|Year : 2018 | Volume
| Issue : 3 | Page : 356-362
First-trimester prediction of preterm labor using disintegrin and metalloprotease 12, uterine artery Doppler, and maternal characteristics
Mohamoud El Sayed Abd Razek, Ayman Abd El Hakim Abd El Ghany
Department of Obstetrics and Gynecology, Shebin Elkom Teaching Hospital, Egyptian Ministry of Health, Shebin Elkom, Egypt
|Date of Submission||08-May-2018|
|Date of Acceptance||12-Jun-2018|
|Date of Web Publication||07-Jan-2019|
Dr. Ayman Abd El Hakim Abd El Ghany
Menouf, El-Menoufiya Governorate, Menouf City, 7 El\masady Street
Source of Support: None, Conflict of Interest: None
Background A disintegrin and metalloprotease 12 (ADAM12) is a complex placenta-derived protein with proteolytic activity that may serve as a marker of placental dysfunction for the identification of preterm birth. This has benefits of an early intervention and increased antenatal surveillance. In addition, uterine artery Doppler studies are noninvasive measurements of placental vascular flow with increased resistance reflecting impaired trophoblastic invasion.
Objectives The objective of this study is to estimate the efficiency of first-trimester maternal serum ADAM12, uterine artery Doppler, and maternal characteristics in the early prediction of preterm birth.
Patients and methods This cohort study was conducted on 90 pregnant women in their first trimesters with selection criteria. All patients were investigated for ADAM12 protein level, uterine artery Doppler, and maternal characteristics. They were followed up for screening of preterm birth (before 37 weeks).
Results Uterine artery Doppler pulsatility index and maternal serum ADAM12 level either individually or combined are not statistically significant predictors of spontaneous preterm birth. The combination of maternal ADAM12 and BMI with cutoff levels of 162 pg/ml and 32 kg/m2, respectively, was a highly significant effective predictor of preterm birth. Advancing maternal age, increasing parity, increased BMI, and hypertension were maternal characteristics that correlated significantly with preterm birth.
Conclusion Uterine artery Doppler pulsatility index and maternal serum ADAM12 level are not statistically significant predictors of spontaneous preterm birth, but ‘combined’ ADAM12 and BMI can do it significantly.
Keywords: a disintegrin and metalloprotease 12, placental dysfunction, preterm birth, uterine artery Doppler
|How to cite this article:|
Abd Razek ME, Abd El Ghany AA. First-trimester prediction of preterm labor using disintegrin and metalloprotease 12, uterine artery Doppler, and maternal characteristics. Benha Med J 2018;35:356-62
|How to cite this URL:|
Abd Razek ME, Abd El Ghany AA. First-trimester prediction of preterm labor using disintegrin and metalloprotease 12, uterine artery Doppler, and maternal characteristics. Benha Med J [serial online] 2018 [cited 2020 May 28];35:356-62. Available from: http://www.bmfj.eg.net/text.asp?2018/35/3/356/249407
| Introduction|| |
Preterm birth is defined as delivery before 37 weeks of gestation. It is considered to be one of the most challenging problems in obstetrics. Prematurity became nationally visible as the most frequent cause of death in infancy . Obstetrical approaches are guided in large part by expectations that the obstetrician has for survival of the premature neonate . Chances for survival increase appreciably at or above 1000 g of birth weight. In most of the cases, survival in prematurity are primarily influenced by gestational age and maturity rather than simply by birth weight . The frontier for infant survival has been progressively pushed earlier into gestation primarily as a result of continued innovations in neonatal-intensive care .
Preterm birth has morbid issues. Respiratory distress syndrome caused by lack of lung surfactant formation is the major and most frequent cause of morbidity , retinopathy as a result of hypoxemia has become the largest cause of infant blindness , periventricular hemorrhage, and perinatal hypoxic ischemic encephalopathy have a crucial link to the cause of birth asphyxia, neurological injury, and cerebral palsy ,.
The exact causes for preterm birth are not yet clearly identified, but some postulated the role of infections that are either genital  and/or extragenital , placental insufficiency , and preterm premature rupture of membranes .
Several risk factors for preterm birth were identified including; black races, poor nutrition with maternal underweight, less education, socioeconomic variables , maternal smoking , psychological stress , overstretched uterus , congenital uterine , fetal malformation , and genetic predisposition .
