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A prior placenta accreta is an independent risk factor for post-partum hemorrhage in subsequent gestations

European Journal of Obstetrics & Gynecology and Reproductive Biology, pages 20 - 24

Abstract

Objective

The rate of placenta accreta, a life threatening condition, is constantly increasing, mainly due to the rise in the rates of cesarean sections. This study is aimed to determine the effect of a history of placenta accreta on subsequent pregnancies.

Study design

A population based retrospective cohort study was designed, including all women who delivered at our medical center during the study period. The study population was divided into two groups including pregnancies with: (1) a history of placenta accreta (n = 514); and (2) control group without placenta accreta (n = 239,126).

Results

(1) A history of placenta accreta is an independent risk factor for postpartum hemorrhage (adjusted OR 4.1, 95% CI 1.5–11.5) as were placenta accreta (adjusted OR 22.0, 95% CI 14.0–36.0) and placenta previa (adjusted OR 7.6, 95% CI 4.4–13.2) in the current pregnancy, and a prior cesarean section (adjusted OR 1.7, 95% CI 1.3–2.2); (2) in addition, placenta accreta in a previous pregnancy is associated with a reduced rate of mild preeclampsia in future pregnancies (1.8% vs. 3.4%, RR 0.51, 95% CI 0.26–0.98); (3) however, in spite of the higher rate of neonatal deaths in the study group, a history of placenta accreta was not an independent risk factor for total perinatal mortality (adjusted OR 1.0, 95% CI 0.5–1.9) after adjusting for confounders.

Conclusion

A history of placenta accreta is an independent risk factor for postpartum hemorrhage. This should be taken into account in order to ensure a safety pregnancy and delivery of these patients.

Keywords: Blood transfusion, GEE model, Maternal complication, Neonatal mortality, Placenta previa, Previous cesarean section.

Introduction

Placenta accreta complicates 0.3% of pregnancies in the United States[1] and [2]. The incidence of placenta accreta has tripled since the 1980s, mainly due to the steep rise in the rate of cesarean sections[2] and [3], especially in the presence of placenta previa. Placenta accreta is associated with increased maternal morbidity and mortality, being the most severe and life threatening complications represented by intraoperative or postpartum hemorrhage (PPH)[4] and [5]and peripartum hysterectomies[6], [7], [8], [9], [10], and [11], multisystem organ failure and maternal death[4] and [5].

The principal goal in women with placenta accreta is to minimize the morbidity and potential damage to the uterus and reproductive tract, in order to preserve future fertility. This is reached in 78.4% of women, with a severe maternal morbidity rate of 6% (associated to severe intrauterine synechiae, recurrent placenta accreta, placenta previa in following pregnancies and postpartum hemorrhage), while in the remaining cases hysterectomy is not avoidable[9] and [12]. However, this success does not come without a price, since there is 18–28% of recurrence rate of placenta accreta in subsequent pregnancies[9], [12], and [13].

Moreover, due to the low incidence of placenta accreta, there is a lack of large scale population based studies that aim to define the long term effects of placenta accreta on future pregnancies in the absence of recurrent disease.

Thus, the aim of the present study is to determine the maternal and perinatal outcomes in women with placenta accreta in a previous pregnancy, who were successfully managed expectantly.

Materials and methods

This population based retrospective cohort study, included 239,640 deliveries of 90,247 women who delivered at Soroka University Medical Center from 1988 until 2010, and was aimed to determine the maternal and perinatal outcomes in women with placenta accreta in a previous pregnancy, who were successfully managed expectantly. Women having a fetus with chromosomal abnormalities or congenital anomalies were excluded. Data were collected from an electronic database that included demographic, obstetric and general information about the mother and fetus of all the deliveries at our medical center. Placenta accreta was diagnosed according to clinical definition (abnormal adherence of the placenta to the uterine wall) and pathologic examination of the placenta (direct apposition of placental villi to the myometrium) and was coded accordingly in the database (ICD-9 code 66702). Two groups were created: (1) pregnancies following an event of placenta accreta (n = 514); and (2) normal pregnancies (n = 239,126) as a control group.

