Placenta accreta is associated with IVF pregnancies: a retrospective chart review

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General obstetrics

DOI: 10.1111/j.1471-0528.2011.02976.x

Placenta accreta is associated with IVF pregnancies: a retrospective chart review E Esh-Broder,a I Ariel,b N Abas-Bashir,a Y Bdolah,a D Hochner Celnikiera Departments of a Obstetrics and Gynecology and b Pathology, Hadassah-Hebrew University Medical Center, Mt Scopus, Jerusalem, Israel Correspondence: Dr E Esh-Broder, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Mt Scopus, PO Box 24035, Mt Scopus, Jerusalem, Israel. Email [email protected] Accepted 2 March 2011. Published Online 18 May 2011.

Objective To study the association between placenta accreta (PA)

and in vitro fertilisation (IVF) pregnancies. Design Retrospective chart review. Setting Tertiary care centre in Jerusalem, Israel. Sample During January 2004–February 2009, 25 193 deliveries

occurred in our hospital, including 752 (3%) deliveries of IVF pregnancies. Methods Placenta accreta was only diagnosed when there were

histological findings from the placenta associated with the suitable clinical course. Demographic, obstetrical and fertility characteristics of these patients were retrieved from hospital files. Main outcome measure Rates of PA in pregnancies achieved with

Results The rate of PA in the IVF group was 12/752 (16/1000) pregnancies, compared with 30/24 441 (1.2/1000) among spontaneous pregnancies (P < 0.0001; OR 13.2; 95% CI 6.7–25.8). Among the variables examined, parity, rate of caesarean delivery in the index pregnancy, and birthweight differed significantly between IVF and spontaneous pregnancies. Conclusions The odds of developing PA are significantly

higher in IVF pregnancies than in spontaneous pregnancies. These differences may stem from differences in the endometrial environment, or from changes to the endometrium wrought by IVF treatment protocols. Keywords In vitro fertilization, placenta accreta.

IVF versus rates of PA in spontaneous pregnancies. Please cite this paper as: Esh-Broder E, Ariel I, Abas-Bashir N, Bdolah Y, Hochner Celnikier D. Placenta accreta is associated with IVF pregnancies: a retrospective chart review. BJOG 2011;118:1084–1089.

Introduction Placenta accreta (PA) is a potentially catastrophic obstetric complication. Whether the placenta is completely or focally adherent to the myometrium, PA is associated with massive postpartum haemorrhage, and has become one of the most common indications for emergent peripartum hysterectomy.1–3 PA develops when the placental implantation is abnormal: the decidua basalis that normally separates the anchoring placental villi and the myometrium is missing. More invasive types include placenta increta and placenta percreta, in which the placenta extends to and through the uterine myometrium, respectively. The exact pathogenesis is unknown. Possible hypotheses include: (1) a mechanical factor, i.e. primary deficiency of the decidua caused by local trauma to the uterine wall; (2) a biological factor, i.e. abnormal maternal response to trophoblast invasion; and (3) a combination of both processes.


The most common and defined risk factor associated with PA is a previous caesarean delivery. The most common setting is placenta previa after a prior caesarean delivery. The risk of PA increases progressively in correlation with the number of repeated caesarean deliveries.4,5 Other significant independent risk factors include coexistent placenta previa and maternal age.5,6 Multiparity, previous uterine curettage and previous uterine surgery other than caesarean sections were found to be risk factors in some studies, whereas no significant association between these factors and PA was found in others.3,7–9 In addition, in trisomy 21 screening programmes, an association was found between PA and abnormally elevated second-trimester alpha fetal protein (AFP) and free b subunit of human chorionic gonadotrophin (b-hCG) levels in maternal serum.10 The reported incidence of PA varies widely, mainly as it is affected by differences in diagnostic criteria, i.e. whether the diagnosis was based on clinical findings only or

ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG

Placenta accreta is associated with IVF pregnancies

together with histological criteria.7 The average reported incidence has increased ten-fold in the last 50 years, from 0.03 to 0.3% in studies from the last two decades. The highest incidence, 0.9%, was reported in a recent study based on clinical diagnostic criteria.11 The increase in PA in recent years is attributed to the increase in the prevalence of known risk factors, particularly caesarean deliveries. Pathologically, PA is defined as the direct apposition of placental villi to the myometrium. A finding of basal plate myometrial fibres adherent to the placenta confirms the diagnosis of PA that was suspected clinically, but it is not indicative of PA in the absence of a clinical history. Another feature of PA is larger radial and arcuate arteries showing pregnancy-induced changes (a loss of muscular and elastic tissue from their walls), which are morphological changes usually confined to the smaller spiral arteries.12,13 The early prenatal diagnosis of PA is based on the presence of characteristic findings on targeted ultrasound examination, whenever PA is suspected or in the presence of risk factors.14 Magnetic resonance imaging (MRI) is also effective in prenatal diagnosis, and is useful in the case of inconclusive findings.15 Sonographic signs suspicious of PA have been described as early as the first trimester in a highrisk population.16 Prenatal diagnosis of PA is critical to obstetric outcome, by enabling early arrangements for elective caesarean section and possible hysterectomy, and decreases PA-associated complications such as the need for the transfusion of blood products.17 In recent years we have had a clinical impression of a higher incidence of PA among women undergoing in vitro fertilization (IVF) treatment. No association between pregnancies achieved by assisted reproductive techniques (ART) and PA has been described in the literature. This study aimed to assess the hypothesis of increased incidence of PA among IVF pregnancies.

sampling of all placentas was performed by a perinatal pathologist (IA), according to the guidelines developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists,18 which provides general recommendations related to indications and methods for placental examination. Emphasis was put on sampling the mixed (intact and torn) areas of maternal surface, according to the method described by Khong and Werger.13 A similar number of slices (average five) was examined in clinically suspected PA in both groups. The original diagnosis was made on the basis of muscle fibres, and in cases of doubt immunochemistry staining for desmin was also performed. In cases of inconclusive results, immunochemistry and haematoxylin/eosin-stained slides were reviewed. All cases of complete as well as partial PA were included in the study. The study was approved by our institutional review board (Helsinki committee). We surveyed all placenta pathology reports performed during the study period and found 51 cases of histologically confirmed PA. We excluded one case in which the gestational age was 5 Previous uterine surgery (%) Caesarean section 0 1 >1 Other Miscarriages Curettage Previous placenta accreta Index pregnancy and delivery details Pregnancy (%) Single Multiple Maternal complications Fetal complications Placenta pathology visualized by ultrasound (%) Placenta praevia (complete, partial or marginal) Suspected placenta accreta Gestational age (weeks), mean ± 2 SE Mode of delivery (%) Vaginal Caesarean section Caesarean section + hysterectomy Fetal weight (g), mean ± 2 SE)

Spontaneous pregnancy n = 30

IVF n = 12


33.57 ± 1.31

37.83 ± 5.47


4 (13) 26 (87)

1 (8) 11 (92)


5 (17) 23 (77) 2 (6)

9 (75) 3 (25) 0


25 3 2 0 13 10 2

(83) (10) (7) (43) (33) (7)

29 (97) 1 (3) Hypertension n = 1

11 1 0 1 7 5 0

(92) (8) (8) (58) (42)

9 (75) 3 (25) Hypertension n = 1; gestational diabetes n = 2 IUGR* n = 1


0.4994 0.7260 1.0000


– –

4 (13) 1 (3) 38.03 ± 1.36

2 (17) 0 37.58 ± 1.64

1.0000 1.0000 0.2729

25 (84) 1 (3) 4 (13) 3151.97 ± 282.16

5 (42) 7 (58) 0 2712.83 ± 335.22



*IUGR, intrauterine growth restriction.


ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG

Placenta accreta is associated with IVF pregnancies

Table 3. Details of the treatment protocols received in the IVF group Case

1 2 3 4 5 6 7 8 9 10 11 12


IVF indication

Induction protocol

Endometrial thickness (cm/days before b-hCG)

30 43 44 31 49 35 35 40 28 31 59 29

Tubal factor Unexplained Male factor Unexplained Age Unexplained Male factor Unexplained Unexplained Anovulatory after failed COH Age

Short-antagonist Long OD Long OD Short-antagonist Frozen Long Frozen Frozen OD

0.65/2 1.1/1 0.7/8* 1.0/2 0.79/8* 0.73/0 0.87/4* 1.3/1 0.78/8*


Embryo transfer

Early pregnancy support


Day Day Day Day Day Day Day Day Day


5 3 3 3 3 3 3 3 5

+ + + + + + + + +


b-hCG, b subunit of human chorionic gonadotrophin; E + P, estrogen plus progesterone; ICSI, intracytoplasmic sperm injection; OD, ovum donor. *Number of days before embryo transfer.

