Primiparity [odds ratio (95 % confidence interval) 4.06 (2.49–6.63)], age \20 years [2.44 (1.07–5.58)], presence of hypertension [28.7 (20.5–40.1)],
M. Morikawa (&) K. Cho T. Yamada T. Yamada H. Minakami Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita-ku N15 W7, Sapporo 060-8638, Japan e-mail: [email protected] S. Sato Maternal and Perinatal Care Center, Oita Prefectural Hospital, Bunyo 476, Oita 870-8511, Japan
and advancing gestation [1.28 (1.11–1.47)] were significant independent risk factors for eclampsia. Conclusion The use of uterotonics did not increase the risk of abruptio placentae and eclampsia. Keywords Abruptio placentae Eclampsia Uterotonics Oxytocin Prostaglandins Risk factor
Introduction Uterotonic drugs (uterotonics), including intravenous oxytocin, intravenous prostaglandin F2a (dinoprost), and oral prostaglandin E2 (dinoprostone), are widely used in Japan for the induction and augmentation of labor. However, concerns have been raised regarding possible associations between the use of uterotonics and serious complications, such as stroke, amniotic fluid embolism, eclampsia and abruptio placentae [1]. Studies have indicated that the induction of labor or the use of uterotonics are risk factors for amniotic fluid embolism [2–4]. One study suggested that the use of uterotonics was not associated with fatal stroke [5]. However, whether the use of uterotonics increases the risk of abruptio placentae or eclampsia has not been studied extensively. Controversial results have been obtained regarding the risk of abruptio placentae after the use of misoprostol (prostaglandin E1 preparation) and dinoprostone vaginal inserts [6, 7]. Approximately 2,800 facilities provide obstetric services in Japan, delivering a total of 1,100,000 infants annually [8]; thus, most Japanese obstetric service providers perform only a small number of deliveries. The current prevalence rates of eclampsia and abruptio placenta are estimated to be \0.1 % [9] and *1.0 % [10], respectively, in Japan. Therefore, a large cohort is needed to determine whether the use of uterotonics increases the risk of abruptio
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placentae and eclampsia. We conducted this retrospective study in a large number of women with singleton pregnancies who participated in the registry system established by the Japan Society of Obstetrics and Gynaecology (JSOG) to determine the association between use of uterotonics and the occurrence of eclampsia and abruptio placentae at present in Japan.
Methods This study was conducted with the approval of the institutional review board at Hokkaido University Hospital. Approximately 120 secondary and tertiary hospitals participated in the JSOG Successive Pregnancy Birth Registry System, which collected information on successive deliveries occurring at C22 weeks of gestation in these hospitals. The available information from this system included maternal age, parity, gestational week at delivery, delivery mode, singleton or multifetal pregnancies, the use of oxytocin and prostaglandins, including intravenous dinoprost and oral dinoprostone, the birth weight of the neonates, outcome of infants, including stillbirth and early neonatal death within 7 days of life, and maternal complications including hypertensive disease during pregnancy, eclampsia, and abruptio placentae. However, we were unable to determine which prostaglandin (dinoprost or dinoprostone) was used and whether the administration of uterotrophics was performed before the development of abruptio placentae and eclampsia. We assumed that all uterotonic agents were administered before the development of abruptio placentae and eclampsia. Table 1 Demographic characteristics of study subjects No of women Nullipara a
Preeclampsia GW gestational week, PGs prostaglandins including F2a (dinoprost), and/or oral E2 (dinoprostone) * P \ 0.05 vs. counterparts without abruptio placentae for women with abruptio placentae or without eclampsia for women with eclampsia a
Including gestational hypertension and preeclampsia
b
With or without PGs
c
With or without oxytocin
123
Results Of the 260,174 women, 53.2 % were nulliparous, 24.7 % underwent cesarean section, and 3.1 % women developed hypertension, including preeclampsia and gestational hypertension (Table 1). Abruptio placentae and eclampsia developed in 1,058 and 147 women, respectively. The frequencies of all characteristics, including primipara, cesarean delivery, hypertension, preeclampsia, and gestational hypertension, were significantly higher in women with abruptio placentae or eclampsia than their counterparts without these conditions. Overall
Abruptio placentae
Eclampsia
260,174 (100 %)
1,058 (100 %)
147 (100 %)
138,355 (53.2 %)
Cesarean delivery Hypertension
A total of 302,795 pregnant women with singleton pregnancies were registered in this system over the 5-year period between 2005 and 2009, corresponding to *5.6 % of all singleton pregnancies that occurred in Japan during this period. Of these, 260,174 women were analyzed in this study after excluding 1,060 women (0.4 %) whose age, gestational week at delivery, and/or parity were unknown and 41,561 women (13.7 %) who delivered at \37 weeks. Statistical analyses were performed using the statistical software IBM SPSS statistics, version 19.0 (SPSS Inc., Chicago, IL, USA). The data are presented as the mean ± SD or median (range). The v2 test was used to compare the frequencies among categorical data. Multivariate logistic regression analyses were performed to determine the independent risk factors for abruptio placentae and eclampsia using selected parameters with a P \ 0.05 after univariate analyses (v2 test). In all analyses, P \ 0.05 was taken to indicate statistical significance.
