original article Wien Med Wochenschr (2015) 165:199–209 DOI 10.1007/s10354-015-0358-5
Predictive accuracy of the first trimester Doppler scan: a meta-study Naira Roland Matevosyan
Received: 15 March 2015 / Accepted: 29 April 2015 / Published online: 16 June 2015 © Springer-Verlag Wien 2015
Summary Aim To determine sensitivity and cut-off indices of the uterine artery Doppler (UAD) in prediction of preeclampsia and fetal growth restriction (FGR). Methods Seventy-six studies published in 1995–2014, present 298,329 prenatal Doppler screenings performed in nullipara in the first and early second trimesters of singleton pregnancies. The sample is stratified into four groups based on the Doppler sensitivity and specificity indices pertaining to the major clinical endpoints of the cohort. Results The FGR diagnostic specificity (r = 0.728) and bilateral notching index (r = 0.803) correlations indicate that the UAD accuracy depends on the placental bed and the screening mode. Conclusions Predictive sensitivity of the UAD increases after 16 weeks + 3 days (115 days) of gestation. The best predictive parameter of preeclampsia and FGR is the placental side uterine artery resistance index which confers to the highest means when the placenta is on the midline (OR 0.9). Keywords Uterine artery Doppler · Placenta · Preeclampsia · Fetal growth restriction · Predictive value
Prädiktive Genauigkeit der Dopplersonographie im Ersttrimester: eine Metastudie Zusammenfassung Grundlagen Ziel der vorliegenden Studie war es, die Sensitivitäts- und Spezifitätsindizes des Gebärmutterarterien-Dopplers (UAD) bei der Prädiktion von PräeklamN. R. Matevosyan, MD, PhD () New European Surgical Academy (NESA) and Emory University, Atlanta, USA e-mail: obgynvienna@myway.com
13
psien und fetalen Wachstumsrestriktionen (FGR) zu überprüfen. Methodik Im Rahmen von 76 zwischen 1995 und 2014 veröffentlichten Studien wurden 298.329 pränatale Doppleruntersuchungen bei Erstgebärenden mit Einlingsschwangerschaften im ersten und frühen zweiten Trimester durchgeführt. Auf der Grundlage der Sensitivitäts- und Spezifitätsindizes wurde die Stichprobe in Bezug auf die wesentlichen klinischen Endpunkte der Kohorte in vier Gruppen stratifiziert. Ergebnisse Die Korrelationen der diagnostischen Spezifität (r = 0,728) und Indizes bilateraler postsystolischer Inzisuren (r = 0,803) bei der FGR deuten auf eine Abhängigkeit der UAD-Genauigkeit sowohl vom Plazentabett als auch vom Screeningmodus hin. Schlussfolgerungen Die prädiktive Sensitivität des UAD erhöhte sich nach 16 Wochen + 3 Tagen (115 Tagen) Gestation. Der stärkste prädiktive Parameter für Präeklampsien und FGR war der Index plazentaseitiger Gebärmutterarterien-Resistenz, wobei die höchsten Mittelwerte bei einer Mittellinienlage der Plazenta erzielt wurden (OR 0,9). Schlüsselwörter Gebärmutterarterien-Doppler · Plazenta · Präeklampsie · Fetale Wachstumsrestriktion · Prädiktiver Wert
Problem definition The uterine artery Doppler (UAD) waveform has been extensively investigated, yet its widespread clinical use as a predictor of perinatal outcomes remains dubious. Attempts to use predictive models combining measurements of placental structure and blood flow produce mixed results. The determinants of the waveform are classically ascribed to transformation of the spiral arteries and development of a low resistance uterine–
Predictive accuracy of the first trimester Doppler scan: a meta-study
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original article
placental circulation, failure of which predisposes to preeclampsia and fetal growth restriction (FGR). Although spiral artery transformation determines in some part the characteristics of the Doppler waveform, factors pertaining to maternal vascular and endothelial function are also important. Maternal factors of preeclampsia include HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), prostacycline–thromboxane imbalance, circulation disorders, renal failure, endocrine disorders (type-1 diabetes mellitus, nonsugar and bronze diabetes, Cushing’s syndrome, thyroid and parathyroid dysfunction), systematic autoimmune disorders (lupus, thrombocytopenia, type-2 diabetes, Sjögren syndrome, Addison disease, celiac sprue), poor maternal health habits, and placentation defects (second wave trophoblastic invasion). The FGR has similar etiology, with two additional causation groups: vertical infections (ToRCH), and chromosomal anomalies (trisomy 13, trisomy 18, trisomy 21, triploidy, chromosome 4p deletion syndrome, NeuLaxova syndrome, Pena-Shokier syndrome, Seckel syndrome, Smith-Lemli-Opitz syndrome, among others). In such