Abnormal placental development and function threaten the fetus and the mother in terms of health and wellbeing. There have been enormous efforts to identify the markers of placental dysfunction that can predict the development of complications before the symptoms develop. Such predictive tools would enable earlier detection, closer monitoring, and potentially preventative treatment . A disintegrin and metalloprotease 12 (ADAM12) is a protease important in regulating healthy placenta development by controlling cell migration and invasion, signaling networks essential for placental establishment in early pregnancy. It spatially localizes to multiple trophoblast populations within placental villi and primarily localized to trophoblasts in distal anchoring columns, as well as in invasive matrix-degrading extravillous trophoblasts ,.
ADAM12, is expressed as two alternatively spliced gene variants, a long transmembrane isoform (ADAM12L) and a short secreted variant (ADAM12S) .
Multiple ADAM12 substrates have been described, including insulin-like growth factor binding proteins 3 and 5, heparin-binding epidermal growth factor-like growth factor .
ADAM12’s extracellular domain components may also affect cell migration through proteolytic independent mechanisms, as both its disintegrin and cysteine-rich regions interact with and activate promigratory β1-integrins expressed on the cell surface .
Impaired maternal spiral arteries trophoblastic invasion is associated with increased risk for subsequent development of intrauterine growth restriction, pre-eclampsia, and preterm birth. A series of screening studies involving assessment of impedance to flow in the uterine arteries have examined the potential value of Doppler in identifying pregnancies at risk of impaired placentation complications. The availability of power Doppler color flow mapping has enabled a precise identification with accurate measurement of the velocimetric signal of the uterine arteries, leading to a considerable improvement in the reproducibility of the data . Clinically, the utero-placental vascular resistance can be evaluated through Doppler indices, such as systolic/diastolic ratio, resistance index, and pulsatility index (PI) obtained from the Doppler velocity waveform . The qualitative description focuses on the of early diastolic notch detection that could be either unilateral or bilateral .
| Patients and methods|| |
The ethical rules of human medical research of Helinski, 7th revision (2013). An informed consent from each patients after clear explanation of the study elements was fulfilled. This research was a prospective cohort study including women attending for antenatal care at Shibeen Elkom teaching hospital, between December 2015 till October 2017. Out of 400 patients were recruited for the study 126 patients were selected based on inclusion and exclusion criteria.
Singleton pregnancy, gestational age between 11 to 13 weeks, and high risk for preterm labor (previous history of preterm birth, diabetic patients, hypertensive patients, patients with uterine anomalies, or patient with IVF).
Multifetal pregnancy, gestational age (beyond 13 weeks or below 11 weeks), or fetal congenital anomalies.
All patients were subjected to the following:
- History (age, parity, tobacco use, chronic medical disease, such as diabetes mellitus and hypertension, previous surgeries and prior preterm birth). Menstrual history was reviewed for the date of last menstrual period for estimation of the gestational age.
- Examination: general, BMI, and abdominal examination.
- Transabdominal two-dimensional ultrasonography to confirm gestational age and fullfilment of the inclusion and exclusion selection criteria.
- Uterine artery Doppler evaluation with (GE Voluson 730 expert ultrasound machine, GE Medical Systems, New York, USA) transabdominal ultrasound with color flow; A mid sagittal view of the uterus with the cervical canal in view was obtained; the transducer was rotated until the para-cervical vessels were visualized, pulsed Doppler gate was placed over the whole width of the vessel. Angler correction was then applied and the signal updated until three similar consecutive waveform had been obtained. The PI of both the right and left uterine arteries were measured three times using pulse wave Doppler and the average PI was calculated.
- Laboratory sampling: 3 ml of peripheral venous blood was collected under complete aseptic technique, sera were separated after centrifugation, stored at −20°C epindorph tubes after careful labeling till the time of assay. For ADAM12 determination; ELISA kit was used from Cohesion Biosciences (Aachen, Germany) with catalog no. CEK1003 with test principle: range (156–10 000 pg/ml), sensitivity (<10 pg/ml), specificity (natural and recombinant human ADAM12), cross-reactivity (no detectable cross-reactivity with other relevant proteins). This assay employs an antibody specific for human ADAM12 coated on a 69-well plate. Standards and samples are pipetted into the wells and ADAM12 present in a sample is bound to the wells by the immobilized antibody. The wells are washed and biotinylated anti-human ADAM12 antibody is added. After washing away unbound biotinylated antibody, horseradish peroxidase-conjugated streptavidin is pipetted into the wells. The wells are again washed, a 3,3’, 5, 5’-tetramethybenzidine substrate solution is added to the wells and color develops in proportion to the amount of ADAM12 . The stop solution changes the color from blue to yellow, and the intensity of the color is measured at 450 nm.