64,162 (24.7 %) 8,007 (3.1 %) 3,418 (1.3 %)
595 (56.3 %)
*
128 (87.1 %)*
622 (58.8 %)
*
98 (66.7 %)*
*
74 (50.3 %)*
*
39 (26.5 %)*
*
86 (8.1 %)
44 (4.2 %)
Gestational hypertension
4,589 (1.8 %)
42 (4.0 %)
35 (23.8 %)*
Age (years)
31.4 ± 5.1
31.7 ± 5.3*
30.1 ± 5.8*
3,101 (1.2 %)
12 (1.1 %)
6 (4.1 %)*
B19 20–34
184,022 (70.7 %)
705 (66.7 %)
106 (72.1 %)
C35
73,051 (28.1 %)
341 (32.2 %)*
35 (23.8 %)
GW at delivery
38.9 ± 1.2
38.3 ± 1.2*
39.2 ± 1.3*
Oxytocin and/or PGs
61,857 (23.8 %)
177 (16.7 %)*
42 (28.6 %)
53,925 (20.7 %)
150 (14.2 %)*
39 (26.5 %)
46,383 (17.8 %)
129 (12.2 %)*
38 (25.9 %)*
Oxytocin
b
Oxytocin alone c
*
PGs Prostaglandins alone
15,474 (5.9 %) 7,932 (3.0 %)
48 (4.5 %) 27 (2.6 %)
4 (2.7 %) 3 (2.0 %)
Oxytocin and PGs
7,542 (2.9 %)
21 (2.0 %)*
1 (0.7 %)
Arch Gynecol Obstet
The incidence of eclampsia was significantly elevated among teenagers and that of abruptio placentae was significantly higher among older women (C35 years). Gestational age at delivery was significantly smaller among women with abruptio placentae and was significantly advanced in women with eclampsia. Use of uterotonics and prevalence of abruptio placentae and eclampsia Of the 260,174 women, 17.8 % were given oxytocin alone, 3.0 % received prostaglandins alone (F2a or E2 alone, or both F2a and E2), and 2.9 % were given both oxytocin and prostaglandins (Table 1). Thus, 23.8 % of the women were given oxytocin and/or prostaglandins, 20.7 % were given oxytocin, and 5.9 % were given prostaglandins. These uterotonics were used significantly less frequently among women with than without abruptio placentae [16.7 % (177/ 1,058) vs. 23.8 % (61,680/259,116), respectively], whereas oxytocin alone was used significantly more frequently among women with than without eclampsia [25.9 % (38/ 147) vs. 17.8 % (46,345/260,027), respectively]. Among the 61,857 women given oxytocin and/or prostaglandins, 177 (0.29 %) developed abruptio placentae, while this complication occurred in 881 (0.44 %) of the 198,317 women who did not receive uterotonics (P \ 0.001) (Table 1), suggesting that use of uterotonics did not increase the risk of abruptio placentae. However, a larger number of women developed eclampsia among those given oxytocin and/or prostaglandins than among those who were not given uterotonics [0.07 % (42/61,857) vs. 0.05 % (105/198,317), respectively, P = 0.175]. Multivariate regression analyses Many characteristics were suggested to be associated with the development of abruptio placentae and eclampsia. However, most cesarean sections may have been conducted after the development of abruptio placentae or eclampsia. Therefore, we excluded cesarean delivery as a possible candidate independent risk factor for abruptio placentae and eclampsia. The following characteristics were entered into multivariate regression analysis for determining independent risk factors for abruptio placentae: primipara (yes or no), hypertension (yes or no), preeclampsia (yes or no), gestational hypertension (yes or no), age (year) C35 (yes or no), gestational week at delivery (continuous variable), use of oxytocin and/or prostaglandins (yes or no), use of oxytocin (yes or no), use of oxytocin alone (yes or no), use of prostaglandins (yes or no), and use of oxytocin and prostaglandins (yes or no). For eclampsia, the following characteristics were entered into multivariate regression analysis: primipara (yes or no), hypertension (yes or no),
Table 2 Independent risk factors for abruptio placentae b
SE
Odds
95 % CI
P value \0.001
Primiparity
0.342
0.064
1.41
1.24–1.60
Age (years) C35
0.156
0.067
1.17
1.03–1.33
0.020
Hypertension
0.884
0.115
2.42
1.93–3.03
\0.001
Oxytocin
-0.378
0.090
0.69
0.57–0.82
\0.001
GW at delivery
-0.404
0.028
0.67
0.63–0.71
\0.001
95 % CI
P value
GW gestational week, CI confidence interval b0 = 9.899, SE = 1.053 Table 3 Independent risk factors for eclampsia b
SE
Primiparity
1.401
0.250
4.06
2.49–6.63
\0.001
Age (years) \20 Hypertension
0.894 3.356
0.421 0.171
2.44 28.7
1.07–5.58 20.5–40.1
0.034 \0.001
GW at delivery
0.249
0.072
1.28
1.11–1.48
0.001
Odds
GW gestational week, CI confidence interval b0 = -18.958; SE = 2.814
preeclampsia (yes or no), gestational hypertension (yes or no), age (years) \20 (yes or no), gestational week at delivery (continuous variable), and use of oxytocin alone (yes or no). Primiparity [odds ratio (95 % confidence interval) 1.41 (1.24–1.60)], age C35 years old [1.17 (1.03–1.33)], and presence of hypertension [2.42 (1.93–3.030)] were significant independent risk factors for abruptio placentae, while use of oxytocin [0.69 (0.57–0.82)] and advancing gestation [0.67 (0.63–0.71)] decreased risk of abruptio placentae (Table 2). Thus, the use of any uterotonic agent did not increase the risk of abruptio placentae. Primiparity [odds ratio (95 % confidence interval) 4.06 (2.49–6.63)], age\20 years old [2.44 (1.07–5.58)], presence of hypertension [28.7 (20.5–40.1)], and advancing gestation [1.28 (1.11–1.47)] were significant independent risk factors for eclampsia (Table 3). Thus, use of oxytocin was a confounding factor and did not increase risk of eclampsia.
