Does Endometriosis Affect PAPP-A Concentration in First Trimester Fetal Screening Test?

Abstract

Objective

Pregnancy-associated plasma protein A (PAPP-A) is a macromolecular glycoprotein. The peritoneal fluid of women affected by endometriosis shows a significant increase of PAPP-A levels. Given the important role of PAPP-A in first trimester screening test, we wondered if its presence in the peritoneal fluid of women with endometriosis could affect biochemical parameters of the test performed during pregnancy.

Methods

A prospective study enrolled 78 women with singleton pregnancy who performed combined test between 11 + 0 and 13 + 6 weeks of gestation: 25 women with previous histological diagnosis of endometriosis and 53 women without. All patients were sampled to determine PAPP-A concentrations. Serum levels of PAPP-A were expressed in UI/L and in MoM (multiples of median). The two groups – endometriosis women and non-endometriosis women – were compared in order to find a possible different concentration of serum PAPP-A.

Results

We found an increased concentration of both PAPP-A UI/L and PAPP-A MoM in deep endometriosis patients versus ovarian endometriosis with significant difference in PAPP-A MoM (p = 0.018).

We also found a significant association between the stage of the disease and PAPP-A UI/L and MoM levels (PAPP-A UI/L p = 0.05, PAPP-A MoM p = 0.01).

Conclusions

Women with deep endometriosis show increased serum PAPP-A concentrations compared to women with ovarian endometriosis. Likewise, women with moderate or severe stage of the disease show increased serum PAPP-A concentrations compared to women with minimum or mild disease. This increase could affect first trimester aneuploidy screening test and endometriosis could represent a confounding factor in the calculation of aneuploidy risk.

Keywords

Endometriosis First trimester screening Pregnancy-associated plasma protein

Introduction

Pregnancy-associated plasma protein A (PAPP-A) is a trophoblastic, macromolecular glycoprotein, metalloproteinase, that belongs to the super-family of zinc proteases. PAPP-A was isolated for the first time in 1974 from serum obtained from pregnant woman (1). Detection of this protein in the serum circulation is specific of pregnancy, plasma concentration is detectable from the fifth week of gestation and it is produced in increasing concentrations with a peak at delivery (2). Maternal serum PAPP-A has prognostic value in first trimester screening test for aneuploidies in combination with maternal age, free beta-human chorionic gonadotropin (free beta-hCG) and fetal nuchal translucency (NT) measurements (3-4-5). Several studies indicate an association between abnormal PAPP-A levels and some adverse perinatal and birth outcomes. In fact, low first trimester PAPP-A relates to preterm birth, early onset preeclampsia, intrauterine growth retardation and threatened abortion (6-7-8-9-10-11-12); high first trimester PAPP-A relates to placenta accreta (13). PAPP-A has been considered as a marker of oxidative stress that could be responsible in the pathogenesis of several important adverse perinatal outcomes due to placental insufficiency like preeclampsia and intrauterine growth retardation (14-15-16-17-18-19-20-21-22-23-24-25). As marker of preeclampsia, PAPP-A in combination with other biomarkers and maternal characteristics was considered a more reliable prognosticator than PAPP-A alone (26). Serum PAPP-A concentration can be influenced by several factors such as method of conception, ethnicity, maternal weight, gestational age, smoking status.

Although it has been studied mainly in pregnancy, PAPP-A was identified in serum of non-pregnant patients as well, in colon, kidney, in human ovary in granulosa cells, in myometrium and in endometrial tissue (27). It has been observed that in multiple species PAPP-A plays a role in the processes of dominant follicle development, ovulation and luteogenesis. In particular, PAPP-A expression in ovary is limited to dominant follicles and the corpus luteum (28-29-30-31-32-33-34).

In 2014 Wang et al (35) studied the relationship between PAPP-A and progesterone and the role of PAPP-A on embryo adhesion and proliferation. They demonstrated that PAPP-A secretion is regulated by progesterone which fosters embryo adhesion and trophoblastic cell proliferation. It was also shown that serum progesterone level and PAPP-A are tightly related. They assumed that PAPP-A may play a role in implantation and development of embryo thus it could be taken into account as a new diagnostic marker to assess embryo quality.

