To examine associations with morbidly adherent placenta (MAP) among women with placenta previa.
Women with MAP (cases) and previa alone (controls) were identified from a cohort of 236 714 singleton pregnancies with both first and second trimester prenatal screening, and live birth and hospital discharge records; pregnancies with aneuploidies and neural tube or abdominal wall defects were excluded. Logistic binomial regression was used to compare cases with controls.
In all, 37 cases with MAP and 699 controls with previa alone were included. Risk for MAP was increased among multiparous women with pregnancy-associated plasma protein-A (PAPP-A) ⩾95th percentile (⩾2.63 multiple of the median (MoM); adjusted OR (aOR) 8.7, 95% confidence interval (CI) 2.8 to 27.4), maternal-serum alpha fetoprotein (MS-AFP) ⩾95th percentile (⩾1.79 MoM; aOR 2.8, 95% CI 1.0 to 8.0), and 1 and ⩾2 prior cesarean deliveries (CDs; aORs 4.4, 95% CI 1.5 to 13.6 and 18.4, 95% CI 5.9 to 57.5, respectively).
Elevated PAPP-A, elevated MS-AFP and prior CDs are associated with MAP among women with previa.
Morbidly adherent placenta (MAP), including placenta accreta, increta and percreta, is characterized by failure of the placenta to separate at delivery, with potential for significant perinatal and maternal morbidity and mortality.1 Once rare, with an average reported occurrence of 1 in 7000 deliveries during the century preceding 1972,2, 3 placenta accreta occurrence has risen steadily4 to 1 in 533 between the years 1982 and 2002.5 This ~13-fold increase parallels the increase in cesarean delivery (CD).1 When prior CD is combined with placenta previa, the risk for accreta increases with each prior CD, from 11 to 40%, 61 and 67% for one, two, three and four prior CDs, respectively.6
While multiple risk factors for MAP have been described7, 8, 9, 10, 11, 12, 13, 14, 15 mechanisms of accreta development remain opaque and pre-delivery prediction is limited. Proposed mechanisms of accreta include excessive trophoblast invasion into the myometrium,16, 17 deficient decidua enabling placental implantation onto the myometrium,18 suggested by increased accreta risk with previa alone,19 and a combination of both.20, 21
Antenatal diagnosis of accreta is critical, as it can reduce maternal morbidity by enabling for a scheduled delivery22 by a multidisciplinary team in a tertiary care center.23 Ultrasound identifies many, but not all, women with MAP, and without significant benefit from magnetic resonance imaging.24, 25 Elevated serum markers second trimester maternal-serum alpha fetoprotein (MS-AFP)26, 27, 28, 29 and beta-human chorionic gonadotropin28, 29 have been associated with MAP. Low first trimester pregnancy-associated plasma protein-A (PAPP-A), a zinc metalloproteinase implicated in local proliferation,30 is associated with adverse pregnancy outcomes related to poor placental invasion;31, 32, 33 its overexpression could plausibly be associated with abundant placental invasion and MAP. While not thought to be associated with adverse obstetrical outcomes,34 elevated PAPP-A was recently reported among women with accreta in a small, retrospective study.35
Our objective was to examine the strength of the associations between routinely collected first and second trimester maternal serum markers and maternal and obstetric characteristics with MAP among a large population-based cohort of women with placenta previa to aid in pre-delivery prediction of MAP.
Our study sample was drawn from all singleton pregnancies undergoing first and second trimester prenatal serum screening through the California Prenatal Screening Program with expected delivery between December 2009 and May 2010. Women were included if they also had linked live birth and hospital discharge records in a birth cohort database maintained by the Office of Statewide Health Planning and Development, a diagnosis of placenta previa based on ICD-9 codes (ICD-9 641.0 or 641.1) or linked records, and underwent cesarean delivery (CD). Women were considered to have MAP if they had ICD-9 codes for both placenta previa and retained placenta (ICD-9 666.0, 666.2 and/or 667.1). Women were excluded if their fetuses had chromosomal abnormalities or neural tube or abdominal wall defects.
