Связь сывороточных уровней плацентарно-ассоциированного белка плазмы А у беременных в сроке гестации 11—14 нед с развитием самопроизвольного аборта и преждевременных родов

Successful implantation and persistence of pregnancy is the result of a wide range of relationships between maternal and embryonic tissues, including a variety of factors, such as oestrogen and progesterone [1, 2], human placental gonadotropin [3—6], inhibin [5, 7], and placental associated plasma protein A (PAPP-A) [6, 8, 9], as well as the balance between T-helper1 and T-helper2 cells. [10]. Although there is a unified immunological interaction to prevent embryo rejection by the mother, we have very little information about the specific factors that determine the coordinated evolution between the endometrium and the embryo for implantation [11]. Abortion is the most common complication of pregnancy [12, 13]. There is currently no definite treatment to prevent abortion, and there is no definite test to predict it. Although about 50% of abortions are related to chromosomal errors, the remaining half of abortions can be attributed to non-optimal implantation, which may be preventable and save the embryo [13]. Using a miscarriage test can be useful for counselling and reassuring women in early pregnancy. The presence of such a test could also enable researchers and physicians to provide treatments to prevent miscarriage in high-risk individuals [14—16]. PAPP-A is a large glycoprotein of placental origin that appears in the mother’s bloodstream about 30 days after fertilization [17] and at about 6 weeks of gestation [18]. Levels of this protein increase exponentially during pregnancy and reach their maximum at the time of delivery and then reach unmeasurable levels up to about 6 weeks after delivery [18]. Due to this delay in the onset of secretion, this protein is not of high value in the early diagnosis of pregnancy, however, some studies in pregnancies with vaginal bleeding have reported decreased levels of this protein even before the fetal heart rate disappears [17]. However, in some other studies, no predictive effect has been reported in terms of the possibility of abortion for this protein [18]. The low levels of PAPP-A in the first trimester might be useful for identifying women at high risk of preterm labour as well as those at high risk of abortion. Furthermore, it can simplify the triage of patients and planning of more prenatal care as well as possible treatments. Therefore, due to differences in this field and the lack of similar studies in the Iranian population, we decided to conduct a study on plasma protein A levels associated with pregnancy in patients referred to Amir Al-Momenin Hospital in Zabol and evaluate the adverse pregnancy outcomes in patients with low levels PAPP-A.

In this descriptive-analytical study, all pregnant patients referred to the obstetrics clinic of Amir Al-Momenin Hospital of Zabol in 2019, who were in their 11 to 14 weeks of pregnancy, underwent clinical examination. After completing the demographic information of the subjects and clinical examination, the first screening tests including serum level of PAPP-A were requested for the patients. The time of termination of pregnancy was followed, finally, the statistics of patients were entered to SPSS software version 22.

SPSS version 22 software was used to analyse the data. P<0.05 was considered as the criteria for significance of the results. Data were characterized by central and scattering, charting, table setting, and frequency distribution. Logistic regression models were used to determine the relationship between variables and the ROC curve to determine the diagnostic accuracy of pregnancy-related proteins.

In the present study, 827 patients were evaluated. The overall mean age of mothers was 28.69±3.45 years. No significant difference was observed between the mean age of mothers and preterm delivery (28≤GA<37), extremely early preterm delivery (22≤GA<28) and abortion. So, we ignored this variable in the rest of the study. The levels of serum PAPP-A are presented in the table 1.

Table1. Evaluation of serum PAPP-A levels in the study population by type of delivery

Table 1 shows that there was a significant difference in the mean PAPP-A levels among women who developed each of the studied adverse outcomes.

In order to increase the accuracy of the results we considered we divided the patients to three groups based on their PAPP-A multiples of the median (MoM) rates and then, evaluated the outcomes in each of these groups, separately.

Table 2 shows that most of our patients had a PAPP-A MoM level between 0.35 and 2.42 (740/827). Our results also revealed that the prevalence of all three different adverse outcomes were significantly higher among patients in the group having the lowest level of PAPP-A MoM level (<0.35). In the group of patients with PAPP-A MoM levels higher than 2.42 no cases of abortion or extremely early preterm labor was observed, and only 1 case of preterm delivery was reported.

Table2. Comparison of the prevalence of adverse outcomes in different PAPP-A, MoM levels

Our regression models showed that each unit decrease in PAPP-A increased the chances of preterm delivery, extremely early preterm delivery and abortion respectively by 39% (p=0.37), 50% (p=0.011) and 93% (p=001).

The following ROC curves (figure) showed the accuracy of pregnancy-related plasma protein index in predicting preterm delivery, extremely early preterm delivery, and abortion. The area under the ROC curve for abortion is significantly higher than the ones for preterm and extremely early preterm delivery, indicating that the pregnancy-related plasma protein index is more accurate in predicting abortion than preterm or extremely early preterm delivery.