Arici et al (36) reported that peritoneal fluid levels of PAPP-A change through the menstrual cycle and peak during the secretory phase, suggesting that the mechanism controlling the extratrofoblastic PAPP-A secretion is progesterone related. They also found that PAPP-A levels were significantly increased in peritoneal fluid of women with endometriosis and this increase relates to the extent of disease. Moreover, Bersinger et al (37), in 2006, have determined the concentrations of PAPP-A in the peritoneal fluid collected from patients undergoing laparoscopy. Their study showed that PAPP-A concentrations were markedly increased in peritoneal fluid of women affected by endometriosis in proportion to disease severity. Authors concluded that PAPP-A may be one of the factors involved in endometriosis inflammatory process. Scholl et al (38), in 2009 confirmed earlier hypothesis by demonstrating higher PAPP-A concentrations in the peritoneal fluid during laparoscopic interventions for endometriosis.

In literature, so far no studies have determined the concentrations of PAPP-A in the serum of women with endometriosis.

Given the important role of this protein in the first trimester screening test, we wondered if the presence of PAPP-A in peritoneal fluid of women affected by endometriosis could influence the biochemical parameters in the calculation of aneuploidy risk. Therefore, the purpose of this work is to assess the concentration of serum PAPP-A in patients with endometriosis undergoing first trimester screening test compared to that of non-endometriosis women.

Materials and methods

A prospective study was designed to assess the serum PAPP-A level in pregnant women affected by endometriosis during the first trimester of pregnancy. The study involved women with singleton pregnancy that have received a combined first trimester screening test at the Unit of Prenatal Diagnosis, Policlinico Tor Vergata, Rome, between August 2010 and March 2016. All women who had reported gynecological laparoscopies 12 months before were included in the study and were requested to show documentation of their surgery. The ultrasound examination was performed by sonologists accredited for first-trimester screening using a Voluson E6 ultrasound machine (GE Healthcare, Italy) fitted with a transabdominal 3.5 Mhz convex probe. The measurement of nuchal translucency (NT) and crown-rump length (CRL) was performed between 11 + 0 and 13 + 6 weeks as recommended by Fetal Medicine Foundation (FMF). A kit for Brahms Kriptor assay was used to measure maternal serum PAPP-A. Serum levels of PAPP-A are expressed in UI/L and in MoM (multiples of median), determined from CRL measurement at ultrasound scan, maternal weight, smoking status, racial origin, parity and method of conception. MoM value provides more reliable results since it eliminates these confounders. Pregnant women were divided in two groups: endometriosis group (E: women with a histological diagnosis of endometriosis after surgery) and non-endometriosis group (NE: patients undergoing laparoscopy for other reasons, without a histological diagnosis of endometriosis after surgery). Before participation in the study, all patients were asked to express their informed consent. The two groups were compared based on maternal characteristics (age, height, weight, BMI, gestational week, parity, smoking and racial origin), fetal ultrasonographic findings (NT) and biochemical markers (PAPP-A IU/L, PAPP-A MoM, beta-hCG UI/L and beta-hCG MoM). All the blood samples were addressed to a single laboratory. All patients included in the study were followed during pregnancy. Exclusion criteria were: in vitro fertilization pregnancy, multiple pregnancy, pregnancy complication that might be associated with abnormal PAPP-A (hypertensive disorder), fetal demise, fetal NT >95^th percentile, fetus with structural or chromosomal abnormalities and lack of documentation of the surgery.

Statistical Analysis

An EXCEL database (Microsoft, Redmond, Washington – USA) was created and initially fed with all data. Subsequently, analysis was performed using the Statistical Package for the Social Sciences Windows, version 15.0 (SPSS, Chicago, Illinois, USA). Descriptive statistics consisted of the mean ± standard deviation for parameter with Gaussian distributions (after confirmation with histograms and the Kolmogorov-Smirnov test) or frequencies (%) for occurrences. Comparison of variables continuous and Gaussian was performed with one-way ANOVA. Post hoc multiple comparisons were performed by Bonferroni test. Comparison of frequencies among groups was performed with chi-Square test or Fisher's exact test (if cells >5) for categorical variables. A p value of <0.05 was considered statistically significant.

Results

Overall, 78 patients were enrolled in the study: 25 women with histological diagnosis of endometriosis and 53 women without. All patients were of Caucasian ethnicity and we found no statistically significant difference between the two groups in relation to maternal age, weight, height, BMI, gestational age, parity and smoking status (Tab. I).