Maternal serum analytes included first trimester PAPP-A and total human chorionic gonadotropin (hCG), collected between 10 weeks 0 days and 13 weeks 6 days gestation, and second trimester MS-AFP, hCG, unconjugated estriol (uE3) and dimeric inhibin A (INH), collected between 15 weeks 0 days and 20 weeks 0 days gestation. All analytes were measured on automated equipment (Auto DELFIA, Perkin-Elmer Life Sciences, Waltham, MA, USA and Applied Biosystems, Brea, CA, USA) and results were entered directly into the State’s database. All analyte multiple of the median (MoM) values were adjusted for gestational age, maternal weight, race/ethnicity, smoking status and pre-existing diabetes. Biomarker MoM percentiles were calculated based on the entire screened population (n=236 714).
Maternal and obstetric variables including body mass index (BMI), parity, prior CD, history of prior preterm birth and interpregnancy interval (IPI) were obtained from the linked live birth and hospital discharge records. BMI was calculated using height and pre-pregnancy weight. IPI was calculated from the date of the previous live birth (month and year) to the conception of the index pregnancy. Procedures and labor and delivery complications were obtained from live birth and hospital discharge records, and birth weight and gestational age at delivery were obtained from GDSP (Genetic Disease Screening Program) prenatal and newborn screening records.
Analyses utilized logistic binomial regression methods to estimate odds ratios (ORs, Tables 1 and 2). To measure associations between serum markers or maternal characteristics and MAP, calculations were performed with the following pre-defined referent groupings: biomarker MoMs between the 6th and 94th percentile, White race/ethnicity, maternal age 18 to 34 years, normal BMI (18.5 to 24.9), non-diabetic, non-smoker and parity=1. Among women with parity ⩾2, referent groups included those without a prior preterm birth and an IPI of 24 to 59 months. Final models were built using backwards stepwise logistic regression populated with maternal characteristics and biomarkers with crude OR findings P<0.10, and were stratified by parity after current birth =1 and ⩾2. (Table 3) The predictive performance of variables (isolated and co-occurring) found to be significantly associated with MAP was also calculated.
All analyses were conducted using Statistical Analysis Software (SAS) version 9.3 (Cary, NC, USA) and were based on data received by the screening program as of 31 March 2013. The study was approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California.
Thirty-seven women with previa and MAP and 699 women with previa alone were identified from a population of 236 714 women (Figure 1) and included in this analysis. Maternal and obstetric demographics and characteristics are shown in Table 1. The greatest proportion of the population was Hispanic (45.9%), age 18 to 34 years (51.6%), of normal weight (52.2%), non-diabetic (88.6%), non-smoking (98.6%) and multiparous (63.9%). Of multiparous women, 46% had a prior CD and 37% had an IPI of 24 to 59 months. Women with MAP were more likely to be ⩾35 years old (OR 2.0, 95% CI 1.0 to 4.1, P<0.05), overweight (OR 2.2, 95% CI 1.0 to 4.9, P<0.05) or obese (OR 2.7, 95% CI 1.1 to 6.7), diabetic (OR 2.3, 95% CI 1.0 to 5.1) and multiparous (OR 2.5, 95% CI 1.1 to 5.8). Among multiparous women, prior CD was a risk for MAP (OR 6.4, 95% CI 2.4 to 17.1), and risk increased with increasing numbers of prior CDs (OR 3.7, 95% CI 1.3 to 10.9 for 1 prior; OR 15.0, 95% CI 5.2 to 43.8 for ⩾2 prior). Racial/ethnic differences were not observed.