a complex causality, early and accurate prediction of preeclampsia and FGR is crucial. Yet, studies investigating the predictive accuracy of the UAD indices (placental bed vascularization index, pulsatility index (PI), resistance index (RI), bilateral notching, early diastolic blood flow velocity—either alone or combined with notching) obtain considerably inconsistent results with a vast global variation. It is established that low end-diastolic velocities and early diastolic notch characterize the waveforms of the uterine artery blood flow in nonpregnant women and in the first trimester of pregnancies. Persistence of a diastolic notch (over 24 gestation weeks) or abnormal flow velocity ratios are found to be associated with inadequate trophoblastic invasion [1]. The first trimester uterine artery mean RI and prevalence of bilateral notching are significantly higher in women destined to deliver small for gestational age (SGA) neonates than in women with uneventful pregnancies (median uterine artery RI, 0.74 vs. 0.70, P < 0.001; prevalence of bilateral notches, 56 vs. 43 %, P < 0.001). There is a statistically significant inverse relationship between the mean uterine artery RI and gestational age in pregnancies with SGA and without preeclampsia (R = − 0.329, P < 0.01) [2]. Another set of studies indicate that the risk of preeclampsia and FGR is highest when the UAD impedance remains bilaterally high from first to second trimester, whereas the predictive value is the lowest when UAD impedance is low from 11 to 14 gestational weeks [3]. It is reported that transabdominal and transvaginal UAD scans are significantly different—with transvaginal method having significantly higher values [4]. It is also suggested that the best screening test for preeclampsia and FGR is the placental side uterine artery RI or AC ratio above the 90th percentile when the placenta is located on the left or right side, and the highest RI or AC ratio when
the placenta is on the midline. A normal test usually predicts an uneventful pregnancy [5]. Cohort studies show that the uterine artery mean RI is equal on the right and left sides (0.59 ± 0.14); however, unilateral diastolic notches are found to be 34.2 % and bilateral notches in 10.4 % women. Women with a high uterine artery RI are 5.5 times more likely to have FGR [6]. Later studies indicate that antepartum surveillance with Doppler of the umbilical artery should be started when the fetus is viable and when a FGR is suspected. Doppler studies of the ductus venosus, middle cerebral artery, and other vessels have some prognostic value for FGR; however, these studies of vessels other than the umbilical artery in pregnancies with the FGR should be reserved for research protocols, as the results are not derived from the randomized trials [7, 8]. While retrospective case–control studies suggest on strong associations between the UAD pulsatility index and FGR intensified with gestational age [9, 10], prospective cohort studies compliment that the FGR shows associations with the uterine artery PI but no associations with the uterine artery notching (P = 0.83) [11], and that the abnormal PI and [soluble fms-like tyrosine kinase 1 (sFlt-1)]/[placental growth factor] ratio show high specificity but low sensitivity in diagnostics of preeclampsia [12, 13]. The controversial suggestions of the reviewed studies are grouped below: (1) the first trimester UAD indices are highly predictive of both preeclampsia and FGR [5, 7, 9, 10, 14–35]; (2) the first trimester UAD is highly predictive of preeclampsia and fairly predictive or not predictive of the FGR [1, 2, 8, 36–56]; (3) the first trimester UAD has elusive or limited diagnostic accuracy in preeclampsia and FGR [3, 11, 12, 57–70]; and (4) the first trimester UAD indices are not predictive of preeclampsia or FGR [6, 71–78]. It remains moot whether the UAD ultrasonography should be used as a predictive test for preeclampsia and related neonatal outcomes.
Objective Reestablishing the first trimester Doppler ultrasound cut-off indices in a large-scale sample is essential for achieving a highly sensitive and specific prediction of the aberrant perinatal outcomes. Having stringent and measurable parameters from controversial studies, we anticipated to comparatively locate the cut-off lines that would shift the prognostic value for preeclampsia alone to the prognostic value for both preeclampsia and FGR. Put simply, a sensitive and specific velocimetry cut-off line would help us understand the missing parameters in reviewed studies that could predict the restricted fetal growth as early as in the first trimester.
