|Year : 2020 | Volume
| Issue : 2 | Page : 445-451
Association between first-trimester maternal level of pregnancy-associated plasma protein-A and adverse pregnancy outcomes
Mohamed M Fahmy1, Abeer M Mohie-Aldeen2, Tarek M Sayyed1, Samar M Shehata3
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Alexandria, Egypt
3 Department of Obstetrics and Gynecology, El-Amrya Hospital, Alexandria, Egypt
|Date of Submission||24-Mar-2019|
|Date of Decision||25-Apr-2019|
|Date of Acceptance||27-Apr-2019|
|Date of Web Publication||27-Jun-2020|
Samar M Shehata
Source of Support: None, Conflict of Interest: None
To study the association between low first-trimester pregnancy-associated plasma protein-A (PAPP-A) and adverse pregnancy outcomes.
PAPP-A is produced by the placenta during pregnancy. Low plasma level of this protein has been suggested as a biochemical marker for pregnancies with aneuploidy fetuses. Other studies found associations between low PAPP-A and adverse pregnancy outcomes during the first-trimester screening.
Patients and methods
The present study was conducted at Al-Amrya General Hospital, Gynecology and Obstetrics Department, after informed consent from participants was taken. The research ethics committee at Faculty of Medicine, Menoufia University, approved it. The study included 90 pregnant women booked for routine antenatal care while they were in their first-trimester after fulfilling the inclusion criteria. A blood sample (3–4 ml of venous blood) was withdrawn from all study participants. Then, samples were collected in plain tubes, followed by centrifugation of the samples, where the sera were collected for PAPP-A assay and stored at −20°C. Actual assay of PAPP-A would not be done except after development of any of adverse pregnancy outcome, including preeclampsia, gestational hypertension, intrauterine growth restriction, intrauterine fetal death, or spontaneous preterm.
There is an association between low PAPP-A less than or equal to 0.41 in the first-trimester and development of adverse pregnancy outcomes.
Maternal serum PAPP-A level was significantly lower during the first-trimester in women who developed adverse pregnancy outcomes than women who did not develop.
Keywords: aneuploidy, centrifugation, pregnancy outcome, pregnancy-associated plasma protein-A, prenatal care
|How to cite this article:|
Fahmy MM, Mohie-Aldeen AM, Sayyed TM, Shehata SM. Association between first-trimester maternal level of pregnancy-associated plasma protein-A and adverse pregnancy outcomes. Menoufia Med J 2020;33:445-51
|How to cite this URL:|
Fahmy MM, Mohie-Aldeen AM, Sayyed TM, Shehata SM. Association between first-trimester maternal level of pregnancy-associated plasma protein-A and adverse pregnancy outcomes. Menoufia Med J [serial online] 2020 [cited 2020 Jul 16];33:445-51. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/445/287744
| Introduction|| |
A number of studies have evaluated the effect of a low pregnancy-associated plasma protein-A (PAPP-A) value on pregnancy outcomes among pregnancies with no chromosomal abnormality.
In a normal pregnancy, trophoblasts invade through the decidua and transform the small muscular walls of the maternal spiral arteries into larger, more elastic vessels to allow an increase in blood flow to the placenta. PAPP-A, a protease for insulin-like growth factor-binding protein-4, facilitates the breakdown of this protein, resulting in the release of free insulin-like growth factor (IGF).
IGFs are believed to play an important role in the regulation of trophoblast invasion of the decidua. Impaired release of free IGFs may be a cause for poor placenta perfusion, thereby affecting the fetal growth and the onset of other adverse pregnancy conditions,,.
Its concentration increases exponentially with a doubling time of 3–4 days during the first trimesters, and then the level continues to rise throughout pregnancy until delivery. The rapid increase in PAPP-A levels during the first-trimester causes the interpretation of a given value to be very dependent on gestational age.
Most studies have evaluated PAPP-A measurements conducted during the first-trimester screening and some have found an associations between low PAPP-A and fetal loss, small-for-gestational-age (SGA), preterm birth, or preeclampsia,,,, whereas others have not,.