Patients were defined as multipara (2–5 deliveries) and grand-multipara (6 or more deliveries), according to parity. Hypertension was defined as blood pressure above 140/90 mmHg in two separate measurement four to six hours apart. Severe hypertension was defined as blood pressure above 160/110 mmHg. Preeclampsia was determined as the presence of hypertension and proteinuria of more than 300 mg at 24-h urine collection or at least +1 in dipstick; its severity was defined according to the severity of hypertension and/or one of the following +3 proteinuria by dipstick, thrombocytopenia ≤100,000, elevated liver enzymes, persistent headache and/or blurred vision [14] . Gestational hypertension was defined as hypertension developed after 20 weeks of gestation without proteinuria. Placenta accreta was diagnosed according to surgeons’ and physicians’ diagnosis as well as pathological examination of the placentas; the ICD-9 that was used to identify the patients in our database was 66,702.

Gestational diabetes was diagnosed according to 100 g oral glucose tolerance test and was classified according to White's classification [15] .

Small for gestational age (SGA) was defined as birth weight <the 10th percentile, adequate for gestational age (AGA) as birth weight from 10th to 90th percentile, and large for gestational age (LGA) as birth weight >90th percentile according to regional growth curves [16] . Prelabor rupture of membranes (PROM) was defined as rupture of the chorioamniotic membranes before the onset of labor. Preterm delivery was defined as delivery prior to 37 weeks of gestation. Uterine rupture was diagnosed in case of a complete tear of the uterine wall including the visceral peritoneum with establishment of a direct communication between the uterine and abdominal cavities. Dehiscence was defined as an opening of the previous cesarean scar with intact visceral peritoneum and no direct communication between the uterine and abdominal cavities.

Postpartum fever was diagnosed as maternal temperature >38 °C that developed at least 24 h after delivery recorded in two different measurements at least four hours apart or one measurement of maternal temperature of >38.5 °C regardless the time after delivery. Postpartum hemorrhage was considered as amount of bleeding that exceeds 500 mL following vaginal delivery or 1000 mL following cesarean delivery. Endometritis was defined as postpartum maternal fever with clinical signs of tenderness above the uterine fundus or during cervical manipulation, foul vaginal discharge and positive endometrial culture. Wound infection was defined according to either clinical signs of infection or positive wound culture. Wound dehiscence was the spontaneous opening of cesarean section wound including the abdominal fascia.

T-test was used for continuous normally distributed variables and Mann–Whitney for non-normally distributed variables. Chi-square test was used to compare categorical variables. Multivariate logistic models were created to estimate the risk for PPH, total perinatal mortality, and postpartum death (either including or excluding birth weight). Logistic regression was employed for the dichotomous outcomes. Since some women appear a number of times in the database (due to a multiple number of deliveries), we used generalized estimation equation (GEE) models in which every woman constitutes a cluster in the model.

Results

The rate of history of placenta accreta in our population was 0.2% (514/239,640 deliveries). The demographic characteristics and obstetrical history of the study population are presented in Table 1 . Bedouins were more likely to deliver following an episode of placenta accreta than Jews (RR 0.80, 95% CI 0.67–0.95,P = 0.01). Women with a history of placenta accreta were older and had higher gravidity and parity than the control group (P < 0.001, for all comparisons).

Table 1 Background characteristics of the deliveries in the study population by study groups.

Variables History of placenta accreta, n = 514 No history of placenta accreta, n = 239,126 P-value RR (95% CI)
Ethnicity
 Jews 231 (44.9) 120,849 (50.1) 0.01 0.80 (0.67–0.95)
 Bedouins 283 (55.1) 118,277 (49.5)
 
Maternal age 30.29 ± 5.46 28.55 ± 5.83 0.02 n/a
Gravidity 4 (1–13) 3 (0–17) <0.001 n/a
Parity 5 (1–14) 3 (1–17) <0.001 n/a
LOPC 44 (8.6) 20,285 (8.7) 0.9 0.98 (0.72–1.34)
Smoking 5 (1.0) 2634 (1.1) 0.8 0.88 (0.37–2.13)
ART 6 (1.2) 6114 (2.5) 0.1 0.45 (0.2–1.01)

Data is presented as number (percentage), median (range) or mean ± standard deviation. LOPC, lack of prenatal care; ART, assisted reproductive technology; n/a, not available.

The overall rate of hypertensive disorders during pregnancy was lower among patients with a history of placenta accreta than in those in the control group (6.9% vs. 10.2%). This difference was especially prominent in patients with mild preeclampsia (RR 0.51, 95% CI 0.26–0.98). Women with a history of placenta accreta had a higher rate of blood products transfusion during the subsequent pregnancies and deliveries than those in the control group (3.3% vs. 1.5%, RR 2.27, 95% CI 1.39–3.68) ( Table 2 ).

Table 2 Obstetric characteristics during pregnancy and delivery in the study groups.