Discussion The present study demonstrated that the use of uterotonics, including intravenous oxytocin and dinoprost and oral dinoprostone, did not increase the risk of abruptio placentae or eclampsia. Limitations of this study In the present study, we were unable to specify the actual number of women who received uterotonics and
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subsequently developed abruptio placentae or eclampsia using only information from the database. As women with abruptio placentae or eclampsia usually undergo prompt delivery, some should have experienced these complications first and then received uterotonics to precipitate vaginal delivery. However, we assumed that all uterotonic agents were administered before the development of abruptio placentae and eclampsia. This assumption may have overestimated the effect of uterotonics on the prevalence of these complications, but did not alter our results that the use of uterotonics did not increase the risk of abruptio placentae or eclampsia. Although multivariate regression analysis suggested that use of oxytocin decreased the risk of abruptio placentae in this study, this should be confirmed in further prospective randomized studies. Comparison with other studies A very large cohort including women without hypertension was needed to meet the objectives of the present study. A retrospective study by Fontenot et al. [6] raised concerns about the safety of using misoprostol (a prostaglandin E1 preparation) in women with preeclampsia; a higher incidence of abruptio placentae was observed among those receiving misoprostol compared to those receiving dinoprostone [13.7 % (13/95) vs. 1.9 % (2/108), respectively, P = 0.001] [6]. Meanwhile, contradictory results were obtained in a retrospective study by Martinez de Tejada et al. [7], in which abruptio placentae occurred more frequently among preeclamptic women receiving dinoprostone than among those receiving misoprostol [5.4 % (9/ 168) vs. 1.3 % (3/235), respectively, P = 0.03]. In a randomized controlled study (HYPITAT trial) comparing the induction of labor with expectant monitoring for women with gestational hypertension or mild preeclampsia [11], abruptio placentae did not occur in either group [0.0 % (0/ 377) for the induction of labor and 0.0 % (0/379) for expectant monitoring], although information on the number of patients receiving uterotonics was not provided in the report [11]. In these previous reports [6, 7, 11], the study subjects were women with preeclampsia or gestational hypertension. Abruptio placentae, however, occurs in women in the absence of hypertension [10, 12–14]. Therefore, women without hypertension should be included among the study subjects to determine whether the use of uterotonics increases the risk of abruptio placentae. In the present study, the incidences of abruptio placentae among women receiving oxytocin alone [0.28 % (129/ 46,383)], prostaglandin(s) alone (dinoprost alone, dinoprostone alone, or both) [0.34 % (27/7,932)], or both oxytocin and prostaglandin(s) [0.28 % (21/7,542)] were lower than that [0.44 % (881/198,317)] among women not
123
receiving these agents. As the administration of misoprostol to pregnant women is prohibited in Japan, we were unable to determine whether misoprostol increases the risk of abruptio placentae. However, our study strongly suggested that the use of oxytocin, dinoprost, and/or oral dinoprostone did not increase the risk of abruptio placentae. Some Japanese patients with eclampsia insist that their eclamptic fits are induced by the use of uterotonics. As eclampsia is a rare complication, occurring in only 1 in 1,500–3,000 maternities [9, 15–17], even the abovementioned HYPITAT trial involving 756 women with mild preeclampsia or gestational hypertension [11] may have been too small to determine whether the induction of labor increases the risk of an eclamptic fit. In addition, approximately 20–50 % of women do not have hypertension at their last antenatal visit within a week before their first convulsive fit [12, 16, 17]. Thus, a large cohort including women without hypertension is needed to determine the effects of uterotonics on the incidence of eclampsia. The present study using a large cohort demonstrated that use of uterotonics did not contribute to the development of eclampsia, consistent with the results of a