Table I

Maternal characteristics in the two groups

	Group E Mean ± SD (n = 25)	Group NE Mean ± SD (n = 53)	p value
^a ANOVA test
^b Chi square test
E = endometriosis group; NE = non-endometriosis group.
Maternal age (years)	31.7 ± 2.4	30.6 ± 3.4	0.465^a
Weight (kg)	61.4 ± 11.4	64.2 ± 10.8	0.890^a
Height (m)	165.6 ± 7.8	165.3 ± 6.8	0.597^a
BMI (h²/kg)	22.4 ± 4.1	23.5 ± 3.6	0.886^a
Gestational age (weeks)	12.7 ± 0.5	12.5 ± 1.5	0.403^a
Smoke (%)	2/25 (8.6%)	7/53 (13.2%)	0.502^b
Nulliparous (%)	16/25 (64%)	31/53 (58.5%)	0.472^b

No patient had active ultrasound-detectable endometriosis when the combined first trimester screening test was performed.

Based on the localization of endometriosis, we divided endometriosis patients in two different groups: 21 patients with ovarian endometriosis “O” who received surgery for isolated endometrioma and 4 patients with deep endometriosis “DE” who received surgery for deep endometriosis with or without endometrioma.

Based on the stage of endometriosis, we divided the endometriosic patients in 4 groups as AFSr classification of pelvic endometriosis, 1996: minimal, mild, moderate and severe. Of the 25 endometriosis patients, only in 18 cases was it possible to establish disease stage with reasonable certainty (minimal: 7 patients, mild: 7 patients, moderate: 2 patients, severe: 2 patients).

The groups were compared according to nuchal translucency (NT) and biochemical parameters, PAPP-A concentration (UI/L), PAPP-A MoM, free beta-hCG concentration (UI/L) and free beta-hCG MoM (Tab. II).

Table II

Results of nuchal translucency (NT) and biochemical parameters between the two groups

	Group E Mean ± SD (n = 25)	Group NE Mean ± SD (n = 53)	p value^a
E = endometriosis group; NE = non-endometriosis group; PAPP-A = pregnancy-associated plasma protein A; BhCG = beta-human chorionic gonadotropin; MOM = multiples of median.
^a ANOVA test.
NT (mm)	1.53 ± 0.33	1.66 ± 0.42	0.225
PAPP-A (UI/L)	4.24 ± 2.09	3.69 ± 1.83	0.215
PAPP-A MOM	1.30 ± 0.68	1.29 ± 0.59	0.609
Free BhCG (UI/L)	51.77 ± 33.50	40.08 ± 21.15	0.022
Free BhCG MOM	1.26 ± 0.70	1.10 ± 0.80	0.468

Both the plasma concentration of PAPP-A and free beta-hCG, expressed in UI/L are greater in the group of women affected by endometriosis (PAPP-A: E = 4.24 ± 2.09 UI/L vs. NE = 3.69 ± 1.83 UI/L; free beta-hCG: E = 51.77 ± 33.50 UI/L vs. NE = 40.08 ± 21.15 UI/L). The statistical analysis shows that the PAPP-A difference was not significant (PAPP-A UI/L p = 0.215, PAPP-A MoM p = 0.609), the free beta-hCG UI/L difference was significant (p = 0.02) but not significant when it is converted in MoM (p = 0.468) (Tab. II, Fig. 1).

Fig. 1

Maternal serum Papp-A (MoM), free beta-hCG (MoM), Papp-A and free Beta-hCG in patients with endometriosis (E) and without endometriosis (NE).

We found an increased concentration of both PAPP-A UI/L (O = 3.91 ± 1.76 vs. DE = 5.91 ± 3.06, p = 0.078) and PAPP-A MoM (O = 1.16 ± 0.51 vs. DE = 2.02 ± 1.09, p = 0.018) in deep endometriosis patients versus ovarian endometriosis with a significant difference in PAPP-A MoM (p = 0.018). Despite the small sample of our study (25 endometriosis patients: O = 21 patients, DE = 4 patients) the high significance, p = 0.018, suggests that the correlation is effective (Tab. III, Fig. 2).