Variables History of placenta accreta, n = 514 No history of placenta accreta, n = 239,126 RR (95%CI)
Cesarean section 84 (16.3) 34,036 (14.2) 1.17 (0.93–1.49)
Diabetes 31 (6.0) 13,945 (5.8) 1.04 (0.72–1.49)
Hypertension 20 (3.9) 13,533 (5.7) 0.67 (0.43–1.06)
Mild preeclapsia 9 (1.8) 8112 (3.4) 0.51 (0.26–0.98)
Severe preeclapsia 6 (1.2) 2578 (1.1) 1.08 (0.48–2.43)
Placenta previa 4 (0.8) 964 (0.4) 1.94 (0.72–5.19)
Meconium 70 (13.6) 35,547 (14.9) 0.90 (0.70–1.16)
Blood product transfusion 17 (3.3) 3552 (1.5) 2.27 (1.39–3.68)
Hysterectomy 1 (0.2) 106 (0.04) 4.4 (0.6–31.5)
Placental abruption 3 (0.6) 1567 (0.7) 0.89 (0.29–2.77)

Data is presented as number (percentage).

Women with a history of placenta accreta had significantly higher rate of PPH (2.1% vs. 0.6%, RR 3.78, 95% CI 2.07–2.88,P < 0.001) as well as anemia (43.2% vs. 27.9%, RR 1.96, 95% CI 1.65–2.34,P < 0.001) compared to the control group ( Table 3 ).

Table 3 Clinical characteristics during post-partum period in the study groups.

Variables History of placenta accreta, n = 514 No history of placenta accreta, n = 239,126 P-value RR (95%CI)
Anemia 222 (43.2) 66,802 (27.9) <0.001 1.96 (1.65–2.34)
Wound infection 1 (0.2) 295 (0.1) 0.6 1.58 (0.22–11.26)
Postpartum hemorrhage 11 (2.1) 1377 (0.6) <0.001 3.78 (2.07–2.88)
Postpartum fever 0 972 (0.4) 0.1 n/a
Infection 0 19 (0.01) 0.8 n/a

Data is presented as number (percentage).

A history of placenta accreta was significantly associated with an increased rate of very low birth weight (VLBW) neonates (2.7% vs. 1.1%, RR 2.5, 95% CI 1.47–4.26,P < 0.001), postpartum death (1.4% vs. 0.3%, RR 4.24, 95% CI 2.005–8.97,P < 0.001), and total perinatal mortality (2.2% vs. 1.1%, RR 2.26, 95% CI 1.24–4.11,P = 0.006) ( Table 4 ). In addition, the rate of overall and early preterm birth was elevated in women with a history of placenta accreta.

Table 4 Neonatal complications in the study groups.

Variables History of placenta accreta, n = 514 (0.2%) No history of placenta accreta, n = 239,126 (99.8%) P-value RR (95%CI)
Gender
 Male 279 (54.3) 121,926 (51.0) 0.1 1.14 (0.96–1.36)
 Female 235 (45.7) 117,200 (49.0)
 
Malpresentation 41 (8.0) 14,508 (6.1) 0.1 1.34 (0.97–1.85)
VLBW 14 (2.7) 2650 (1.1) <0.001 2.5 (1.47–4.26)
IUGR 9 (1.8) 4624 (1.9) 1 0.90 (0.47–1.75)
SGA 17 (3.3) 12,334 (5.2) 0.1 0.63 (0.39–1.02)
Apgar 1 < 7 34 (6.6) 14,709 (6.2) 0.7 1.08 (0.76–1.53)
Apgar 5 < 7 17 (3.3) 6455 (2.7) 0.4 1.23 (0.76–2.00)
APD 4 (0.8) 1381 (0.6) 0.6 1.35 (0.50–3.62)
IPD 0 136 (0.1) 0.6 0.98 (0.98–0.98)
PPD 7 (1.4) 776 (0.3) <0.001 4.24 (2.005–8.97)
Total perinatal mortality 11 (2.2) 2293 (1.1) 0 2.26 (1.24–4.11)
Preterm delivery (≤37) 58 (11.3) 21,194 (8.9) 0.1 1.31 (0.99–1.72)
Early preterm birth (≤34) 17 (3.3) 5027 (2.1) 0.1 1.59 (0.98–2.58)
Gestational age (weeks) 38.82 ± 2.913 38.37 ± 3.643 0.3 n/a

Data is presented as number (percentage) or standard deviation. VLBW, very low birth weight; IUGR, intrauterine growth restriction; APD, antepartum death; IPD, intrapartum death; PPD, postpartum death; n/a, not available.