recent study [18] examining the incidence of eclampsia in the Netherlands before (January 2001–October 2005) and after (April 2008–December 2009) the HYPITAT trial, which was performed between October 2005 and March 2008 [11]. The induction of labor for women with mild preeclampsia or gestational hypertension increased from 58.3 to 67.1 % (P \ 0.001) and the incidence of eclampsia decreased from 0.85 to 0.19 % (P \ 0.001) before and after the trial, respectively [18]. These results suggest that the induction of labor using pharmacological methods does not increase the risk of eclampsia, but rather reduces the inherent risk of eclampsia during pregnancy among women in whom labor has not yet been induced. Implications for clinicians Our data may help clinicians to understand that uterotonics do not play a role in the genesis of abruptio placentae and eclampsia. The induction of labor is a common obstetric procedure worldwide, with 20–30 % of deliveries being induced [19]. Uterotonics such as oxytocin and prostaglandins, in addition to mechanical methods, are frequently used in the induction of labor. In our study population, 22.4 % of the women received uterotonics for induction and/or augmentation of labor. A considerable number of women may experience abruptio placentae or eclampsia during the use of uterotonics. However, the presence of a causal relationship between the use of uterotonics and such complications is very difficult to determine.
Arch Gynecol Obstet Conflict of interest All the authors declare that they have no financial relationships with a biotechnology manufacturer, pharmaceutical company, or other commercial entity that has an interest in the subject matter or the materials discussed in the manuscript.
11.
References 1. Pharmaceutical and Food Safety Bureau, Japanese Ministry of Labour, Health and Welfare (2010) Concerning revision of package insert (file number 0601-1) 2. Knight M, Tuffnell D, Brocklehurst P, Spark P, Kurinczuk JJ, UK Obstetric Surveillance System (2010) Incidence and risk factors for amniotic-fluid embolism. Obstet Gynecol 115:910–917 3. Roberts CL, Algert CS, Knight M, Morris JM (2010) Amniotic fluid embolism in an Australian population-based cohort. BJOG 117:1417–1421 4. Knight M, Berg C, Brocklehurst P, Kramer M, Lewis G, Oats J, Roberts CL, Spong C, Sullivan E, van Roosmalen J, Zwart J (2012) Amniotic fluid embolism incidence, risk factors and outcomes: a review and recommendations. BMC Pregnancy Childbirth. doi:10.1186/1471-2393-12-7 5. Yamada T, Yamada T, Morikawa M, Takeda M, Akaishi R, Nishida R, Araki N, Koyama T, Minakami H (2011) Do uterotrophic drugs increase the risk of fatal hemorrhagic brain stroke? J Perinat Med 39:23–26 6. Fontenot MT, Lewis DF, Barton CB, Jones EM, Moore JA, Evans AT (2005) Abruptio placentae associated with misoprostol use in women with preeclampsia. J Reprod Med 50:653–658 7. Martinez de Tejada B, Martillotti G, Lapaire O, Hoesli I, Irion O (2010) The risk of placental abruption when using prostaglandins for cervical ripening in women with preeclampsia: comparing misoprostol versus dinoprostone. J Matern Fetal Neonatal Med 23:988–993 8. Minakami H, Hiramatsu Y, Koresawa M et al (2011) Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2011 edition. J Obstet Gynaecol Res 37:1174–1197 9. Morikawa M, Cho K, Yamada T, Yamada T, Sato S, Minakami H (2012) Risk factors for eclampsia in Japan between 2005 and 2009. Int J Gynaecol Obstet 117:66–68 10. Matsuda Y, Hayashi K, Shiozaki A, Kawamichi Y, Sato S, Saito S (2011) Comparison of risk factors for placental abruption and
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placenta previa: case–cohort study. J Obstet Gynaecol Res 37:538–556 Koopmans CM, Bijlenga D, Groen H, Vijgen SM, Aarnoudse JG, Bekedam DJ, van den Berg PP, de Boer K, Burggraaff JM, Bloemenkamp KW, Drogtrop AP, Franx A, de Groot CJ, Huisjes AJ, Kwee A, van Loon AJ, Lub A, Papatsonis DN, van der Post JA, Roumen FJ, Scheepers HC, Willekes C, Mol BW, van Pampus MG; HYPITAT study group (2009) Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet 374:979–988 Minakami H, Kubo T, Takeda S, Kawabata M, Kobayashi T, Nakabayashi M (2009) Placental abruption, HELLP syndrome, and eclampsia in Japan. Nippon Sanka-Fujinka Gakkai Zasshi 61:1559–1567 (in Japanese) Sheiner E, Shoham-Vardi I, Hadar A, Hallak M, Hackmon R, Mazor M (2002) Incidence, obstetric risk factors and pregnancy outcome of preterm placental abruption: a retrospective analysis. J Matern Fetal Neonatal Med 11:34–39 Sheiner E, Shoham-Vardi I, Hallak M, Hadar A, Gortzak-Uzan L, Katz M, Mazor M (2003) Placental abruption in term pregnancies: clinical significance and obstetric risk factors. J Matern Fetal Neonatal Med 13:45–49 Kullberg