Thus, the purpose of our study is to study the implications of how first-trimester PAPP-A levels have an effect on the development of adverse pregnancy outcomes, including miscarriage, preeclampsia, gestational hypertension, intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD), spontaneous preterm delivery, and low birth weight.
| Patients and Methods|| |
This cohort study was conducted at Department of Obstetrics and Gynecology of Al-Amrya Hospital after receiving approval from its institution. It included 90 women with singleton pregnancies booked for routine antenatal care while they were in their first-trimester at the outpatient clinic. All participants provided their consent before being included in the study.
Sample size calculation
Because of expensive material used, we used a special type of study (nest case–control study), where we made PAPP-A evaluation in cases that had adverse pregnancy outcomes. In this type of study (nest case–control study), sample size can be small based on the range of our sample figure.
This study comprised two groups:
- Group A (cases group): 60 pregnant women who developed adverse pregnancy outcomes (study group)
- Group B (control group): 30 normal pregnant women who did not develop adverse pregnancy outcome (control group).
Twin pregnancy or higher order multiple pregnancies, the presence of congenital anomalies, if pregnancy outcome is not known (i.e. no delivery in the study hospital), pregnancies not viable in the first scan, and booking beyond the first-trimester were the exclusion criteria.
All patients included in the study were subjected to the following: verbal and written consent, complete history (personal, past, present, and obstetric history), general examination (blood pressure, pulse, respiratory rate, and temperature), and abdominal examination. Gestational age at the time of blood sampling was determined from the date of the last menstrual period, unless this differed from the ultrasound estimate by more than 7 days, in which case the ultrasound estimate was used.
The considered adverse pregnancy outcomes included miscarriage, preeclampsia, gestational hypertension, IUGR, IUFD, spontaneous preterm delivery, and low birth weight.
The standard definitions used included the following: miscarriage: fetal loss before 20 weeks of gestation; preeclampsia: the presence of systolic blood pressure more than or equal to 140 mmHg after 20 weeks of pregnancy detected on two or more occasions separated by 6 h with the presence of proteinuria more than or equal to + on dipstick or more than 0.3 g/24 h; gestational hypertension: hypertension without proteinuria that occurs after 20 weeks of gestation or in the first 24 h postpartum; IUGR: fetal weight of less than the 10th centile for gestational age; IUFD or stillbirth: fetal death before delivery and after 20 completed weeks of gestation; spontaneous preterm: delivery before 37th week of gestation; and low birth weight: birth weight less than 2500 g.
Pregnancy-associated plasma protein-A measurement
A blood sample (3–4 ml of venous blood) was withdrawn from all study participants (control and study participants). Then, samples were collected in plain tubes, followed by centrifugation of the samples where the sera were collected for PAPP-A assay by ELISA technique and stored at −20°C. Actual assay of PAPP-A would not be done until after the development of any previously mentioned adverse pregnancy outcome for the study group (group A).
The reported first-trimester individual PAPP-A levels were modified by gestational age-specific multiplies of median (MoM) according to their control group.
Calculation of PAPP-A (MoM) was done as follows: maternal serum levels of PAPP-A were measured in nanogram/milliliter, and then converted into MoM by dividing each result (ng/ml) obtained from stored serum samples for each specific gestational age by the expected median marker level in normal pregnancies at the same gestational age.
An MoM value of 1 means that the marker level is equal to the median level for normal pregnancy with the specified gestational age, whereas a value of 2 means that the marker level is twice as high as the median level for normal pregnancy with the specified gestational age.
Data were collected and presented to the statistical package for social science software (SPSS), version 16.
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0(IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level when statistical difference was considered with a probability rate of less than or equal to 0.05.
The used tests were as follows: (a) χ2 test: for categorical variables, to compare between different groups; (b) Fisher's exact correction: correction for χ2 when more than 20% of the cells have expected count less than 5; (c) Student's t test: for normally distributed quantitative variables, to compare between two studied groups; (d) Mann–Whitney test: for abnormally distributed quantitative variables, to compare between two studied groups; (e) Kruskal–Wallis test: for abnormally distributed quantitative variables, to compare between more than two studied groups; (f) odds ratio: used to calculate the ratio of the odds and 95% confidence interval (CI) of an event occurring in one risk group to the odds of it occurring in the nonrisk group; and (g) receiver operating characteristic curve (ROC): generated by plotting sensitivity (TP) on Y-axis versus 1-specificity (FP) on X-axis at different cutoff values. The area under the ROC curve denotes the diagnostic performance of the test. Area more than 50% gives acceptable performance and area about 100% is the best performance for the test. The ROC curve allows a comparison of performance between the two tests.