Maternal serum analyte values are shown in Table 2. PAPP-A ⩾95th percentile and MS-AFP ⩾95th percentile were associated with MAP (PAPP-A MoM ⩾2.63, OR 3.4, 95% CI 1.3 to 8.6; MS-AFP ⩾1.79 MoM, OR 3.2, 95% CI 1.3 to 7.7) while hCG (first and second trimester), uE3 and INH were not. Analyte values were based on the entire screened population. Analyte values for the entire screened population were similar to those of the included population, at ⩽5th and ⩾95th percentiles, as follows: PAPP-A: 0.38 and 2.63 vs. 0.39 and 2.56; hCG: 0.50 and 2.00 vs. 0.51 and 1.95; AFP: 0.60 and 1.79 vs. 0.60 and 1.67; hCG: 0.41 and 2.28 vs. 0.41 and 2.16; uE3: 0.63 and 1.40 vs. 0.63 and 1.42; and INH: 0.54 and 2.14 vs. 0.54 and 1.99.
When final logistic models were created, stratified by parity and adjusted with maternal characteristics and biomarkers that had crude OR findings of P<0.10 (Table 1), no significant risk factors for MAP were identified for nulliparous women. For multiparous women, risk for MAP increased nearly ninefold when PAPP-A MoM was ⩾95th percentile (aOR 8.7, 95% CI 2.8 to 27.4) and nearly threefold when MS-AFP MoM was ⩾95th percentile (aOR 2.8, 95% CI 1.01 to 8.0) (Table 3).
Prior CD independently increased the risk for MAP (1 prior: aOR 4.4, 95% CI 1.5 to 13.6), with the strongest risk found among women with ⩾2 prior CDs (aOR 18.4, 95% CI 5.9 to 57.5). Maternal age, weight and diabetes were no longer independently associated with MAP in the final logistic models. MAP occurred among 1.8% of multiparous women without a prior CD and with normal serum analytes. With one prior CD, MAP occurred among 5.2% (relative risk 2.8, 95% CI 0.8 to 9.4) when serum analytes were normal versus 42.9% (relative risk 23.5, 95% CI 6.4 to 85.6) when PAPP-A was also elevated. Among women with ⩾2 two prior CDs, MAP occurred among 16.3% (relative risk 18.9, 95% CI 2.8 to 28.5) when serum analytes were normal versus 66.7% when PAPP-A was also elevated (relative risk 36.3, 95% CI 10.4 to 128.4) and 50% when MS-AFP was elevated (relative risk 27.4, 95% CI 8.3 to 90.2). The positive and negative predictive values for MAP in the setting of ⩾two prior CDs were 16.3 and 94.8; in the setting of ⩾2 prior CDs and PAPP-A⩾95th percentile, 66.7 and 94.0; and in the setting of ⩾2 prior CDs and MS-AFP ⩾95th percentile, 50.0 and 94.4.
Of the 699 women diagnosed with previa alone, 9 (1.3%) underwent cesarean hysterectomy and 244 (34.9%) experienced hemorrhage. Of the 37 women diagnosed with MAP, 23 (62.2%) underwent cesarean hysterectomy and 32 (86.5%) experienced hemorrhage. There were no maternal or neonatal deaths.
We found that among multiparous women with placenta previa, first trimester PAPP-A values greater than 2.63 MoM conferred a nearly 9-fold increased risk of MAP overall independent of prior CDs, and a 23- and 36-fold increased risk for MAP in the setting of one and two prior CDs, respectively. As expected, prior CD and elevated MS-AFP were associated independently with MAP.
Advanced prediction of accreta is important to optimize outcomes through scheduled preterm delivery23 in a tertiary care center.36 Among women with previa, elevated PAPP- A should be considered, in addition to risk factors such as elevated MS-AFP and prior CD, to help identify women at increased risk for MAP. The high specificities and negative predictive values of these risk factors may also help stratify high-risk women who are less likely to have MAP. While elevated PAPP-A, as well as MS-AFP, should be validated prospectively before becoming a part of standard assessment of MAP risk, our data support the value of examining maternal serum analytes to inform risk of MAP among multiparous women. Why maternal serum biomarkers and other risk factors were not predictive of MAP among nulliparous women with previa is less clear, and may be a function of the lower prevalence of MAP among nulliparous women and a relatively small sample size (n=7) in our study cohort.