G, Lindeberg S, Hanson U (2002) Eclampsia in Sweden. Hypertens Pregnancy 21:13–21 Douglas KA, Redman CWG (1994) Eclampsia in the United Kingdom. BMJ 309:1395–1400 Knight M; UKOSS (2007) Eclampsia in the United Kingdom 2005. BJOG 114:1072–1078 van der Tuuk K, Koopmans C, Groen H, Mol BW, van Pampus MG; HYPITAT study group (2011) Impact of the HYPITAT trial on doctors’ behaviour and prevalence of eclampsia in the Netherlands. BJOG 118:1658–1660 Jozwiak M, Oude Rengerink K, Benthem M, van Beek E, Dijksterhuis MG, de Graaf IM, van Huizen ME, Oudijk MA, Papatsonis DN, Perquin DA, Porath M, van der Post JA, Rijnders RJ, Scheepers HC, Spaanderman ME, van Pampus MG, de Leeuw JW, Mol BW, Bloemenkamp KW; PROBAAT Study Group (2011) Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial. Lancet 378:2095–2103
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MATERNAL-FETAL MEDICINE
Do uterotonic drugs increase risk of abruptio placentae and eclampsia? Mamoru Morikawa • Kazutoshi Cho • Takahiro Yamada Takashi Yamada • Shoji Sato • Hisanori Minakami
•
Received: 5 January 2013 / Accepted: 18 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To determine whether the use of uterotonics, including oxytocin and prostaglandins, increases the risk of abruptio placentae and eclampsia. Materials and methods A retrospective analysis was conducted among 260,174 Japanese women at term. Demographic characteristics were studied as possible candidates for risk factors of abruptio placentae and eclampsia using multivariate logistic regression analyses. Results A total of 1,058 (0.41 %) and 147 (0.06 %) women developed abruptio placentae and eclampsia, respectively. Abruptio placentae and eclampsia occurred in 177 (0.29 %) and 42 (0.07 %) of the 61,857 women treated with uterotonics, respectively. Multivariate regression analyses indicated that uterotonics did not increase risk of developing either abruptio placentae or eclampsia. Primiparity [odds ratio (95 % confidence interval) 1.41 (1.24–1.60)], age C35 years [1.17 (1.03–1.33)], and presence of hypertension [2.42 (1.93–3.03)] were significant independent risk factors for abruptio placentae, while advancing gestation [0.67 (0.63–0.71)] decreased risk of abruptio placentae. Primiparity [odds ratio (95 % confidence interval) 4.06 (2.49–6.63)], age \20 years [2.44 (1.07–5.58)], presence of hypertension [28.7 (20.5–40.1)],
M. Morikawa (&) K. Cho T. Yamada T. Yamada H. Minakami Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita-ku N15 W7, Sapporo 060-8638, Japan e-mail: [email protected] S. Sato Maternal and Perinatal Care Center, Oita Prefectural Hospital, Bunyo 476, Oita 870-8511, Japan
and advancing gestation [1.28 (1.11–1.47)] were significant independent risk factors for eclampsia. Conclusion The use of uterotonics did not increase the risk of abruptio placentae and eclampsia. Keywords Abruptio placentae Eclampsia Uterotonics Oxytocin Prostaglandins Risk factor
Introduction Uterotonic drugs (uterotonics), including intravenous oxytocin, intravenous prostaglandin F2a (dinoprost), and oral prostaglandin E2 (dinoprostone), are widely used in Japan for the induction and augmentation of labor. However, concerns have been raised regarding possible associations between the use of uterotonics and serious complications, such as stroke, amniotic fluid embolism, eclampsia and abruptio placentae [1]. Studies have indicated that the induction of labor or the use of uterotonics are risk factors for amniotic fluid embolism [2–4]. One study suggested that the use of uterotonics was not associated with fatal stroke [5]. However, whether the use of uterotonics increases the risk of abruptio placentae or eclampsia has not been studied extensively. Controversial results have been obtained regarding the risk of abruptio placentae after the use of misoprostol (prostaglandin E1 preparation) and dinoprostone vaginal inserts [6, 7]. Approximately 2,800 facilities provide obstetric services in Japan, delivering a total of 1,100,000 infants annually [8]; thus, most Japanese obstetric service providers perform only a small number of deliveries. The current prevalence rates of eclampsia and abruptio placenta are estimated to be \0.1 % [9] and *1.0 % [10], respectively, in Japan. Therefore, a large cohort is needed to determine whether the use of uterotonics increases the risk of abruptio
123
Arch Gynecol Obstet
placentae and eclampsia. We conducted this retrospective study in a large number of women with singleton pregnancies who participated in the registry system established by the Japan Society of Obstetrics and Gynaecology (JSOG) to determine the association between use of uterotonics and the occurrence of eclampsia and abruptio placentae at present in Japan.