200 Predictive accuracy of the first trimester Doppler scan: a meta-study
13
original article
Table 1 Distribution of study results with regard to the predictive potential of the first trimester uterine artery Doppler Groups
n
Core findings
References
I
26
The first trimester uterine artery Doppler (UAD) is highly predictive of both preeclampsia and FGR
[5, 7, 9, 10, 14–35]
II
24
The first trimester UAD is highly predictive for preeclampsia and fairly predictive or non predictive of the FGR
[1, 2, 8, 36–56]
III
17
The first trimester UAD has elusive or limited diagnostic accuracy in predicting preeclampsia and FGR
[3, 11, 12, 57–70]
IV
9
The first trimester UAD is not predictive of preeclampsia or FGR
[6, 71–78]
Sampling From a total of 84 papers published in 1995–2014 and randomly retrieved from the online databases, only 76 empirical studies from a sample of 298,329 Doppler velocimetrics met the following inclusion criteria: nullipara women (age 16–35 in the incidence studies, and age 16–45 in the prevalence studies), singleton pregnancies, numerical results of the transabdominal or transvaginal Doppler velocimetry, and level I–IIA evidence. Exclusion criteria referred to pregnancies with twins or multitons, pregnancies with reported or detected vertical infections (Toxoplasma gondii, Chlamydia trachomatis, Herpes simplex, rubella, cytomegalovirus, Chagas disease), pregnancies with systematic disorders (type-1 diabetes mellitus, bronze and nonsugar diabetes, Addison disease, antiphospholipid syndrome, anemia, lupus erythematosus, dermatomyositis, Sjögren syndrome celiac disease, cancer, nephrosis, thyroid and parathyroid disorders, obesity, anorexia), ectopic pregnancies, pregnancies with preexisting cardiac or coagulation disorders, smoking women, and studies having type-2 statistical error. The sample was stratified into the four groups with controversial findings as to the sensitivity and specificity of Doppler velocimetry in prediction of preeclampsia and FGR. Table. 1 presents the outcome-wise distribution of the study groups:
Methodology The following quality assessment criteria were utilized to achieve internal validity of the diagnostic studies: (1) Population: Consecutive recruitment of eligible women was considered as suitable. Convenience sampling (arbitrary recruitment, nonconsecutive recruitment, or attrition) was excluded from the sample. (2) Language: There was no restriction on the language of studies. (3) Setting: There was no limit for the study settings (outpatient, inpatient). (4) Restrictions: Studies published before the updated policy of the US Committee on Fetus and Newborn (1995) as to the viability margin of the fetus (age of 22 weeks vs. the former 28 weeks; fetal weight of 430 g vs. the former 1005 g, and fetal height of 27.8 cm vs. the former 37.6 cm) were excluded from the sample.
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(5) Diagnostic intervention: An UAD velocity waveform analysis was included in the sample if the scanning method (continuous wave, pulsed wave, color mapping, transabdominal, transvaginal) was reported together with the gestational age, also if the study presented cut-off values pertained to the abnormal results. (6) Techniques and parametric battery: To predict adverse perinatal outcomes, receiver-operating characteristic curves and velocimetric indices of the right and left uterine artery waveforms were obtained by the color Doppler ultrasound to measure the uterine artery RI, pulsatility index (PI), the ratio between peak systolic (A) and early diastolic (C) blood flow velocities (D/S ratio), placental position, amniotic index, fetal biophysical profile, and other parameters. (7) Major endpoints: Frequencies and the relative risk of preeclampsia, miscarriages, preterm birth, stillbirth, SGA newborns, composite neonatal morbidity, as well as odds of continuous variables (amniotic fluid index, fetal biparietal diameter, femur length, humerus length, occipitofrontal diameter, abdominal circumference, crown-rump length, Apgar scores, neonatal weight and height) were included. (8) Measurable outcomes: The highly sensitive data (fetal anomalies, abortion) or scanning performed out of the specified gestational limits were excluded from the sample. Withdrawal of women from the study, or delivery out of the hospital in which the study was conducted, were defined as attrition. Follow-up was considered ideal if > 90 % of the women, initially recruited for the study, were included in data analysis. The data from 81 to 90 % of recruited women were classified as the second best.