The outcome of this study is the association between the development of adverse pregnancy outcomes and low first-trimester levels of PAPP-A.
| Result|| |
In the current study, there was no difference between the two groups according to the characteristics of the study population [Table 1].
|Table 1: Comparison between the two studied groups according to characteristics of the study population|
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Distribution of adverse pregnancy outcomes among the study group showed single case (1.7%) of IUFD, 12 (20%) cases of IUGR, 25 (25%) cases of SGA and preeclampsia (composite), 11 (18.3) cases of preeclampsia, and single (1.7) case each of oligohydramnios and placenta abruption, as well as nine (15%) cases with preterm labor [Table 2].
|Table 2: Distribution of adverse pregnancy outcomes among the study group|
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The association between gestational age-specific PAPP-A (MoM) of the two studied groups at different sample time revealed that the median PAPP-A (MoM) was 0.10 in 12 pregnant women in group A, 1.0 in six pregnant women in group B, and 0.12 in 18 total pregnant women at 10th week of gestation. The median PAPP-A (MoM) was 0.21 in 18 pregnant women in group A, 1.0 in nine pregnant women in group B, and 0.30 in 27 total pregnant women at 11th week of gestation. The median PAPP-A (MoM) was 0.18 in 18 pregnant women in group A, 1.0 in nine pregnant women in group B, and 0.25 in 27 total pregnant women at 12th week of gestation. The median PAPP-A (MoM) was 0.43 in 12 pregnant women in group A, 1.0 in six pregnant women in group B, and 0.46 in 18 total pregnant women at 13th week of gestation [Table 3].
|Table 3: Association between gestational age-specific pregnancy-associated plasma protein-A (multiple of median) of the two studied groups at different sample time|
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PAPP-A (MoM) was 0.12 in the single case of IUFD, in IUGR was 0.19, in composite was 0.20, in preeclampsia was 0.30, in preterm labor was 0.25, and for oligohydramnios and placenta abruption was 0.39 and 0.11, respectively [Table 4].
|Table 4: Median value of pregnancy-associated plasma protein-A (multiple of median) for different adverse pregnancy outcome categories|
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PAPP-A at cutoff point of less than or equal to 0.4 MoM was more sensitive for detection of composite (SGA and preeclampsia) more than other adverse pregnancy outcomes[Table 5].
|Table 5: Sensitivity of cutoff point of less than or equal to 0.4 multiple of median of pregnancy-associated plasma protein-A in the whole sample size|
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odds ratio for IUFD was 2.143, with 95% CI of 0.085–54.062; for IUGR was 4.069, with 95% CI of 0.836–19.807; for composite was 29.793, with 95% CI of 3.799–233.59; for preterm labor was 2.663, with 95% CI of 0.521–13.616; and for both oligohydramnios and placenta abruption was 2.143, with 95% CI of 0.085–4.062 [Table 6].
|Table 6: Distribution for adverse pregnancy outcomes at pregnancy-associated plasma protein-A cutoff at 0.41 multiple of median in the study population (n=90)|
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| Discussion|| |
There was a statistically significant relation between low PAPP-A less than or equal to 0.41 in the first-trimester and adverse pregnancy outcome. These results are in accordance Gupta et al., who followed up 130 pregnant women with PAPP-A levels less than 0.4 MoM until delivery. They found that 98.5% of the cases group had got adverse pregnancy outcomes mostly low birth weight (43%) and preeclampsia (18.46%).
The cutoff values of PAPP-A to predict adverse pregnancy outcomes were varying in many studies. In the study by Imcha et al., it was found that low levels less than or equal to 0.4 MoM were descriptive of poor early placentation and can be an independent risk factor of complications associated with adverse obstetric outcomes. In addition, Karim et al. found the same cutoff value of PAPP-A to predict adverse pregnancy outcomes. Moreover, Barrett et al. found PAPP-A levels of less than or equal to 0.3 MoM were predictive of increased risk of low birth weight and premature birth.
