|Year : 2019 | Volume
| Issue : 2 | Page : 430-435
Combined second trimester maternal serum α-fetoprotein and uterine artery Doppler in the prediction of pre-eclampsia
Nasser K Abd El-Aal1, Alaa El-Deen F El-Halaby1, Ahmed H Taie2
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, Nasr City Police Hospital, Nasr City, Egypt
|Date of Submission||31-Jul-2017|
|Date of Acceptance||08-Sep-2017|
|Date of Web Publication||25-Jun-2019|
Ahmed H Taie
6 Sharara Building, Hassan El Maamoun Street, Nasr City
Source of Support: None, Conflict of Interest: None
The objective was to evaluate the combination of second trimester maternal serum α-fetoprotein (MSAFP) and uterine artery Doppler (UAD) as a tool for the prediction of pre-eclampsia (PE).
PE is a complex multisystem disease and the main cause of fetomaternal morbidity and mortality. The ultimate aim of antenatal care is to identify women at high risk and provide them with prophylactic treatment. No single test has emerged as a front runner and screening based on risk factors has low sensitivity. This has highlighted the need for an alternative.
Patients and methods
A prospective study on a total of 297 pregnant women had MSAFP measured between 15 and 19 weeks gestation and UAD measured between 19 and 21 weeks of gestation. Resistance index, pulsatility index (PI), and the presence of notches were measured. Receiver operator characteristic curves were created for MSAFP and UAD alone and in combination and then the outcomes were compared. The study was carried out at the Department of Obstetrics and Gynecology of the Faculty of Medicine, Menoufia University and Nasr City Police Hospital during a period from June 2016 to June 2017.
A total of 17 women developed PE. The sensitivity of using UAD (resistance index) was 70.59% and for MSAFP was 52.94%. The combined sensitivity of UAD and MSAFP was 64.7%
The combination of MSAFP with UAD did not improve the screening efficacy for the prediction of PE and UAD performed significantly better as a stand-alone test.
Keywords: α-fetoprotein, pre-eclampsia, screening, second trimester, uterine artery Doppler
|How to cite this article:|
Abd El-Aal NK, El-Halaby AE, Taie AH. Combined second trimester maternal serum α-fetoprotein and uterine artery Doppler in the prediction of pre-eclampsia. Menoufia Med J 2019;32:430-5
|How to cite this URL:|
Abd El-Aal NK, El-Halaby AE, Taie AH. Combined second trimester maternal serum α-fetoprotein and uterine artery Doppler in the prediction of pre-eclampsia. Menoufia Med J [serial online] 2019 [cited 2020 May 27];32:430-5. Available from: http://www.mmj.eg.net/text.asp?2019/32/2/430/260896
| Introduction|| |
Pre-eclampsia (PE) is a severe complication unique to human pregnancy with a worldwide incidence of 2–10%.
PE is one of the leading causes of fetal, maternal, and neonatal mortality and morbidity, even in countries.
Defective trophoblastic tissue differentiation and invasion is one of the principal mechanisms of PE. Doppler ultrasound provides indirect evidence of this process and it has consequently been proposed as a screening test for PE and related complications.
A lot of evidence supports measuring uterine artery Doppler (UAD) at around 20–24 weeks where the detection rate for pregnancies that subsequently develop PE requiring early delivery is 50–70%.
α-Fetoprotein (AFP) is a glycoprotein produced by the secondary yolk sac, the fetal liver, and the gastrointestinal tract. The level of AFP enhanced by the combination of fetal production, clearance through the fetal kidney, and by any perturbation of the placental interface between the fetus and the mother.
Approximately 13% of women with elevated maternal serum α-fetoprotein (MSAFP) developed PE compared with 1% of the women with normal MSAFP. In 1994, Brazerol et al. reported that no clear evidence had described the relation between elevated MSAFP and adverse pregnancy outcome, but it might be a marker of placental dysfunction and abnormal implantation.