group as most of these women were nulliparous. Only five women in 30 (17%) in the SP group and one woman in 12 (8%) in the IVF group had a previous caesarean delivery. One woman in the IVF group underwent uterine myomectomy. The miscarriage rate was higher in the IVF group, but this was not statistically significant (58 versus 43%; P = 0.49). Five of seven women in the IVF group (42%) that miscarried also underwent one or more curettage procedures, compared with ten of 13 who miscarried in the SP group (33%). Data concerning the miscarriages of the three remaining women in the SP group were unavailable; however, counting them either as having undergone curettage or not did not affect the statistical significance. Two women in the SP group had two events of PA in two different pregnancies. Another two women in this group had a previous event of clinically suspected PA that was not confirmed histologically. Regarding the index pregnancy and delivery parameters, in the IVF group there was a higher incidence of multiple pregnancies (three cases versus one in the SP group). The lower mean fetal weight in the IVF group (2713 g versus 3152 in the SP group) is statistically different. No significant difference was seen in mean gestational age at delivery between the groups. Maternal complications during the index pregnancy included hypertension in one woman in the IVF group and in one woman in the SP group, and gestational diabetes in two women in the IVF group. Fetal complications included one case of intrauterine growth restriction in the IVF group. Four women in the SP group and two in the IVF group had a sonographic diagnosis of placenta praevia (PP), and one woman in the SP group

was suspected to have PA before delivery (the detection rate of PA in our institution is similar to the known detection rate; however, most of the women in our study underwent ultrasonographic evaluation in other pregnancy care institutions). There was a statistically significant difference between the two study groups in the mode of delivery. Seven of 12 women in the IVF group (58%) underwent either elective or emergent caesarean delivery, as compared with 5/30 women in the SP group (16%). These data are in accordance with caesarean delivery rates in our hospital during the study period: 17% in the general population versus 50% in IVF pregnancies. Four women underwent hysterectomy: all of them were in the SP group and had had previous caesarean deliveries. Fifteen women among 42 (36%) required transfusion of packed cells and blood products. Among them, 13 women (11 in the SP group and two in the IVF group) consumed more than two units of packed cells. Fertility data and treatment protocols of the IVF group were retrieved from hospital files and are shown in Table 3. We have partial data of three women that were not treated in our hospital. Women in the IVF group were classified by indication for IVF (tubal factor, unexplained infertility, male factor, anovulatory after failed controlled ovarian hyperstimulation, and age-related infertility). The 12 patients in the study group underwent ART treatment as follows: three were treated with a long protocol; two had a short antagonist; three had a frozen–thawed transfer; and three had a transfer of ovum-donation embryos. The IVF protocols were standard ART protocols.19 Endometrial lining thickness was recorded. All

ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG


Esh-Broder et al.

patients were treated with luteal phase progesterone, as well as estrogen support. The support was ceased upon completion of the first trimester.

Discussion and conclusion According to our data, the odds ratio for developing PA is markedly higher in IVF pregnancies compared with SPs. To the best of our knowledge, this is the first report of such a phenomenon. The overall incidence of PA in our hospital shown in this study was 42/25 193 (0.167%), and is similar to that described in studies published over the last two decades.7 We included only PA cases diagnosed clinically and proved histologically. These strict inclusion criteria enable us to avoid sources of bias, and are therefore preferable to relying on only one criterion, clinical or histological. The inclusion of only these cases is consistent with the recently standardised histologic definition of PA, which only defines an accreta when a suitable clinical presentation matches the histological findings 13. The relative rarity of PA dictated the small study size. Our strict inclusion criteria further decreased it, but prevented potential biases, ensuring its reliability. Recognised risk factors and other parameters were examined. Among all the variables examined, three were found to be statistically significant: parity, incidence of caesarean delivery in the index pregnancy and fetal weight. Parity was significantly lower in the IVF group, as expected: this should have reduced the incidence of PA in this group, and therefore strengthens our findings. The high CS rate in the index pregnancy in the IVF group is similar to the CS rate in the IVF population at our hospital, and would not influence PA incidence or diagnosis. Fetal weight was significantly lower in the IVF group, secondary to the higher incidence of multiple pregnancies in this group; however, this factor is not recognised as a risk factor for PA. There were no other significant differences in the demographic, obstetric and risk factors examined. The slightly higher maternal mean age in the IVF group was not statistically significant. The higher incidence of PP after ART, described in previous studies,20,21 could not explain our findings, despite its known association with PA, because the incidence of PP in our study did not differ significantly between the two groups (4/30 in the SP group and 2/12 in the IVF group). The possible pathogenesis of PA includes a mechanical factor (primary deficiency of decidua caused by local trauma to the uterine wall) and a biological factor (abnormal maternal response to trophoblast invasion). In our study groups, all four women who underwent hysterectomy had had previous caesarean sections, supporting the notion that ‘mechanical’ PAs are predisposed to more severe out-