Essential definitions Table. 2 presents definitions applied to assess the observational and parametric data, and to make findings comparable with other studies:
Data extraction and analysis A quantitative systematic review was set forth to determine whether the inconsistent results between the studies could be explained by technical quality of the Doppler scans, cut-off values, or country-based perinatal assess-
Predictive accuracy of the first trimester Doppler scan: a meta-study
201
original article Table 2 Applied definitions The problem
Definition
Source
A/C ratio
Ratio of peak systolic to early diastolic velocity.
Cnossen et al. [36]
Any notching
Presence of early diastolic notching in waveform; can be unilateral or bilateral.
Ibid
Bilateral notching
Presence of early diastolic notching in waveform of both main uterine arteries.
Ibid
Composite neonatal morbidity
Combined rates of small for gestational age newborns, respiratory distress, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, proven sepsis, and necrotizing enterocolitis.
American Academy of Pediatrics (AAP)
Cronbach’s alpha
A coefficient of reliability or internal consistency, it is the average intercluster correlation: α = (N × c)/ (v + [N − 1] × c) where N is the number of items, v the variables, c the consistency.
UCLA [84]
D/S ratio
Ratio of diastolic to systolic velocity of the uterine artery.
[12, 17, 25–28, 31–33, 35, 44–48, 50–52, 55, 62–64, 74–76, 78]
Fetal growth restriction (FGR)
A 10-day error of the growth-adjusted sonographic age (GASA) compared with the gestational age. The FGR is diagnosed upon the estimated fetal weight (EFW) below 10th percentile for age, FL/AC greater than 23.5; and elevated BPD/AC.SYMMETRIC (25 %)—a total growth restriction, when the fetal head circumference is in proportion to the rest of the body. ASYMMETRIC (75 %)—restriction of the fetal weight followed by length, while the head continues to grow at normal rates (head sparing).
American College of Obstetrics and Gynecology (ACOG); Royal College of Obstetricians and Gynecologists (RCOG)
Growth-adjusted sonographic age (GASA)
GASA is estimated by ultrasonographic measurements of crown-rump length, biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC).
ACOG, RCOG
Fetal breathing movements (FBM)
Presence of at least 30 seconds of sustained FBM in 30 minutes of observation.
Iams et al. [81]
Fetal reactivity
Presence of two or more fetal heart accelerations of at least 15 beats/min that last at least 15 seconds and are associated with fetal movement in 40 minutes.
Ibid
Fetal tone
At least one episode of motion of a limb from a position of flexing to extension and a rapid return to flexing.
Ibid
HELLP syndrome
Hemolysis, elevated liver enzymes, and low platelet counts observed after 20 weeks of gestation.
ACOG; Mayo Clinic
Notch index (or notch depth index)
Notch flow minus early diastolic flow divided by notch flow: (D−C)/D.
Cnossen et al. [36]
Odds
The ratio of probability of the outcome to the probability of not having the outcome: p/(1 − p).
Fletcher et al. [82]
Odds ratio (OR)
A comparison of event rates between exposed and unexposed groups, calculated using odds instead of probabilities.
Ibid
Ponderal index
A ratio of the fetal body weight to the length. PI = [weight × 100] ÷ [length].
The World Health Organization (WHO)
Predictive value
Positive and negative predictive values (PPV and NPV) are the proportions of positive and negative results in statistics and diagnostic tests that are true positive and true negative results. The PPV and NPV describe the performance of a diagnostic test.
Fletcher et al. [82]
Preeclampsia
Diastolic blood pressure increased to 15 mmHg, on two occasions, at least 6 hours apart—with a difference > 5 mmHg between the arms; proteinuria (presence of 0.3 g protein in 24-h urine specimen on two random samples collected at least 4 hours apart), and HELLP syndrome—all occurring after 20 gestation weeks.
ACOG; Mayo Clinic
Preterm birth
Delivery of an infant from 23rd to 37th weeks of gestation, which approximates an average fetal weight from 500 to 2500 g, and height from 28 to 48 cm.
WHO
Pulsatility index (PI)
Peak systolic flow minus end diastolic flow divided by mean flow: (A − B)/M.
[7, 13, 31–34, 37, 55, 57, 74–77]
PI and notching
Pulsatility index combined with unilateral or bilateral early diastolic notching.