Table III

Results of PAPP-A in UI/L and MoM between the two groups

	Group O Mean ± SD (n = 21)	Group DE Mean ± SD (n = 4)	p value^a
O = ovarian endometriosis group; DE = deep endometriosis group; PAPP-A = pregnancy-associated plasma protein A; MOM = multiples of median.
^a ANOVA test.
PAPP-A (UI/L)	3.91 ± 1.76	5.91 ± 3.06	0.078
PAPP-A MOM	1.16 ± 0.51	2.02 ± 1.09	0.018

Fig. 2

Error bar PAPP-A MoM mean ± 1 in patients with ovarian and deep endometriosis.

We also found a significant correlation between the stage of the disease and PAPP-A UI/L (stage minimal = 2.76 ± 1.14 vs. mild stage = 4.38 ± 1.64 vs. moderate stage = 6.86 ± 3.25 vs. severe stage = 7.39 ± 0.28, p = 0.05) and MoM levels (stage minimal = 0.93 ± 0.45 vs. mild stage = 1.29 ± 0.26 vs. moderate stage = 2.37 ± 1.27 vs. severe stage = 2.62 ± 0.16, p = 0.01). PAPP-A levels increase with the stage of the disease. Also for these findings, high significance suggests that, despite the small sample of endometriosis patients, the correlation is effective (Tab. IV, Fig. 3).

Table IV

Results of PAPP-A in UI/L and MoM between the four groups

	Stage 1 Minimal Mean ± SD (n = 7)	Stage 2 Mild Mean ± SD (n = 7)	Stage 3 Moderate Mean ± SD (n = 2)	Stage 4 Severe Mean ± SD (n = 2)	p value^a
PAPP-A = pregnancy-associated plasma protein A; MOM = multiples of median.
^a ANOVA test.
PAPP-A (UI/L)	2.78 ± 1.14	4.3786 ± 1.64	6.86 ± 3.25	7.39 ± 0.28	0.005
PAPP-A MOM	0.93 ± 0.45	1.29 ± 0.26	2.38 ± 1.27	2.62 ± 0.16	0.001

Fig. 3

PAPP-A MoM variation in minimal, mild, moderate and severe endometriosis.

There were no significant differences between the groups with regard to the values of NT.

We also noticed that in our population PAPP-A MoM values seem to decrease with the number of previous miscarriages not only in patients affected by endometriosis but also in controls (Fig. 4). This decrease seems to be less important in the endometriosis group than in controls; however, this gap is not statistically significant (p = 0.856) (Fig. 5).

Fig. 4

Scatter plot graphs. PAPP-A MoM values and number of previous miscarriages in patients with endometriosis (E) and without endometriosis (NE).

Fig. 5

Scatter plot graphs. PAPP-A MoM values and number of previous miscarriages in patients with endometriosis (E) and without endometriosis (NE).

Based on obstetrical outcome, we tested the population for diabetes, premature preterm rupture of membranes, preterm delivery, small for gestational age, large for gestational age, operative delivery, Cesarean section, Apgar score, postpartum maternal complications, postpartum fetal complications.

We did not find any differences in pregnancy or delivery or postpartum maternal complications between the two groups.

Unexpectedly, we found significant postpartum fetal complications in the endometriosis group (E = 43.8% vs. NE = 8.3%, p = 0.009, Fisher's exact test = 0.013). We gathered data on neonatal outcome of 40 women, 16 with endometriosis and 24 without. Of the 16 endometriosis patients, 7 reported fetal complications (43.8%). Mostly two types of complications occurred: malformation diseases (macrocrania with psychomotor retardation, Hirschsprung disease, persistence of right umbilical vein) and inflammatory disease-like infections.

Discussion

An excessive immune response appears to be involved in the pathophysiological mechanism of endometriosis. Studies have shown increased concentration of several inflammatory markers in the peritoneal fluid of women with endometriosis. These markers seem to affect both the development and progression of endometrial peritoneal implants (36-37-38-39-40-41). One of these markers is the PAPP-A, whose biological function is still unknown though it is shown to carry out several functions including embryo adhesion, proliferation of trophoblastic cells (35) and tolerance of the fetus by the maternal immune system. PAPP-A seems also to be released by endometrial and ovarian cells with a progesterone-related secretion (42, 43), which may explain its concentrations in peritoneal fluid of patients affected by endometriosis and its correlation with the disease stage and endometrial peritoneal implants volume (36).