comes. Nevertheless, biological PAs, although milder in clinical presentation, are not free of complications. In our study 13 women with PA consumed at least two units of packed cells after delivery, and among these nine could be categorised as biological PA, as they had no previous uterine surgeries. Our findings support the existence of biological factor(s) in PA formation that are not coincidental. The early recognition or higher index of suspicion could therefore enable proper preparation, and improve such outcomes in the ‘biological’ cases. The main question remains, therefore, as to the reason for this observed higher incidence of PA among the IVF population. Differences may stem from alterations in the endometrial environment of the IVF patient population. This notion is partially supported by the high proportion of unexplained infertility cases among our patients, as compared with the general IVF population in our IVF unit. However, some of the patients in the IVF study group could not be presumed to suffer from endometrial problems, as their indication for IVF was male factor or anovulation. Another hypothesis may attribute the higher incidence of PA in IVF patients to the treatment protocols. Previous studies have shown that the stimulation protocols in IVF induce morphological and structural changes, and disturb the expression of relevant genes in the endometrium; such changes could contribute to abnormal implantation.22 This cannot explain the phenomenon in all patients in the IVF study group, as some patients underwent frozen–thawed embryo transfer or ovum donation cycles without ovarian stimulation. Another factor that could theoretically influence implantation and early embryo development is the fertilisation and embryo culture in vitro that, as described before, can change key metabolic pathways in the embryo.23 Scrutinizing the endometrial environment in the first week of pregnancy, when implantation occurs, the main difference between IVF and spontaneous pregnancies is the hormonal support routinely given to women in the IVF group. During the study period women treated in our IVF unit received estrogenic and progestative support in the first 10–12 weeks of pregnancy [usually Estrofem (estradiol; Novo Nordisk, Begsraerd, Denmark), 2 mg three times daily orally, and Utrogestan (micronised progesterone; Ferring Pharmaceuticals Ltd, Saint-Prex, Switzerland) 400 mg twice daily intravaginally]. In mice, it has been demonstrated that different doses of exogenous estrogen influenced the duration of the window of implantation;24 therefore, we may speculate that the hormonal support of estrogen in addition to the progesterone given in the first 10 weeks of pregnancy to IVF patients might have an adverse effect on implantation, and may play an important role in the pathological implantation

ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG

Placenta accreta is associated with IVF pregnancies

seen in this study. Further studies are needed to explore the influence of hormonal administration in the peri-implantation period on parameters important for the adherence of the placenta to the uterine wall. In conclusion, we present here for the first time a markedly higher incidence of PA in IVF pregnancies. Larger studies are needed to confirm this finding and elucidate its causes. Nevertheless, IVF pregnancies should be considered as being associated with a higher risk of PA. We therefore recommend considering a targeted ultrasound survey of IVF pregnancies prior to delivery, as well as a higher level of suspicion when managing complications in the third stage of delivery in this population.

Disclosure of interest None.

Contribution to authorship EE-B coordinated the study, assisted in chart review, and prepared the article. IA examined placentas and participated in article preparation, NA-B assisted in chart review, YB assisted in chart review, and reviewed and commented on the manuscript draft, DHC coordinated the study and prepared the manuscript.

Details of ethics approval Our institutional ethical review board (Helsinki committee) at Hadassah Medical Center, Jerusalem, Israel, reviewed the protocol and approved this study. Date of approval: 11 December 2009; ref. no. 204-11.12.09.

Funding None.

Acknowledgement None. j

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