Both Doppler ultrasound and MSAFP provide indirect markers of impaired placentation, which forms the basis of the pathophysiology of PE.
| Patients and Methods|| |
The study was a longitudinal, prospective study performed at the Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University and Nasr City Police Hospital during a period from June 2016 to June 2017 on 300 pregnant women recruited from those who attended antenatal clinics in which 297 pregnant women had completed the study with three cases lost to follow-up.
The inclusion criteria: low-risk primigravdas between 15 and 20 weeks of gestation.
The exclusion criteria: multiparous women, women with multiple pregnancies, also women with a history of hypertension, diabetes, immunology, and chronic renal diseases were excluded.
After approval of our mentioned hospital ethics committee, each procedure was explained in detail to each patient and each patient gave a written informed consent.
All patients were then subjected to careful and detailed history taking as well as thorough general and pelvic examination.
Routine laboratory investigations (complete blood count, blood group, Rhesus factor, urinalysis, and a random blood sugar test) were conducted.
The participants were then followed up monthly till the end of the second trimester, every 2 weeks till the end of the 36th week, and every week until delivery. Arterial blood pressure (BP) was measured and urine analysis was performed every visit. All participants underwent routine obstetric ultrasonography and were screened for gestational diabetes. Blood samples for MSAFP level measurement were collected between 15 and 20 weeks of gestation and bilateral UAD was done after obtaining consent from the participant.
Samples of MSAFP were collected by venepuncture, allowed to clot naturally, and the serum was separated as soon as possible to prevent hemolysis. The serum was stored at 2–8°C for up to 48 h before assay and for prolonged storage it was kept at − 20°C. MSAFP was assayed by ARCHITECT AFP assay using ARCHITECT AFP kits purchased from Abbott Bio Inc. (Ireland: Lake Bluff, Illinois, USA). The assay is a chemiluminescent microparticle immunoassay for in-vitro measurement of AFP in human serum.
Owing to variation in the population and as the levels of MSAFP increased with increasing gestation and decreased with greater maternal weight, its values should be expressed as multiples of the median (MoM) which is calculated by dividing the actual serum AFP value (ng/ml) by the median value of the completed gestational week at which the sample was obtained.
Uterine artery flow velocity waveforms were obtained at 19–21 weeks gestation using a Medisone ×6 ultrasound machine (Samsung Medisone, 2-dong Alpharium Tower, 145, Pangyoyeok-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea) equipped with a C 3–7 MHz convex probe and Siemens ACUSON Antares ultrasound machine (1991 Crocker Road, Suite 600-679, Cleveland, OH 44145, USA) equipped with a C 3–13 MHz convex probe, pulsed-wave Doppler with color Doppler option.
On ultrasound examination, a midsagittal section of the uterus was obtained, followed by identification of the cervical canal and moving the transducer laterally till visualization of the paracervical vascular plexus. Color Doppler imaging was then used to identify the uterine artery while turning cranially to make its ascent to the uterine body. At this point pulsed-wave Doppler was used to obtain three similar consecutive waveforms. The resistance index (RI) and pulsatility index (PI) were measured. A notch was considered to be present when there was a clearly defined upturn of the flow velocity waveform at the beginning of diastole which was present in all the waveforms. Hard copies of Doppler waveforms were independently reviewed by two observers for the presence of notches.
Data collected included age, BMI, gestational age at delivery, and BP. The main outcome measure was the development of PE.
During data collection the investigators were blinded to the MSAFP and Doppler data.
PE was diagnosed according to the definition of the American College of Obstetricians and Gynecologists (ACOG2013) as BP 140 mmHg or higher systolic or 90 mmHg or higher diastolic in previously normotensive pregnant woman, proteinuria 300 mg or greater in a 24 h urine collection in the absence of urinary infection or protein concentration of 1 g/l (on two occasions of at least 6 h apart), or in the absence of proteinuria(thrombocytopenia <100 000/μl, serum creatinine >1.1 mg/dl, or doubling the concentration in the absence of renal disease, visual symptoms, and pulmonary edema).