Since PAPP-A is known to be a protein whose secretion depends on progesterone, we wondered why its levels are increased in endometriosis, which is an estrogen-related disease, while progestogens should mitigate it. If PAPP-A secretion was solely progesterone-related, endometriosis should not determine its increase. Correlation between PAPP-A levels, disease extent and disease localization suggests that PAPP-A secretion might be triggered by something other than progesterone, possibly inflammation.

PAPP-A secretion seems to be related to:

Hormonal stimulation, due to progesterone. This could explain its high values in pregnancy and in the secretive phase of menstrual cycle;

Inflammation. This could explain its high concentration in peritoneal fluid of patients affected by endometriosis, its role as a marker of oxidative stress in the pathogenesis of adverse perinatal outcomes due to placental insufficiency and its correlation with the presence of a dominant follicle and ovulation.

Increased risk of Down Syndrome.

In our study we measured the amount of serum PAPP-A in women who underwent combined first trimester screening test and we noticed that the concentration of this protein is higher in patients with deep endometriosis and moderate/severe stage of disease. These findings could be explained because in moderate/severe stage and in deep endometriosis there could be a greater inflammatory component.

Probably there are two reasons why we do not detect significant differences in the amount of PAPP-A in patients with mild/minimum disease and with ovarian endometriosis disease:

The levels of PAPP-A in peritoneal fluid are too low to significantly alter the levels of PAPP-A in maternal plasma;

Pregnancy turns off the endometrial peritoneal implants, reducing the concentration of inflammatory markers.

Increased PAPP-A levels in serum of pregnant endometriosis patients might indicate that this protein is not only produced locally in the peritoneal fluid of women with active endometriosis, but it can also be present in serum when the disease is not active due to pregnancy or medical therapy. One hypothesis could be that there is a constant inflammation, also when the disease is not in active phase. Could PAPP-A be increased also in women who have not yet developed endometriosis symptoms and therefore play a prognostic role? Further studies are needed to answer these questions.

Arici et al (36) found that PAPP-A levels were increased in all endometriosis patients. They also found a huge variability of PAPP-A values (10.5-492.1 mIU/mL). These findings concur with ours since PAPP-A could vary only in some specific cases of endometriosis that are moderate/severe disease, and deep endometriosis localization.

With this study we prove that PAPP-A levels vary not only in peritoneal fluid but also in serum of pregnant women. These findings suggest an effective potentiality of PAPP-A as a marker of endometriosis disease, not for all the localizations of the disease but specifically for the deep localization.

Our study reveals a significant increase of free beta-hCG in women affected by endometriosis versus controls (p = 0.02); this result could suggest a different trophoblastic production of beta-hCG in these women that could be linked to a different placentation and subsequent adverse perinatal outcomes related to placental insufficiency. Further studies are needed to confirm these results.

We did not find any difference in pregnancy, delivery or postpartum maternal complications between endometriosis patients and controls. This finding does not agree with literature (44, 45), maybe because our population is too small to evaluate these rare complications. Unexpectedly we found significant postpartum fetal complications. Further studies are needed to confirm these results.

To our knowledge this is the first study in literature investigating serum PAPP-A in pregnant women with endometriosis. Repercussions of elevated PAPP-A in endometriosis could be important:

During pregnancy because elevated PAPP-A in women with deep endometriosis or moderate/severe stage of the disease could affect first trimester aneuploidy screening test. Endometriosis could represent a confounding factor in the calculation of aneuploidy risk. As the Down Syndrome risk increases with lower levels of PAPP-A, an increase of PAPP-A in women affected by deep endometriosis or moderate/severe stage of the disease could increase false negatives. This confounding factor should be taken into account in the calculation of aneuploidy risk.

Out of pregnancy because the increase of serum PAPP-A in patients with deep endometriosis or moderate/severe stage disease could suggest that PAPP-A may potentially play a role as a marker of deep endometriosis disease, the most difficult to diagnose with ultrasound when a concurring ovarian localization does not occur.

Footnotes

Acknowledgment

Prof. Errico Zupi for expert opinion.

Financial support: No grants or funding have been received for this study.

Conflict of interest: None of the authors has financial interest related to this study to disclose.

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. Women with endometriosis at first pregnancy have an increased risk of adverse obstetric outcome. J Matern Fetal Neonatal Med 2015 28 (15) 17951798