Ibid
Qualitative amniotic fluid score
A pocket of amniotic fluid that measures at least 1 cm (up to maximal 10 cm) in two perpendicular planes is considered normal (score 2). Largest pocket of amniotic fluid that measures < 1 cm in two perpendicular planes is abnormal (score 0).
ACOG
Relative risk reduction (RRR)
The percentage of diseases prevented by a treatment: RRR = (risk in unexposed−risk in exposed)/ risk in unexposed.
Fletcher et al. [82]
Resistance index (RI)
Peak systolic flow minus end diastolic flow divided by peak systolic flow: (A−B)/A.
[3, 4, 23, 25–29, 44–48, 50–54, 62–66, 71, 73]
S/D ratio
S/D ratio with or without unilateral of bilateral early diastolic notching.
[7, 11, 17, 21, 23, 25–28, 38, 44–48, 50–52, 57, 62–64, 71]
Small for gestational age (SGA)
A weight of newborn below the 10th percentile for gestational age.
Iams et al. [81]
202 Predictive accuracy of the first trimester Doppler scan: a meta-study
13
original article Table 2 (continued) The problem
Definition
Source
Sensitivity index
The ability of a test to become positive in the presence of the disease. It is defined as Tp (true positive)/(Tp + Fn [false negative]) or Tp/ (total number of clinical cases). A negative result RULES OUT a disease.
O’Conneell [83]
Specificity index
The ability of a test to remain negative in the absence of the disease. It is defined as Tn(true negative)/(Tn + Fp [false positive]) or Tn/(total number of control cases). A positive result RULES IN a disease.
Ibid
Unilateral notching
Presence of early diastolic notching in the waveform of one main uterine artery.
[7, 11, 12, 17, 20, 21, 23, 25–28, 37, 38, 44–48, 50–52, 57, 62–64, 71]
ment protocols. Calculations used the Doppler records as units of analysis. Receiver-operating characteristic curves (ROC) were utilized for multiple comparisons. The UAD medians of PI, RI, and D/S ratio were used for developing indices describing velocity changes. Studies were considered as highly informative if they had: (1) prospective design with consecutive recruitment, (2) appropriate reference standard, (3) adequate description of the index test, and (4) follow-up data in more than 90 % of patients. In each cluster, one-way analysis of variance (ANOVA) was used for continuous data; Kruskal–Wallis ANOVA was used for ranked ordinal data; and chi-squared (v2) was used where data were categorical. For binary variables, relative risk (RR) and its 95 % confidence interval (CI) were computed on an intention-to-treat basis. Continuous data were presented by weighted mean statistic with a 95 % CI. For multivariate scores, generalized estimating equations were used with an exchangeable correlation structure into which Poisson regression was fitted. Pearson’s correlations computed associations between the continuous data: PI, RI, or D/S values, fetal size, and birth weight in the completed cohorts. Spurious comparisons between the groups were checked with the help of Cronbach’s alpha (intraclass correlation). A Cronbach’s coefficient above 0.700 proved the groups comparative. Heterogeneity of results was assessed by the BreslowDay test. In presence of significant variations of study results as to the Doppler sensitivity, confounders were observed in relation to the study methods, Doppler technique (continuous wave vs. pulsed wave scanning), and gestational age at the assessment (before and after 16 pregnancy weeks) [79]. A benchmark likelihood ratio was measured for diagnostic accuracy. A likelihood ratio of 1 indicated that the test had no predictive value. Prediction was considered conclusive with likelihood ratios of > 10 or < 0.1 for a positive and negative test result, respectively. Moderate prediction was explored with likelihood ratios of 5–10 and 0.1–0.2, and minimal prediction with ratios 1–5 and 0.2–1. Sensitivity and specificity measures were obtained from the results of studies with similar Doppler indices and perinatal risk. Data were processed by ASSISTAT (version 7.5b) program [80].