Women who developed PE were admitted to the mentioned hospital with delivery of fetus of 37 weeks or later. In mild PE less than 37 weeks close monitoring for the woman and her fetus was done till delivery with tests to assess platelet counts, liver enzymes, kidney function, and urinary protein levels. Tests for the fetus include ultrasound, heart rate monitoring, assessment of fetal growth, and amniotic fluid assessment. In cases of severe PE, the woman was admitted to the hospital, monitored closely, had intravenous medication to control BP and prevent seizures and delivery of the fetus was done as soon as possible.
Sample size justification: depending on the Allen et al. study who found that the sensitivity and specificity of combined MSAFP and UAD method of prediction of PE are 64.7 and 96.6%, respectively, and assuming the power of 0.80 and α = 0.05 against null sensitivity and specificity of 50.0%, and by using SPSS 11th release the minimal sample size for a prospective study is 300 cases.
This study was done using IBM SPSS Statistics version 21 (IBM Corp., Armonk, New York, USA). Numerical data were presented as mean and SD and inter-group differences were compared using the unpaired Student's t-test.
Receiver operating characteristic (ROC) curve analysis was used to examine the value of variables for discrimination between patients with or without PE. For categorical predictors, simple binary logistic regression was run. For a combination of multiple predictors, multivariable binary logistic regression was used to estimate the predicted probabilities of PE, and then used as latent predictor variables for the construction of ROC curves. The DeLong method was used for comparison of the areas under ROC curves. A P value of less than 0.05 was considered statistically significant and less than 0.001 was considered highly statistically significant.
| Results|| |
A total of 297 pregnant women had completed the study that was classified in 280 (94.3%) with no PE and 17 (5.7%) developed PE.
There was no statistically significant difference between the two groups as regards age, height, weight, and gestational age at enrollment (P > 0.05). There was a significant difference regarding BMI as P value of less than 0.05, with more increasing BMI and decreasing gestational age at delivery in the PE group in comparison with the no PE group [Table 1].
|Table 1: Patients' characteristics and maternal serum a-fetoprotein level (multiples of the median) in the study population|
Click here to view
There was no statistically significant difference between the two groups as regards systolic BP and diastolic PB at the first visit for both groups (P > 0.05).
There was statistically highly significant difference between the two groups regarding the MSAFP level as a P value of less than 0.0001, with higher levels of MSAFP levels in the PE group [Table 1].
There was a highly significant statistical difference between the two groups as regards uterine artery RI and PI as P value of less than 0.001 with higher PI and RI in the PE than in the no PE group [Table 2].
|Table 2: Uterine artery Doppler indices in the study population at first visit|
Click here to view
There was a highly significant association between the presence of diastolic notch and the development of PE [Table 3].
|Table 3: Presence of diastolic notches on uterine artery Doppler in the study population|
Click here to view
A significant association was found with uterine artery RI being a significant predictor with higher values in PE cases than normal cases as presented on an ROC curve [area under the curve (AUC)]=0.83, 95% confidence interval (CI) 0.783–0.871, best cut-off (>0.63), sensitivity of 70.59%, specificity of 93.57%, positive predictive value (PPV) of 39.8%, and negative predictive value (NPV) of 98.1% [Figure 1].
|Figure 1: Receiver operator characteristic curve, sensitivity and specificity, diagnostic performance of mean resistance index, pulsatility index, and diastolic notch in discrimination of pre-eclampsia.|
Click here to view
A significant association with uterine artery PI being a significant predictor with higher values in PE cases than normal cases as presented on an ROC curve (AUC)=0.741, 95% CI: 0688–0.790, best cut-off of greater than 1.35, sensitivity of 64.71%, specificity of 90.71%, PPV of 29.6%, and NPV of 97.7% [Figure 1].