In order to determine the risk factors for PPH and especially the role of a history of placenta accreta, we performed a GEE model ( Table 5 ). After adjusting for maternal and obstetrical characteristics, we found that a history of placenta accreta is an independent risk factor for PPH (adj. OR = 4.1, 95% CI 1.5–11.5). Additional independent risk factors are placenta accreta (adj. OR = 22.0, 95% CI 14.0–36.0) and placenta previa (adj. OR = 7.6, 95% CI 4.4–13.2) in the current pregnancy, history of cesarean sections (adj. OR = 1.7, 95% CI 1.3–2.2), as well as Jewish origin (adj. OR = 1.3, 95% CI 1.0–1.6). Of interest, maternal age, parity and fertility treatments were not independently associated with PPH.

Table 5 Risk factors for postpartum hemorrhage; GEE multivariate logistic model.

Co-variates Adj. OR 95% CI
Placenta accreta 22.0 14.0–36.0
History of placenta accreta 4.1 1.5–11.5
History of cesarean section 1.7 1.3–2.2
Placenta previa 7.6 4.4–13.2
Any fertility treatment 1.4 0.8–2.4
Maternal age 0.99 0.97–1.02
 
Ethnicity
 Bedouins 1.3 1.0–1.6
 Jews
 
Parity 1.01 0.95–1.07

Modelc-statistics: 59.1,P < 0.001.

In the study of the association between perinatal mortality and a history of placenta accreta the model testing total perinatal mortality as the independent factor revealed no independent association between the two factors ( Table 6 ). We then studied the association between neonatal death and a history of placenta accreta ( Table 7 ), but only gestational age at delivery, the delivery of an SGA neonate, maternal ethnicity, and placenta accreta at the index pregnancy were independently associated with neonatal death.

Table 6 Risk factors for perinatal mortality; GEE multivariate logistic model.

Co-variates Adj. OR 95% CI
Placenta accreta 2.9 1.7–4.87
History of placenta accreta 1.05 0.59–1.9
History of cesarean section 0.69 0.6–0.81
Parity 1.11 1.09–1.14
Maternal age (years) 1.004 0.99–1.02
Gestation age at delivery (weeks) 0.87 0.85–0.88
Birthweight (g) 0.998 0.998–0.998
 
Ethnicity
 Bedouins 0.68 0.60–0.77
 Jews

Modelc-statistics: 57.5,P < 0.001.

Table 7 Risk factors for postpartum death; GEE multivariate logistic model.

Co-variates Adj. OR 95% CI
Placenta accreta 2.26 1.19–4.33
History of placenta accreta 1.87 0.97–3.58
History of cesarean section 0.99 0.77–1.29
Parity 1.03 0.98–1.08
Maternal age (years) 1 0.98–1.02
Gestation age at delivery (weeks) 0.66 0.64–0.67
SGA < 10th 2.15 1.72–2.68
 
Ethnicity
 Bedouins 0.69 0.56–0.86
 Jews

Modelc-statistics: 92.3%,P < 0.01.

Comments

The principal findings of the study are: (1) a history for placenta accreta is an independent risk factor for PPH in following pregnancies, even without an evidence for placenta accreta in the current pregnancy (OR = 4.1,P = 0.007); and (2) placenta accreta in a previous pregnancy is associated with a reduced rate of mild preeclampsia in future pregnancies (1.8% vs. 3.4%, RR 0.51, 95% CI 0.26–0.98).

Previously, there are numerous reports on the association between placenta accreta and maternal hemorrhage in the ongoing pregnancy[4] and [5]. This association is mainly due to either retained placental tissue that prevents the uterus from contractions or as a result of the trauma to the uterus during the removal of the adherent placenta [17] . Moreover, the finding that a history of placenta accreta is an independent risk factor for PPH is novel.

A similar result was recently published by Kabiri et al. [18] , based on pregnancies obtained from 268 women that were divided in two groups (patients with a history of placenta accreta in previous pregnancies and controls; RR 3.29, 95% CI 1.43–7.53,P < 0.001). However, the authors performed a match cohort study and did not adjust for confounding factors.