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Results Table 3 demonstrates the country-based distribution of study clusters. As illustrated, the leading contributors in prenatal Doppler studies were from the UK (19.7 %) and the USA (15.8 %), followed by Italy (7.9 %), Spain (6.8 %), and Turkey (6.8 %). Roughly the one-third of studies held in the UK (29.2 %) suggested that the first trimester UAD was predictive of preeclampsia and was fairly predictive of the FGR. Studies conducted in the USA (29.4 %), Italy (11.7 %), and Turkey (11.7 %) indicated a limited predictive accuracy of the first trimester and early second trimester UAD. Absence of the UAD’s predictive value was predominately reported by Australia, Canada, and Denmark. Contributions from other countries were statistically incomparable. Table. 4 and Fig. 1 present the distribution of study designs between and within the clusters. As seen from Table. 4 and Fig. 1, the overwhelming majority of the Doppler studies were prospective cohorts scans (69.7 %), which were also overwhelmingly present in each study cluster. However, the prospective cohort studies and randomized trials prevailed in the third and fourth groups. Studies supporting the high predictive value of the UAD contained more cross section (11.5 %) and case control (19.2 %) designs than other groups. Table. 5 reports the numerical findings from each study cluster. Studies reporting the highest prediction values for preeclampsia and FGR (group 1) and for preeclampsia only (group 2) failed to show any difference in sensitivity rates (85.6 and 80.27 %, correspondingly). For example, the likelihood ratio in the first group was negative rather than positive (24.8 vs. 19.5). This can be explained by the lowest rate of prospective cohort studies in this group (61.5 %). The specificity index was higher in the second group (80.5 vs. 72.9 %). Substantial differences in bilateral and unilateral notching indices (RR 1.4 and RR 2.2, respectively) and prevalence of SGA (RR 1.7) were found between the groups at the end of the cohort. The average gestational age was 16 weeks + 4.2 days in the first group, and 16 weeks + 1 day in the second group, showing that the UAD sensitivity in predicting the FGR would sufficiently increase at 16 weeks + 3 days (or 115 days) of pregnancy.
Predictive accuracy of the first trimester Doppler scan: a meta-study
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original article
Table 3 Distribution of countries per the UAD study clusters Total Sample N (%) CI 95%
References
1 (11.1)
4 (5.2)
[2, 20, 48, 72]
–
2 (2.6)
[55, 59]
–
–
1 (1.3)
[61]
–
1 (5.9)
1 (11.1)
2 (2.6)
[67, 78]
–
1 (4.2)
–
–
1 (1.3)
[51]
1 (3.8)
–
–
–
1 (1.3)
[33]
Denmark
–
–
1 (5.9)
1 (11.1)
2 (2.6)
[11, 76]
Egypt
–
1 (4.2)
–
–
1 (1.3)
[41]
France
–
–
1 (5.9)
–
1 (1.3)
[3]
Germany
2 (7.7)
–
–
–
2 (2.6)
[21, 23]
India
–
1 (4.2)
–
–
1 (1.3)
[50]
Iran
–
1 (4.2)
–
–
1 (1.3)
[49]
Italy
3 (11.5)
–
2 (11.7)
1 (11.1)
6 (7.9)
[15, 18, 26, 60, 69, 75]
Korea
–
1 (4.2)
–
–
1 (1.3)
[44]
Mexico
–
2 (8.3)
–
–
2 (2.6)
[37, 46]
Norway
–
2 (8.3)
–
–
2 (2.6)
[38, 39]
Peru
1 (3.8)
–
–
–
1 (1.3)
[19]
Poland
2 (7.7)
–
–
–
2 (2.6)
[16, 25]
Romania
1 (3.8)
–
–
–
1 (1.3)
[32]
Russia
1 (3.8)
–
–
–
1 (1.3)
[10]
Country
Group I (n = 26)
Group II (n = 24)
Group III (n = 17)
Group IV (n = 9)
First and early second trimester UAD is predictive for preeclampsia and FGR
First and early second trimester UAD is predictive for preeclampsia, but not predictive for the FGR