ROC curves for estimating the association between PE and any uterine artery diastolic notch showed (AUC) = 0.735, 95% CI: 0.681–0.785, sensitivity of 47.06%, specificity of 100%, PPV of 100%, and NPV of 96.8% [Figure 1].
A significant association MSAFP being a significant predictor with higher values in cases with PE than in normal cases as presented on an ROC curve (AUC)=0.697, with 95% CI: 0.624–0.749), best cut-off of greater than 1.62, sensitivity of 52.94%, specificity of 91.43%, PPV of 27.18%, and NPV of 96.9% [Figure 2].
|Figure 2: Receiver operator characteristic curve, sensitivity and specificity, diagnostic performance of α-fetoprotein (multiples of the median) in discrimination of pre-eclampsia.|
Click here to view
A cut-off value of MSAFP at which the patient was screened positive was greater than or equal to 2, with a sensitivity of 29.4%, specificity of 95.7%, PPV of 31.2%, and NPV of 95.7%.
MSAFP and mean uterine artery RI combined showed a high statistical significance. When operated on ROC curve (AUC = 0.829 and P < 0.0001), it has 64.71% sensitivity, 99.46% specificity, 79.41% PPV, and 97.8% NPV [Figure 3].
|Figure 3: Receiver operator characteristic curve, sensitivity and specificity, diagnostic performance combination of mean resistance index and maternal serum α-fetoprotein, mean pulsatility index and maternal serum α-fetoprotein in discrimination of pre-eclampsia.|
Click here to view
MSAFP and mean uterine artery PI combined showed a statistical significance. When operated on ROC curve (AUC = 0.744 and P < 0.0087), it has 58.82% sensitivity, 95.36% specificity, 43.38% PPV, and 97.45% NPV [Figure 3].
| Discussion|| |
The study included pregnant women for whom transabdominal Doppler was performed to measure the uterine artery indices at 19–21 weeks pregnant and the blood sample was collected to measure the MSAFP level at 15–20 weeks of pregnancy.
On a follow-up study of the population, 300 women were recruited, 297 cases completed the study, and three cases are missed, 17 cases developed PE, whereas 280 cases are considered normal.
Regarding MSAFP levels in the normal and PE groups, it was significantly higher in the PE group. ROC curves were created to demonstrate its prognostic value to the development of PE with a cut-off more than or equal to 1.6 (sensitivity of 52.94%, specificity of 91.43%, PPV of 27.18%, and NPV of 96.9%). For a cut-off greater than or equal to 2.0 MoM, there was a sensitivity of 29.4%, specificity of 95.7%, PPV of 31.2%, and NPV of 95.7%). There was a highly significant positive correlation between mean uterine RI, PI, and MSAFP and there was no significant correlation between MSAFP and the gestational age of delivery.
This goes with the work of Allen et al. who pointed out in their study that there was a highly significant association between elevated MSAFP levels (with normal cut-off defined as 2.0 MoM) and each of the adverse pregnancy outcomes as PE.
Agreeing with this study, another study was carried by Taché et al. on pregnancies that obtained second trimester prenatal screening of AFP. High levels of MSAFP were associated with severe PE (relative risk: 2.5–11.7).
Our findings were in agreement with those of Williams et al.; Kuo et al. who made a comparison between women with elevated MSAFP (≥2.0 MoM) and women with normal MSAFP and found a significant association between elevated MSAFP and PE.
However, no similarity was found with Davidson et al., Kang et al.) who pointed out in their study that there was no significant increase in AFP in those who developed PE compared with controls.
ROC curves were created to demonstrate the prognostic value of RI and PI of uterine arteries regarding the development of PE as for mean RI (70.59% sensitivity, 93.57% specificity, 39.8% PPV, and 98.1% NPV). As regards mean PI there was 64.71% sensitivity, 90.71% specificity, 29.6% PPV, and 97.7% NPV. In addition, there were statistically significant positive correlations between mean RI and mean PI and each other and significant positive correlation between mean uterine RI, PI, and age at the time of delivery.