- A follow-up of all patients till delivery was done to estimate the incidence of preterm birth and get subdivided into:
- Case group: those who delivered preterm (before completion of 37 weeks of gestation).
- Compare group: those who delivered at (>37–42 weeks of gestation).
IBM SPSS statistics software package (version 23; SPSS Inc., Chicago, Illinois, USA) was used for data analysis. Data were expressed as mean±SD for quantitative parametric measures in addition to median and percentiles for quantitative nonparametric measures as both number and percentage for categorized data. The following tests were done corresponding to the type of data and the purpose of analysis: Student’s t test, Wilcoxon’s rank sum test, ranked Spearman’s correlation, χ2 test, and logistic multiregression analysis.
The probability of error less than 0.05 was considered significant, whereas P value less than 0.01 and 0.001 as highly significant.
Diagnostic validity test: the sensitivity, specificity, and efficacy, besides, the receiver operating characteristic (ROC) graph representation were used as the cutoff for each technique, area under the curve (AUC) could also be calculated.
| Results|| |
[Table 1] shows a comparison of maternal characteristic (age, BMI). This table shows significantly increased mean age and BMI among cases in comparison with the compare group (P<0.05).
|Table 1 Comparison between cases and compare groups with respect to age and BMI|
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[Table 2] shows the risk relation of the obstetric risk factors of parity and before preterm birth and the incidence of preterm delivery as follows: a significant increase in high parity among preterm birth cases than that of the compare group (P<0.05), a higher number of cases with prior history of preterm birth. However, this difference did not reach the level of significance (P>0.05).
|Table 2 Comparison between cases and compare groups with respect to gravidity and history of preterm birth|
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[Table 3] shows the risk relation of the medical risk factors of diabetes mellitus and chronic hypertension with preterm birth. The relative risk of diabetes mellitus toward preterm birth is present [risk ratio (RR=1.3)]. However, low statistical significance (P>0.05), but significant difference with higher incidence and relative RR with respect to the risk factor of chronic hypertension.
|Table 3 Comparison between cases and compare as regards diabetes and chronic hypertension risk factors|
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[Table 4] shows the relation between ADAM12 and PI of uterine artery Doppler with no significant difference among cases compared with the compare group of preterm birth.
|Table 4 Comparison between cases and compare groups with respect to ADAM12 and uterine artery Doppler|
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In [Table 5] multiregression analysis shows that both BMI and ADAM12 are most sensitive predictor for preterm (ADAM12=162 pg/ml with BMI>32) (F ratio=7.8, P<0.01).
|Table 5 Multiregression analysis dependent variable: preterm for three models|
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The diagnostic validity tests show; the best cutoff for BMI as a single predictor to discriminate preterm from normal=28, at which specificity=79.5, sensitivity=52.3, and efficacy=65.9. The best cutoff for ADAM12 as a single predictor to discriminate preterm from normal=162, at which specificity=68.2, sensitivity=56.8, and efficacy=62.5. The best cutoff for multiuse of both ADAM12 and BMI to discriminate preterm from normal=162 pg/ml for ADAM12 + 32 for BMI, at which specificity=100, sensitivity=100, and efficacy=100 ([Table 6]).
|Table 6 Diagnostic validity test for BMI, ADAM12, and their combination in the prediction of preterm birth|
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Using multi-ROC ADAM12 at 161.8+ BMI at 32 all preterm birth can be distinct from nonpreterm (specificity, sensitivity, efficacy 100%). AUC for BMI, ADAM12, and the combination of them were 0.784, 0.688, and 1, respectively ([Figure 1]).
|Figure 1 ROC curve analysis showing the diagnostic performance of BMI=32 and ADAM12 161.8 pg/ml and their combination for discriminating patients with preterm birth from those without. ADAM12, a disintegrin and metalloprotease 12; ROC, receiver operating characteristic.|
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PI of uterine artery Doppler of pregnant women (11 weeks) delivered preterm (34weeks) ([Figure 2]).
|Figure 2 PI of uterine artery Doppler of pregnant women (11 weeks) delivered preterm (34 weeks). PI, pulsatility index.|
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| Discussion|| |
From 126 pregnant women as the study population, 44 of them had developed preterm birth (case group), while 82 had not and were selected as a compare group for the case group that had preterm delivery.