Methods This study was conducted with the approval of the institutional review board at Hokkaido University Hospital. Approximately 120 secondary and tertiary hospitals participated in the JSOG Successive Pregnancy Birth Registry System, which collected information on successive deliveries occurring at C22 weeks of gestation in these hospitals. The available information from this system included maternal age, parity, gestational week at delivery, delivery mode, singleton or multifetal pregnancies, the use of oxytocin and prostaglandins, including intravenous dinoprost and oral dinoprostone, the birth weight of the neonates, outcome of infants, including stillbirth and early neonatal death within 7 days of life, and maternal complications including hypertensive disease during pregnancy, eclampsia, and abruptio placentae. However, we were unable to determine which prostaglandin (dinoprost or dinoprostone) was used and whether the administration of uterotrophics was performed before the development of abruptio placentae and eclampsia. We assumed that all uterotonic agents were administered before the development of abruptio placentae and eclampsia. Table 1 Demographic characteristics of study subjects No of women Nullipara a
Preeclampsia GW gestational week, PGs prostaglandins including F2a (dinoprost), and/or oral E2 (dinoprostone) * P \ 0.05 vs. counterparts without abruptio placentae for women with abruptio placentae or without eclampsia for women with eclampsia a
Including gestational hypertension and preeclampsia
b
With or without PGs
c
With or without oxytocin
123
Results Of the 260,174 women, 53.2 % were nulliparous, 24.7 % underwent cesarean section, and 3.1 % women developed hypertension, including preeclampsia and gestational hypertension (Table 1). Abruptio placentae and eclampsia developed in 1,058 and 147 women, respectively. The frequencies of all characteristics, including primipara, cesarean delivery, hypertension, preeclampsia, and gestational hypertension, were significantly higher in women with abruptio placentae or eclampsia than their counterparts without these conditions. Overall
Abruptio placentae
Eclampsia
260,174 (100 %)
1,058 (100 %)
147 (100 %)
138,355 (53.2 %)
Cesarean delivery Hypertension
A total of 302,795 pregnant women with singleton pregnancies were registered in this system over the 5-year period between 2005 and 2009, corresponding to *5.6 % of all singleton pregnancies that occurred in Japan during this period. Of these, 260,174 women were analyzed in this study after excluding 1,060 women (0.4 %) whose age, gestational week at delivery, and/or parity were unknown and 41,561 women (13.7 %) who delivered at \37 weeks. Statistical analyses were performed using the statistical software IBM SPSS statistics, version 19.0 (SPSS Inc., Chicago, IL, USA). The data are presented as the mean ± SD or median (range). The v2 test was used to compare the frequencies among categorical data. Multivariate logistic regression analyses were performed to determine the independent risk factors for abruptio placentae and eclampsia using selected parameters with a P \ 0.05 after univariate analyses (v2 test). In all analyses, P \ 0.05 was taken to indicate statistical significance.
64,162 (24.7 %) 8,007 (3.1 %) 3,418 (1.3 %)
595 (56.3 %)
*
128 (87.1 %)*
622 (58.8 %)
*
98 (66.7 %)*
*
74 (50.3 %)*
*
39 (26.5 %)*
*
86 (8.1 %)
44 (4.2 %)
Gestational hypertension
4,589 (1.8 %)
42 (4.0 %)
35 (23.8 %)*
Age (years)
31.4 ± 5.1
31.7 ± 5.3*
30.1 ± 5.8*
3,101 (1.2 %)
12 (1.1 %)
6 (4.1 %)*
B19 20–34
184,022 (70.7 %)
705 (66.7 %)
106 (72.1 %)
C35
73,051 (28.1 %)
341 (32.2 %)*
35 (23.8 %)
GW at delivery
38.9 ± 1.2
38.3 ± 1.2*
39.2 ± 1.3*
Oxytocin and/or PGs
61,857 (23.8 %)
177 (16.7 %)*
42 (28.6 %)
53,925 (20.7 %)
150 (14.2 %)*
39 (26.5 %)
46,383 (17.8 %)
129 (12.2 %)*
38 (25.9 %)*
Oxytocin
b
Oxytocin alone c
*
PGs Prostaglandins alone
15,474 (5.9 %) 7,932 (3.0 %)
48 (4.5 %) 27 (2.6 %)
4 (2.7 %) 3 (2.0 %)
Oxytocin and PGs
7,542 (2.9 %)
21 (2.0 %)*
1 (0.7 %)
Arch Gynecol Obstet