This goes with the work of Yu et al. who detected similar results with statistically significant correlation (P < 0.001).
Our findings were in agreement with those of O'Gorman et al., who detected similar results with PI and stated that pregnancies which developed PE had increased uterine artery PI.
Similarity was found with Bodovaa et al. who stated the presence of a statistically significant relation (P < 0.005) between the uterine artery changes on Doppler and the development of PE. The sensitivity of PI and RI to detect adverse pregnancy outcomes was 53.8% for both and the specificity of both PI and RI was 86%.
Prajapati and Maitra found that the mean PI value for participants who had an adverse pregnancy outcome as PE was significantly higher than the mean PI value for participants who had a normal pregnancy outcome which agrees with our findings.
Using MSAFP and mean uterine artery RI combined shows statistical significance; when operated on ROC curve (P < 0.0001), it has 64.71% sensitivity, 99.46% specificity, 79.41% PPV, and 97.8% NPV.
Using MSAFP and mean uterine artery PI combined shows statistical significance; when operated on ROC curve (P < 0.0087), it has 58.82% sensitivity, 95.36% specificity, 43.38% PPV, and 97.45% NPV.
There is an increase of MSAFP sensitivity and specificity as a predictor for PE when used combined with mean uterine artery RI and PI, but still it is less than the sensitivity of UAD.
This goes with the work of Allen et al. who pointed out in their study that the performance of combined MSAFP and UAD did not improve the sensitivity of the test for all cases of PE. The sensitivity of the combination was 48.8%, this is less than the sensitivity of UAD alone, but better than MSAFP alone (24.4%).
In our study, the combination of MSAFP with UAD ultrasound improved the positive predictive, that improves the identification of women at risk for PE.
This goes with the work of Audibert et al. on 2615 women, who found that an elevated MSAFP in combination with the presence of uterine artery notching on Doppler ultrasound improved the PPV to 21% from 3.9% for PE.
Chung et al. work in 2000 on 179 women with MSAFP greater than 2.5 MOMs and abnormal UADs between 26 and 28 weeks showed a PPV of 14.5% for MSAFP alone.
Our study shows that the use of MSAFP alone as a screening tool for PE is not satisfied because of the low sensitivity as all women who had a result of MSAFP level higher than 2.0 MoM, for every one pregnant woman diagnosed as affected there will be 3–4 who are not affected, the sensitivity is only 29% of the level greater than 2 MOM.
Our study shows that UAD performed significantly better as a stand-alone test.
Our study shows that a combination of MSAFP level with UAD ultrasound did not improve the sensitivity for PE.
| Conclusion|| |
The combination of MSAFP and UAD did not improve the screening efficacy for the prediction of PE and UAD performed significantly better as a stand-alone test.
This study demonstrates that higher level of MSAFP in the early second trimester (15–20 weeks gestation) and an abnormal increase in uterine artery indices (PI and RI) were associated with developing PE later in pregnancy.