With respect to the demographic characters of the population study, the age of the patients had a significant difference (P<0.05) between case and compare groups with a higher mean of 32.3 years in the case group compared with 30.3 years in the compare group ([Table 1]). This finding was parallel to the report  that revealed the incidence of preterm birth had increased with advancing age being 23% at more than 35 years maternal age, 35% at more than 40 years maternal age, whereas it is 0.6% at less than 20 years maternal age.
Another factor was the BMI with statistical significant difference elicited (P<0.05) between case and compare groups with higher mean BMI toward the case group (26.7 kg/m2) compared with (24.3 kg/m2) in the compare group ([Table 1]). The best cutoff value of BMI as a single predictor to discriminate preterm from term delivery was 28 at which specificity=79.5, sensitivity=54.3, and efficacy=65.9 ([Table 6]). This finding was in accordance with the report  that concluded that higher risks have been observed between obesity and early spontaneous preterm birth, whereas other study  revealed that risk of preterm birth increased more steeply as BMI drops below 24 kg/m2 than as it rises above 24 kg/m2 so that, low normal BMI 19 kg/m2 is associated with nearly three-folds increase in preterm birth risk compared with a high normal BMI of 24 kg/m2, and also, at higher risk than that associated with obese patients of BMI 34 kg/m2.
In terms of the gravidity of demographic criterion, a positive significant correlation was present between preterm birth and increased parity with higher incidence in multigravida with about two times relative RR=2.09 and 52% of preterm birth may be due to the risk of multigravidity (attributed risk, AR) ([Table 2]). This was in contrast to the study  that stated that null-parity is associated with significant increase in low birth weight and preterm birth more than grand multiparity.
With respect to previous preterm birth our results show no statistically significant difference between cases who delivered preterm compared with the compare group with RR of 1.03 and AR of 27.9% of preterm birth, may be due to the risk before preterm birth ([Table 2]).This result was against the study  that revealed fivefold increase in premature rupture of membranes and preterm births with a previous history.
The nonsignificant statistical difference between case and compare groups with respect to the diabetes mellitus risk factor was similar but still the relative risk of preterm birth is more in patients with diabetes (RR=1.6), 37.5% of preterm condition may be attributed (AR) to the risk of diabetes ([Table 3]). This was comparable with the report  denoting that increased incidence of preterm birth is an adverse outcome of poorly managed diabetes during pregnancy. Another risk factor for preterm birth was the chronic hypertension with the results found significant difference between the two study groups with higher incidence in the case group (53 vs. 26 %) with RR=1.8 and AR=45% ([Table 3]). This finding was in accordance with the research  that ascertained a significant increase in preterm birth in hypertensive patients compared with the compare group.
In this study, it was found that no significant difference between case and compare group with respect to first-trimester maternal serum ADAM12 and uterine artery Doppler PI (P>0.05) ([Table 4]). This result was consistent with previous studies and revealed no difference in ADAM12 level or uterine artery Doppler indices in patients who delivered preterm, but were not appropriate diagnostic predictors for preterm birth ,. In contrast, another research , demonstrated that first-trimester maternal serum ADAM12 level were significantly reduced in patients who subsequently delivered preterm, it also reported that uterine artery PI was significantly elevated but only in subgroup of patient who delivered (<34 weeks).
Individually, ADAM12 or uterine artery Doppler PI had a limited predictive efficiency for preterm birth, but multiple regression analysis ([Table 5]) revealed that the combination of maternal serum ADAM12 and BMI had a highly significant predictive efficacy (P<0.001).
The best cutoff value for individual ADAM12 was 162 pg/ml with specificity=68.2, sensitivity=56.8, and efficiency=65.2, whereas that of BMI was 28 kg/m2 with sensitivity=52.3, specificity=79.5, and efficiency=65.9 ([Table 6]).
Combination of BMI= 32 and ADAM12=161.8 together revealed highly diagnostic accuracy with sensitivity, specificity, and efficacy of 100% ([Table 6]),which is represented by ROC graph and AUC=1 ([Figure 1]).
Strengths of our study include its prospective cohort design and no loss to follow-up rate. Additionally, given our robust data set, we were able to perform a rigorous epidemiologic evaluation, capturing maternal characteristics, obstetrical history, and first-trimester biomarkers in predicting pre-term birth (PTB).
| Conclusion|| |
Uterine artery Doppler PI and the maternal serum ADAM12 level either individually or combined have a limited value in prediction of spontaneous preterm birth, but combined ADAM12 and BMI can do the prediction. Advancing maternal age, increasing parity, increased BMI, and hypertension were maternal characteristics that had correlated with significant prediction of preterm birth.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]