The incidence of eclampsia was significantly elevated among teenagers and that of abruptio placentae was significantly higher among older women (C35 years). Gestational age at delivery was significantly smaller among women with abruptio placentae and was significantly advanced in women with eclampsia. Use of uterotonics and prevalence of abruptio placentae and eclampsia Of the 260,174 women, 17.8 % were given oxytocin alone, 3.0 % received prostaglandins alone (F2a or E2 alone, or both F2a and E2), and 2.9 % were given both oxytocin and prostaglandins (Table 1). Thus, 23.8 % of the women were given oxytocin and/or prostaglandins, 20.7 % were given oxytocin, and 5.9 % were given prostaglandins. These uterotonics were used significantly less frequently among women with than without abruptio placentae [16.7 % (177/ 1,058) vs. 23.8 % (61,680/259,116), respectively], whereas oxytocin alone was used significantly more frequently among women with than without eclampsia [25.9 % (38/ 147) vs. 17.8 % (46,345/260,027), respectively]. Among the 61,857 women given oxytocin and/or prostaglandins, 177 (0.29 %) developed abruptio placentae, while this complication occurred in 881 (0.44 %) of the 198,317 women who did not receive uterotonics (P \ 0.001) (Table 1), suggesting that use of uterotonics did not increase the risk of abruptio placentae. However, a larger number of women developed eclampsia among those given oxytocin and/or prostaglandins than among those who were not given uterotonics [0.07 % (42/61,857) vs. 0.05 % (105/198,317), respectively, P = 0.175]. Multivariate regression analyses Many characteristics were suggested to be associated with the development of abruptio placentae and eclampsia. However, most cesarean sections may have been conducted after the development of abruptio placentae or eclampsia. Therefore, we excluded cesarean delivery as a possible candidate independent risk factor for abruptio placentae and eclampsia. The following characteristics were entered into multivariate regression analysis for determining independent risk factors for abruptio placentae: primipara (yes or no), hypertension (yes or no), preeclampsia (yes or no), gestational hypertension (yes or no), age (year) C35 (yes or no), gestational week at delivery (continuous variable), use of oxytocin and/or prostaglandins (yes or no), use of oxytocin (yes or no), use of oxytocin alone (yes or no), use of prostaglandins (yes or no), and use of oxytocin and prostaglandins (yes or no). For eclampsia, the following characteristics were entered into multivariate regression analysis: primipara (yes or no), hypertension (yes or no),
Table 2 Independent risk factors for abruptio placentae b
SE
Odds
95 % CI
P value \0.001
Primiparity
0.342
0.064
1.41
1.24–1.60
Age (years) C35
0.156
0.067
1.17
1.03–1.33
0.020
Hypertension
0.884
0.115
2.42
1.93–3.03
\0.001
Oxytocin
-0.378
0.090
0.69
0.57–0.82
\0.001
GW at delivery
-0.404
0.028
0.67
0.63–0.71
\0.001
95 % CI
P value
GW gestational week, CI confidence interval b0 = 9.899, SE = 1.053 Table 3 Independent risk factors for eclampsia b
SE
Primiparity
1.401
0.250
4.06
2.49–6.63
\0.001
Age (years) \20 Hypertension
0.894 3.356
0.421 0.171
2.44 28.7
1.07–5.58 20.5–40.1
0.034 \0.001
GW at delivery
0.249
0.072
1.28
1.11–1.48
0.001
Odds
GW gestational week, CI confidence interval b0 = -18.958; SE = 2.814
preeclampsia (yes or no), gestational hypertension (yes or no), age (years) \20 (yes or no), gestational week at delivery (continuous variable), and use of oxytocin alone (yes or no). Primiparity [odds ratio (95 % confidence interval) 1.41 (1.24–1.60)], age C35 years old [1.17 (1.03–1.33)], and presence of hypertension [2.42 (1.93–3.030)] were significant independent risk factors for abruptio placentae, while use of oxytocin [0.69 (0.57–0.82)] and advancing gestation [0.67 (0.63–0.71)] decreased risk of abruptio placentae (Table 2). Thus, the use of any uterotonic agent did not increase the risk of abruptio placentae. Primiparity [odds ratio (95 % confidence interval) 4.06 (2.49–6.63)], age\20 years old [2.44 (1.07–5.58)], presence of hypertension [28.7 (20.5–40.1)], and advancing gestation [1.28 (1.11–1.47)] were significant independent risk factors for eclampsia (Table 3). Thus, use of oxytocin was a confounding factor and did not increase risk of eclampsia.