Further, studies on a large number of cases are needed to confirm the current study results.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ2005;330
Saleem S, McClure EM, Goudar SS, Patel A, Esamai F, Garces A, et al
. A prospective study of maternal, fetal and neonatal deaths in low-and middle-income countries. Bull World Health Organ 2014; 92
Bower S, Bewley S, Campbell S. Improved prediction of pre-eclampsia by two-stage screening of uterine arteries using the early diastolic notch and color Doppler imaging. Obstet Gynecol1993; 82
Papageorghiou AT, Yu CKH, Cicero S, Bower S, Nicolaides KH. Second-trimester uterine artery Doppler screening in unselected populations: a review. J Matern Fetal Neonatal Med 2002; 12
Anfuso S, Soncini E, Bonelli P. Second-trimester maternal serum alpha-fetoprotein elevation and its association with adverse maternal/fetal outcome: ten years experience. Acta Biomed 2007; 78
Allen R, Marleen S, Velauthar L, Harrington K, Aquilina J. Improved early prediction of preterm pre-eclampsia by combining second trimester maternal serum alpha-fetoprotein and uterine artery doppler. J Clin Gynecol Obstet 2014; 3
Walters BNJ, Lao T, Smith V, Swiet M. α-Fetoprotein elevation and proteinuric pre-eclampsia. Int J Obstet Gynaecol 1985; 92
Brazerol WF, Grover S, Donnenfeld AE. Unexplained elevated maternal serum α-fetoprotein levels and perinatal outcome in an urban clinic population. Am J Obstet Gynecol 1994; 171
American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics. Hypertension in pregnancy. Obstet Gynecol 2013; 122
Machin D, Campbell MJ, Tan SB, Tan SH. Sample size tables for clinical studies
ed. Chichester, UK: Wiley-Blackwell; 2008.
Allen R, Marleen S, Velauthar L, Harrington K, Aquilina J. The relationship between second trimester alpha fetoprotein levels and adverse pregnancy outcome. Open J Obstet Gynecol 2013; 3
Taché V, Baer RJ, Currier RJ, Li CS, Towner D, Waetjen LE, Jelliffe-Pawlowski LL. Population-based biomarker screening and the development of severe preeclampsia in California. Am J Obstet Gynecol 2014; 211
Williams MA, Hickok DE, Zingheim RW, Luthy DA, Kimelman J, Nyberg DA, Mahony BS. Elevated maternal serum α-fetoprotein levels and midtrimester placental abnormalities in relation to subsequent adverse pregnancy outcomes. Am J Obstet Gynecol 1992; 167
Kuo PL, Lin CC, Lin YH, Guo HR. Placental sonolucency and pregnancy outcome in women with elevated second trimester serum alpha-fetoprotein levels. J Formos Med Assoc 2003; 102
Davidson E, Riley S, Roberts S, Shearing C, Groome N, Martin C. Maternal serum activin, inhibin, human chorionic gonadotrophin and alpha-fetoprotein as second trimester predictors of preeclampsia. Br J Obstet Gynaecol 2003; 110
Kang JH, Farina A, Park JH, Kim SH, Kim JY, Rizzo N, et al
. Down syndrome biochemical markers and screening for preeclampsia at first and second trimester: correlation with the week of onset and the severity. Prenat Diagn 2008; 28
Yu CK, Khouri O, Onwudiwe N, Spiliopoulos Y, Nicolaides KH. Prediction of preeclampsia by uterine artery Doppler imaging: relationship to gestational age at delivery and small to gestational age at delivery. Ultrasound Obstet Gynecol 2008; 31
O'Gorman N, Tampakoudis G, Wright A, Wright D, Nicolaides KH. Uterine artery pulsatility index at 12, 22, 32 and 36 weeks' gestation in screening for pre-eclampsia. Ultrasound Obstet Gynecol 2016; 47
Bodovaa K, Biringera K, Dokusa K, Ivankovab J, Staskob J, Dankoa J. Fibronectin, plasminogen activator inhibitor type 1 (PAI-1) and uterine artery doppler velocimetry as markers of preeclampsia. Disease Markers 2011; 19
Prajapati SR, Maitra N. Prediction of pre-eclampsia by a combination of maternal history, uterine artery Doppler, and mean arterial pressure (a prospective study of 200 cases). J Obstet Gynecol India 2013; 63
Audibert FBY, Benhatter C, Champagne C, Frydman R. Prediction of preeclampsia or intrauterine growth restriction by second trimester serum screening and uterine doppler velocimetry. Fetal Diagn Ther 2005; 20
Chung JE, Cho JS, Han SS, Park YW, Kim JW. Uterine artery Doppler velocimetry in the prediction of adverse obstetric outcomes in unexplained MSAFP elevations. Yonsei Med J 2000; 41
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]