The fact that a history of placenta accreta is an independent risk factor for PPH even in the absence of recurrent placenta accreta deserves further discussion. This association implies that the mechanisms leading to placenta accreta may also be involved in the process underlying to PPH in subsequent pregnancies. In vitro studies bring evidence of differences in the potential of trophoblast invasion following decidual injury [19] . Of interest, there is a difference in decidual leukocyte population between patients who delivered spontaneously or had a cesarean section [19] . These findings suggest that surgical manipulation may alter the decidual ecosystem in women with a history of placenta accreta. Thus, these changes may be also relevant to the physiologic hemostatic mechanisms of the decidua predisposing the affected women for PPH. This assumption awaits further study.

The finding of a lower rate of hypertensive disorders during pregnancy in women with a history of placenta accreta is novel in our cohort. Some of the major obstetrical syndromes, including pre-eclampsia, pre-eclampsia with fetal growth restriction, intrauterine growth restriction, pre-term premature rupture of the fetal membranes [20] and pre-term birth [21] have been associated with defective deep placentation. The pathogenesis of defective deep placentation is frequently related to defective trophoblast invasion [22] . Our findings may suggest that placentas of patient with a history of placenta accreta may have better implantation and trophoblast invasiveness. Evidence in support of this view can be derived from the study by McMahon et al. [23] who assessed the activity of the antiangiogenic molecule soluble fms-like tyrosine kinase (sFLT-1) on trophoblast invasion. sFLT-1 irreversibly binds to circulating VEGF, a potent angiogenic growth factor, preventing its interaction to the endothelial cell receptor and the expression of its physiologic activity [24] . Indeed, in humans, a syndrome associated with treatment with VEGF inhibitors characterized by hypertension, proteinuria, and cerebral edema, in some ways similar to preeclampsia, has been described [25] . Human and animal studies[23], [26], [27], [28], and [29]support the effect of an overexpression of sFLT-1 in the pathogenesis of preeclampsia. In contrast to the pathogenesis of preeclampsia the characteristic invasiveness of trophoblast of patients with placenta accreta include a lower expression of sFLT-1 at maternal–fetal interface than that observed in normal placentation [23] . Overall the epidemiologic data presented in the current manuscript, the tendency of placenta accreta to reoccur, along with the existing in vitro evidence [19] , support the assumption that trophoblast of women who had placenta accreta in the past, is more invasive and thus associated with less hypertensive disorders of pregnancy. Nevertheless, since when we adjusted for other risk factor a prior placenta accreta did not have a protective effect against preeclampsia suggest that this association should be treated with caution and targeted studies may be needed to address this question appropriately.

The univariate analysis demonstrated an association between a history of placenta accreta and total perinatal mortality, especially postpartum death. However, we tested this association in the multivariate models and it was insignificant as long as birth weight was included in the model, becoming significant if it was excluded (Supplementary Table S1). This tendency may imply that the major cause of the neonatal death might be related to prematurity and very low birth weight that were more prevalent in the study group. Overall it seems that in our cohort these findings are more related to sequel of prematurity rather the history of placenta accreta.

The strength of the current study is the large dataset of deliveries that enable us to study even rare complications in sufficient power. Nevertheless, the pitfalls of our study include its retrospective design and the fact that it is based on a dataset with its inherent limitations (for example data regarding the extent of placental invasiveness were not retrievable. As a consequence the proportions of women with placenta accreta, increta or precreta are not available for the present study).

In conclusion, the pathogenesis of PPH in patients with history of placenta accreta or recurrence of this pathology is not completely understood.

Moreover, as we found, even the simple history of placenta accreta without recurrent disease, is associated with an increased risk of obstetric complications in future pregnancies. These complications, as in the case of PPH, might be life threatening without a proper and immediate treatment. For this reason adequate counseling of the patient and increased awareness of the obstetrician attending these deliveries are needed in order to manage possible complications such as massive PPH. In addition, efforts should be made to achieve a safe prevention of the primary cesarean delivery as a way to reduce the incidence of placental abnormalities, thus, preventing the morbidity associated with an invasive placentation [30] .

Appendix A. Supplementary data

The following are the supplementary data to this article:

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Footnotes

a School of Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel

b Department of Epidemiology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel

c Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Ben Gurion University of the Negev, Beer Sheva, Israel

d Department of Obstetrics and Gynecology, Azienda Ospedaliera-Universitaria Policlinico di Bari, School of Medicine, University of Bari “Aldo Moro”, Bari, Italy

lowast Corresponding author at: Acting Director, Maternal Fetal Medicine Unit, Department of Obstetrics and Gynecology “B”, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben Gurion University of the Negev, P.O. Box 151, Beer Sheva 84101, Israel. Tel.: +972 8 6400061; Fax: +972 8 6403294.