First and early second trimester UAD has elusive or limited diagnostic accuracy in predicting preeclampsia and FGR
First and early second trimester UAD is not predictive for preeclampsia or FGR
N (%)
N (%)
N (%)
N (%)
Australia
1 (3.8)
2 (8.3)
–
Austria
1 (3.8)
1 (4.2)
–
Brazil
–
1 (4.2)
Canada
–
Chile Colombia
Spain
2 (7.7)
1 (4.2)
2 (11.7)
–
5 (6.8)
[12, 22, 31, 53, 59]
Swissa
1 (3.8)
–
–
–
1 (1.3)
[5] (co-authors from the UK, and the Netherlands)
Thailand
–
The Netherlands
–
–
1 (11.1)
1 (1.3)
[73]
1 (4.2)
1 (5.9)
–
2 (2.6)
[36, 70]
Turkey
2 (7.7)
1 (4.2)
2 (11.7)
–
5 (6.8)
[24, 34, 52, 58, 65]
UK
4 (15.3)
7 (29.2)
2 (11.7)
2 (22.2)
15 (19.7)
[6, 9, 27, 28, 35, 37, 42, 43, 45, 47, 54, 57, 56, 63, 74]
USA
4 (15.3)
1 (4.2)
5 (29.4)
2 (22.2)
12 (15.8)
[7, 8, 13, 14, 29, 30, 62, 64, 66, 68, 71, 77]
The average gestational age and other core indices did not vary in low prediction (group III) and no prediction (group IV) studies, with exceptions of bilateral notching index as being high in the third group (RR 2.1). Poisson regression revealed significant connections between the specificity in all groups and the frequency of SGA neonates (r2 ranged from 0.69 to 0.78). Significant correlations were found between the specificity of the third (low prediction) group, low rates of SGA newborns (r = 0.728), and bilateral notching index (r = 0.803), indicative that the prediction value of the Doppler scan depended of the uterine artery side, placental location, and the screening method (transvaginal, transabdominal). We tended to rely on findings of the
third group -- the only group pertaining to empirical evidence from the randomized control trials. In group-three, the mean PI was 0.74 if measured transabdominally, and 2.09 if measured transvaginally (RR 2.82, 95 % CI 1.95–3.02). The transabdominal mean PI was negatively correlated with the CRL index (r = − 0.405). Pearson’s correlations between the transvaginally measured PI index and CRL index proved to be negative too, but statistically stronger (r = − 0.526). The diastolic notch for preeclampsia and SGA was 29.4 and 16.5 %, with a corresponding specificity of 66.7 and 64.8 %. The best screening test for preeclampsia and SGA infants appeared to be the placental side uterine artery RI or D/S ratio above the 90th percentile for gestational
204 Predictive accuracy of the first trimester Doppler scan: a meta-study
13
original article Fig. 1 Intra- and intercluster distribution of study designs
Table 4 Intra- and intercluster distribution of the study designs Study design
Group I (n = 26)
Group II (n = 24)
Group III (n = 17)
Group IV (n = 9)
N (%)
N (%)
N (%)
N (%)
Total N (%)
Case control
5 (19.2)
3 (12.5)
–
1 (11.1)
7 (9.2)
Cross section
3 (11.5)
2 (8.4)
–
–
5 (6.6)
Prospective cohort
16 (61.5)
15 (62.5)
14 (82.3)
8 (88.9)
53 (69.7)
Randomized control
–
–
1 (5.9)
–
1 (1.3)
Systematic reviews
2 (7.7)
3 (12.5)
2 (11.8)
–
7 (9.2)
age when the placenta was located on either side of the uterus, and the highest—when the placenta was on the midline. In the first (highly prediction) group, this method identified 57 % of women with subsequent preeclampsia (versus 51.6 % from the group total) and had a positive predictive value (71 %). For the FGR, the pooled likelihood ratios were similarly disappointing in all groups: the obtained averages were 57.8, 35, 7.8, and 18.9 % for the positive test results and 14, 10.2, 1.4, and 2.9 %—for the negative test results, respectively.