Discussion The present study demonstrated that the use of uterotonics, including intravenous oxytocin and dinoprost and oral dinoprostone, did not increase the risk of abruptio placentae or eclampsia. Limitations of this study In the present study, we were unable to specify the actual number of women who received uterotonics and
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subsequently developed abruptio placentae or eclampsia using only information from the database. As women with abruptio placentae or eclampsia usually undergo prompt delivery, some should have experienced these complications first and then received uterotonics to precipitate vaginal delivery. However, we assumed that all uterotonic agents were administered before the development of abruptio placentae and eclampsia. This assumption may have overestimated the effect of uterotonics on the prevalence of these complications, but did not alter our results that the use of uterotonics did not increase the risk of abruptio placentae or eclampsia. Although multivariate regression analysis suggested that use of oxytocin decreased the risk of abruptio placentae in this study, this should be confirmed in further prospective randomized studies. Comparison with other studies A very large cohort including women without hypertension was needed to meet the objectives of the present study. A retrospective study by Fontenot et al. [6] raised concerns about the safety of using misoprostol (a prostaglandin E1 preparation) in women with preeclampsia; a higher incidence of abruptio placentae was observed among those receiving misoprostol compared to those receiving dinoprostone [13.7 % (13/95) vs. 1.9 % (2/108), respectively, P = 0.001] [6]. Meanwhile, contradictory results were obtained in a retrospective study by Martinez de Tejada et al. [7], in which abruptio placentae occurred more frequently among preeclamptic women receiving dinoprostone than among those receiving misoprostol [5.4 % (9/ 168) vs. 1.3 % (3/235), respectively, P = 0.03]. In a randomized controlled study (HYPITAT trial) comparing the induction of labor with expectant monitoring for women with gestational hypertension or mild preeclampsia [11], abruptio placentae did not occur in either group [0.0 % (0/ 377) for the induction of labor and 0.0 % (0/379) for expectant monitoring], although information on the number of patients receiving uterotonics was not provided in the report [11]. In these previous reports [6, 7, 11], the study subjects were women with preeclampsia or gestational hypertension. Abruptio placentae, however, occurs in women in the absence of hypertension [10, 12–14]. Therefore, women without hypertension should be included among the study subjects to determine whether the use of uterotonics increases the risk of abruptio placentae. In the present study, the incidences of abruptio placentae among women receiving oxytocin alone [0.28 % (129/ 46,383)], prostaglandin(s) alone (dinoprost alone, dinoprostone alone, or both) [0.34 % (27/7,932)], or both oxytocin and prostaglandin(s) [0.28 % (21/7,542)] were lower than that [0.44 % (881/198,317)] among women not
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receiving these agents. As the administration of misoprostol to pregnant women is prohibited in Japan, we were unable to determine whether misoprostol increases the risk of abruptio placentae. However, our study strongly suggested that the use of oxytocin, dinoprost, and/or oral dinoprostone did not increase the risk of abruptio placentae. Some Japanese patients with eclampsia insist that their eclamptic fits are induced by the use of uterotonics. As eclampsia is a rare complication, occurring in only 1 in 1,500–3,000 maternities [9, 15–17], even the abovementioned HYPITAT trial involving 756 women with mild preeclampsia or gestational hypertension [11] may have been too small to determine whether the induction of labor increases the risk of an eclamptic fit. In addition, approximately 20–50 % of women do not have hypertension at their last antenatal visit within a week before their first convulsive fit [12, 16, 17]. Thus, a large cohort including women without hypertension is needed to determine the effects of uterotonics on the incidence of eclampsia. The present study using a large cohort demonstrated that use of uterotonics did not contribute to the development of eclampsia, consistent with the results of a recent study [18] examining the incidence of eclampsia in the Netherlands before (January 2001–October 2005) and after (April 2008–December 2009) the HYPITAT trial, which was performed between October 2005 and March 2008 [11]. The induction of labor for women with mild preeclampsia or gestational hypertension increased from 58.3 to 67.1 % (P \ 0.001) and the incidence of eclampsia decreased from 0.85 to 0.19 % (P \ 0.001) before and after the trial, respectively [18]. These results suggest that the induction of labor using pharmacological methods does not increase the risk of eclampsia, but rather reduces the inherent risk of eclampsia during pregnancy among women in whom labor has not yet been induced. Implications for clinicians Our data may help clinicians to understand that uterotonics do not play a role in the genesis of abruptio placentae and eclampsia. The induction of labor is a common obstetric procedure worldwide, with 20–30 % of deliveries being induced [19]. Uterotonics such as oxytocin and prostaglandins, in addition to mechanical methods, are frequently used in the induction of labor. In our study population, 22.4 % of the women received uterotonics for induction and/or augmentation of labor. A considerable number of women may experience abruptio placentae or eclampsia during the use of uterotonics. However, the presence of a causal relationship between the use of uterotonics and such complications is very difficult to determine.
Arch Gynecol Obstet Conflict of interest All the authors declare that they have no financial relationships with a biotechnology manufacturer, pharmaceutical company, or other commercial entity that has an interest in the subject matter or the materials discussed in the manuscript.
11.
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