Figure. ROC Curves showing the accuracy of PAPP-A in predicting preterm delivery, extremely early preterm delivery and abortion (a, b, c).

In the present study, lower serum levels of plasma protein associated with pregnancy A showed a significant relationship with preterm delivery, extremely early preterm delivery and abortion. The relationship between low levels of PAPP-A and miscarriage has been approved by previous studies [17, 18]. C. Ong et al. [17] in their study indicated that 20% of patients who experienced an abortion had PAPP-A levels lower than the 10^th centile. On the other hand, H. Cuckle et al. [18] demonstrated that all of (100%) the cases of abortion were associated with PAPP-A levels <0.5 MoM. The results of the present study were in line with the above-mentioned studies regarding the higher risk of miscarriage among patients with lower levels of PAAP-A with the highest prevalence of abortion in levels lower than 0.35 MoM [19].

In a retrospective study by TK Lo et al. (2016) [20] in China, 4,936 women with spontaneous singleton pregnancies underwent their first screening test at the centre between 2010 and 2014, and their delivery information was available. They examined the consequences of pregnancy. According to this study, a threshold of 0.626 or 0.23 median for the serum level of plasma protein associated with pregnancy A has a positive predictive value of 21.4% and a negative predictive value of 97.7% for predicting adverse pregnancy outcomes including abortion, preterm delivery before 32 weeks and low fetal birth weight [21]. I. Todorov et al. (2021) [21] in their study reported that PAPP-A levels lower than 0.5 are significantly associated with a 7 to 14 -times higher risk of preterm birth. Our findings are in line with this study indicating a 39% increase in the risk of preterm birth by decreasing each unit of PAPP-A. In a prospective study conducted by O. Hanita et al. (2012) [22] in Malaysia, 42 pregnant women aged 6 to 22 weeks with threatened abortion symptoms including pain and spotting, as well as 40 pregnant women in the control group with the same gestational age range. Serum levels of pregnancy-related plasma proteins were measured without signs of threatened abortion. Pregnancies up to 22 weeks of gestation were monitored. Of these, 9 patients (11%) had a miscarriage and 73 patients (89%) successfully completed their pregnancies. Mean median levels of pregnancy-associated plasma protein A were significantly lower in the group with spontaneous abortion than in the group with successful pregnancy. The highest sensitivity (44%) and specificity (93%) were obtained at the equivalent point 0.66 times the median [22].

In all of these studies, as in our study, low serum levels of pregnancy-associated plasma protein A were associated with pregnancy risks.

The results of this study showed that PAPP-A level, as a serum marker for screening in the first trimester, could be an independent predictor of preterm birth and abortion. PAPP-A data related to preterm delivery and abortion in this study were consistent with the observations of other studies in Western studies [23—28].

PAPP-A was first identified in 1974 [29]. This protein can be detected in the mother’s circulatory system immediately after pregnancy [30]. PAPP-A has a proteolytic action for protein-binding insulin growth factor [31]. Thus, low PAPP-A levels are associated with higher IGF-BP-4 levels, leading to lower IGF levels. Because IGFs play an important role in paracrine action in the control and uptake of glucose and amino acids into trophoblasts, they may play a role in the mechanism of trophoblasts to decidua [32—35]. Therefore, it is reasonable to assume preterm delivery or other pregnancy conditions. Associated with low levels of PAPP-A may be associated with abnormal placental trophoblastic disorders early in pregnancy, although this mechanism is unclear. However, evaluation of this protein serum according to studies may be very useful in predicting preterm delivery [36]. In a more recent study F. Wang et al. (2021) [37] evaluated the association between first trimester PAPP-A levels and developing placenta accrete which showed a significant relationship. Another study by M. Hoseini et al. (2020) [38] indicated that a 0.75 PAPP-A MOM can serve as the optimum cut-off value for predicting fetal growth restriction which demonstrated that lower levels of PAPP-A MOM can be indicative of a high risk of fetal growth restriction. In addition S. Ramezani et al. (2020) [39] reported this factor as a predictive factor for gestational diabetes and indicated a 3.9 fold higher risk of developing gestational diabetes among patients with lower levels of PAAP-A. Our study in combination with all of the above-mentioned studies suggests PAAP-A as a predictive factor with relatively high accuracy for different pregnancy complications and outcomes.

The present study showed a significant relationship between low PAPP-A levels and higher risk of preterm delivery, extremely early preterm delivery and abortion. According to these results, it is suggested to be used as an accurate marker for prediction of these outcomes.

Authors declare lack of the conflicts of interests.