Discussion The current effort covered 76 published studies pertaining to the level I–IIA evidence, and presenting 298,329 prenatal Doppler screenings in nullipara women (age 16–35 in the incidence studies, and age 16–45 in the prevalence studies), performed in the first and early second trimesters of singleton pregnancies. The sample was stratified into the four groups to inform controversial findings as to the sensitivity and specificity of Doppler velocimetry in prediction of preeclampsia and FGR. Of the total sample, 9.2 % were retrospective case control, 69.7 % prospective cohort, 6.6 % cross section, 1.3 % randomized control studies, and 9.3 % were systematic reviews. The leading contributors
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in this field were from the UK (19.7 %), the USA (15.8 %), Italy (7.9 %), Spain (6.8 %), and Turkey (6.8 %). Each subgroups had a statistically solid sample size (ranging from 15,000–115,000 screenings), producing heterogenous estimates confirmed by intra-cluster correlation analysis. Post-test likelihood analysis revealed probability of certain test results, indicative that the findings of this meta-study were clinically accountable. Generally agreed, preeclampsia should only be diagnosed after the 20th gestational week, based on diastolic blood pressure increased to 15 mmHg—on two occasions, at least 6 hours apart, a > 0.3-g proteinuria in 24-hour urine specimen on two random samples, and HELLP syndrome. However, the growing research body suggests that preeclampsia and related FGR are predictable by the Doppler sonography as early as in the first trimester. Bayes’ theorem implies that the predictive accuracy of any test is conditional on the overall prevalence of disease in tested population. Hence, we were determined to analyze the UAD flow velocimetry results with different predictive likelihood ratios. In the line with 17 studies [3, 11, 12, 57–70] forming the third diagnostic group, our findings suggest that the use of UAD has limited diagnostic prediction of preeclampsia and fetal growth retardation. Accordingly, we do not recommend this method in a routine screening of nullipara women at the first and early second trimesters. Never-
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Table 5 Parametric properties of the study clusters Groups I
II
III
IV
Sensitivity
85.6
Specificity
72.9
PLR
19.5
NLR
24.83
Sensitivity
80.27
Specificity
80.5
PLR
69.3
NLR
48.5
Sensitivity
47.6
Specificity
65.6
PLR
3.1
NLR
0.8
Sensitivity
52.9
Specificity
48.9
PLR
12.3
NLR
4.6
Sample
GW
PI
RI
BN (%)
UN (%)
S/D
PE (%)
SGA (%)
64 397
16.6 ± 0.73
0.89 ± 0.73
0.64 ± 0.12
19.6
10.4
2.05 ± 0.32
51.8
56.8
114 933
16.1 ± 0.91
1.4 ± 0.5
0.71 ± 0.34
28.6
23.2
4.5 ± 0.09
42.5
34.1
104 291
15.7 ± 0.59
0.78 ± 0.46
0.59 ± 0.47
39
32.4
5.2 ± 0.36
19.4
7.15
14 708
15.7 ± 0.69
0.83 ± 0.26
1.08 ± 0.75
18.5
23
6.1 ± 0.13
23.9
17.3
The reported outcomes are based on 95 % CI level and P < 0.005 a Abbreviations for the pooled means, percentiles, index averages, and standard deviations: PLR positive likelihood ratio, NLR negative likelihood ratio, GW gestation week at scanning, PI pulsatility index, RI resistance or notch index ((D − C)/D), BN bilateral notching, UN unilateral notching, S/D systolic-diastolic flow ratio, PE preeclampsia, SGA small for gestational age fetus or newborn
theless, this study is clinically informative, for it depicts certain UAD parameters contributing to predictive perinatal diagnostic.
Study limitations Owing to its design, this meta-study was unable to capture the temporal order between the variables. For example, preeclampsia could be both the cause and the outcome of the altered coagulation battery. Next, this study was restricted in terms of the thresholds and Doppler indices from independently reported likelihood ratios. Lastly, our quality assessment was hindered by the lack of information and clinical interpretation of a few scans—a common problem in cross section or case–control studies. The strength of our study was in its multi-cluster assessment, also in its content of the updated research material without language restrictions.
Conclusions The first trimester UAD has limited predictive value for the adverse perinatal outcomes. The UAD sensitivity in prediction of preeclampsia and FGR tacitly increases after the 16 weeks + 3 days (115 days) of gestation. Significant connections are found between the diagnostic specificity (but not sensitivity) and frequency of SGA neonates (r2 = 0.69–0.78). Negative associations are found between the detectionof SGA newborns (r = 0.728) and bilateral notching
index (r = 0.803). Pulsatility index (PI) measured transabdominally is lower than that measured transvaginally (RR 2.82). The PI is negatively correlated with the CRL index, which is more expressed in the transvaginal scans (r = − 0.526). The best predictive parameter for preeclampsia and FGR is the placental side uterine artery RI which is the highest when the placenta is on the midline (OR 0.9).
Disclaimer (1) This study, or any part of it, has not been published elsewhere. (2) As a meta-analysis, this study had no direct interaction with the human subjects, animal models, organs, tissues, or biological liquids, therefore it did not seek an IRB approval. (3) The author reports no financial or strategical relationship with the entities, products, or competing products indicated in this study. Author’s contribution The author solely performed the data collection, data cleaning, double cleaning, prioritizing, quantitative and qualitative analyses, summary, manuscript writing, and editing. Ethics compliance This was a meta-study without involving human subjects or animal models.
206 Predictive accuracy of the first trimester Doppler scan: a meta-study
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original article
Conflict of interest The author declares no conflict of interests with the entities, other authors, products or competing products indicated in this study.
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