Yaron et al. found PAPP-A cutoff less than 0.5 MoM to predict adverse pregnancy outcomes.
In the present study, we found approximately a two-fold risk of IUFD, oligohydramnios, and placenta abruption, with a four-fold risk of IUGR, a 2.5-fold risk of preterm labor, a 3.5-fold risk of preeclampsia, and a 29-fold risk of composite (SGA and preeclampsia) among pregnant women when their PAPP-A in first-trimester was less than or equal to 0.4 MoM.
In agreement with our study, a large randomized clinical trial by Dugoff et al. found that the optimal cutoff PAPP-A level of less than 0.43 MoM (i.e., below the fifth centile) was associated with a 3.2-fold risk for fetal growth restriction, a 2.8-fold risk for birth weight below the fifth centile, a 2.5-fold risk for fetal loss before 24 weeks, a 2.15-fold risk for perinatal loss, a 1.9-fold risk for Preterm delivery (PTD), before 37 weeks, a 1.8-fold risk for placental abruption, and a 1.5-fold risk for pulmonary embolism (PE).
In the present study, the degree of sensitivity of PAPP-A for detection of various categories of adverse pregnancy outcomes at cut-off value less than or equal to 0.4 MoM was 88.33% with more sensitivity (96%) for detection of composite (SGA and preeclampsia). The relatively high detection rate is correlated with relatively high incidence of composite of ∼41.7% in adverse pregnancy outcomes. These results are in agreement with previous publication by Balcı, who followed 158 singleton pregnancies until delivery with respect to the PAPP-A level at the 11th–14th weeks of gestation. The results showed that the cutoff point of 0.72 MoM for the PAPP-A level achieved a sensitivity of 82.4% and a specificity of 29.8% for poor pregnancy outcomes.
In contrast to our study, there were some studies that failed to find an association between low PAPP-A levels in first-trimester and development of adverse pregnancy outcomes. Quattrocchi et al. carried out a retrospective case–control study over a 6-year period between 8th and 11th week of pregnancy to investigate whether low first-trimester PAPP-A levels are associated with an adverse pregnancy outcome. They considered PAPP-A cutoff level as low as 0.3. There were 164 women with PAPP-A MoM levels less than 0.3 and 1640 women with PAPP-A MoM levels more than or equal to 0.3 who served as a control group. The two groups significantly differed only for miscarriages, gestational hypertension, and preeclampsia, which concluded that even if in this study the PAPP-A cutoff considered was lower and was assayed in an earlier period compared with other studies, the detection rate for adverse pregnancy outcomes did not improve.
Moreover, Saruhan et al. conducted a case–control retrospective study including 663 pregnant women whose gestational age ranged between 11 and 14 weeks attending prenatal care at Akdeniz University Hospital Antalya, Turkey. Three hundred eighteen singleton pregnancies were included in this study. Pregnant women whose PAPP-A levels were less than or equal to 10th percentile were compared with PAPP-A levels more than 10th percentile for the frequency of pregnancy complications. Results showed that there was no significant association between low PAPP-A levels and incidence of subsequent pregnancy outcomes. It was concluded that low first-trimester of low PAPP-A level less than or equal to 10th percentile was not associated with SGA, preeclampsia, preterm delivery, gestational hypertension, or gestational diabetes mellitus.
The most probable explanation for these studies to fail to find an association between low PAPP-A levels in first-trimester and development of adverse pregnancy outcomes is the different stratified population included in each one of them.
There were some limitations in the present study as well. First, PAPP-A levels were used alone for first-trimester screening of adverse pregnancy outcomes. No other markers, such as free beta-human chorionic gonadotropin and sonographic measurement of fetal nuchal translucency (NT) were used.
Second limitation was the small size of studied population. However, this is because of financial concern, as there was a limited number of laboratory kits available for evaluation of PAPP-A levels. Accordingly, not all cases that developed adverse pregnancy outcomes had serum PAPP-A levels evaluated.
| Conclusion|| |
At a cutoff value of PAPP-A of less than or equal to 0.41 MoM, there is an increased incidence of adverse pregnancy outcomes. There is a need to conduct further studies with larger population sizes to establish the real potential of the first-trimester maternal PAPP-A levels in predicting adverse pregnancy outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]