PAPP-A is novel zinc metalloproteinase produced by placental syncytiotrophoblasts, secreted into the maternal circulation in increasing concentrations until term;37 its function is not well understood.30 PAPP-A is responsible for proteolysis of IGF from IGFBP-4,38 implying a role in growth. Low PAPP-A has been associated with poor placental invasion with placental insufficiency, intrauterine growth restriction, preeclampsia, stillbirth, abruption and premature birth.32, 39, 40 Elevated PAPP-A could plausibly be implicated in excessive placental invasion. Desai et al.35 recently reported higher median PAPP-A values among 16 women with accreta (1.68 MoM) compared with 82 women with previa alone (0.98 MoM); PAPP-A values of 3 MoM and above were associated with an unadjusted 4-fold increased risk accreta. We adjusted for potential confounding variables and found much higher associations between PAPP-A and MAP among multiparous women. This also suggests a role for excessive trophoblast invasion as a mechanism for accreta. Whether PAPP-A levels continue to rise disproportionately in the second and third trimesters among women with MAP is one area for future investigation.
Elevated maternal serum AFP in the setting of a non-anomalous fetus has previously been shown to be associated with placenta accreta26, 27, 28, 29 potentially due to placental impairment, with breakdown of the fetal–maternal–placental interface.29, 41 We similarly found an association between elevated MS-AFP and placenta accreta. Women with AFP greater 1.79 MoM, the 95th percentile, independently experienced a nearly 3-fold increased risk for placenta accreta.
The incidence of MAP in our study was far lower than the 1/533 incidence of accreta reported in the general population.5 There are several possible explanations. Our study was based on a large data set that relied on medical billing codes for the diagnosis of MAP; we lacked access to surgical or pathologic records for confirmation. Without an ICD-9 code for placenta accreta, we took a conservative approach to ensure that cases would be expected to carry a diagnosis of MAP. We excluded women who were not delivered by CD and women who did not have a previa, and included women with a code for adherent placenta. Our approach appears to have resulted in our missing some cases of accreta, which may limit the generalizability of our findings. However, we created a study cohort that experienced significant pathology related to MAP, as 87% hemorrhaged. We excluded pregnancies affected by neural tube defects, abdominal wall defects and aneuploidy, but due to constraints of coding were unable to exclude more rare conditions potentially associated with elevated MS-AFP such as urogenital malformations. Given the rare nature of these conditions, this lack of exclusion is unlikely to have altered our results.
Despite its limitations, our uniquely large, linked data set allowed us to explore maternal serum markers and maternal characteristics among women with placenta previa to identify the relatively novel associations of increased PAPP-A with MAP. Women with placenta previa and prior CD should undergo careful ultrasound examination for signs for accreta. When PAPP-A is elevated in a multiparous woman with placenta previa, a careful ultrasound examination of the placental-uterine interface should also be considered. Future research should explore the combination of ultrasound examination with maternal serum biomarkers to predict placenta accreta.
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This study was supported by California Genetic Disease Screening Program (GDSP) and California Office of Statewide Health Planning and Development, Richmond CA. Dr Lyell received support from the Arline and Pete Harman, Children's Health Research Institute fund at Lucile Packard Children's Hospital at Stanford. This study was presented at the Society for Maternal-Fetal Medicine Annual Meeting on 6 February 2014 in New Orleans, LA.
The authors declare no conflict of interest.
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Lyell, D., Faucett, A., Baer, R. et al. Maternal serum markers, characteristics and morbidly adherent placenta in women with previa. J Perinatol 35, 570–574 (2015). https://doi.org/10.1038/jp.2015.40
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