ABSTRACT
We investigated the value of measuring sFlt‐1/PlGF in people with suspected fetal growth restriction (sFGR) without signs of preeclampsia at recruitment. Angiogenic biomarkers were considered positive when sFlt‐1/PlGF > 38 or PlGF < 100 pg/mL. Clinicians were blinded to the sFlt‐1/PlGF results. In sFGR presenting < 32 weeks, but not ≥ 32–37 weeks, positive angiogenic biomarkers vs. NZ FGR criteria had increased risk of preterm birth RR 5.32 [2.04–13.88] vs. 2.19 [0.89–5.37], respectively, and birthweight < 3rd centile RR 2.11 [1.24–3.58] vs. 1.83 [0.92–3.63], respectively. Larger studies are needed to establish whether routine testing of angiogenic biomarkers in sFGR is recommended for risk stratification.
Keywords: fetal growth restriction, placental growth factor, placental insufficiency, small for gestational age, vascular endothelial growth factor receptor‐1
1. Introduction
The angiogenic factors soluble fms‐like tyrosine kinase 1 (sFlt‐1) and placental growth factor (PlGF) are biomarkers of placental insufficiency. Both sFlt‐1/PlGF and PlGF are useful in ruling in/out preeclampsia, and abnormal levels are associated with a shorter interval to birth and a higher risk of adverse pregnancy outcome [1, 2, 3]. Emerging evidence suggests that angiogenic factors may have added value in the detection and risk stratification of fetal growth restriction (FGR), when used in addition to fetal growth ultrasound and Doppler measurements [4, 5, 6, 7].
The 2023 revised ‘Small for Gestational Age and Fetal Growth Restriction in Aotearoa New Zealand’ clinical practice guideline’ [8] aims to reduce rates of perinatal mortality and morbidity associated with FGR by standardising care across NZ. The focus is on identifying pregnancies complicated by placental insufficiency, the most common cause of FGR.
Our aim was to investigate the potential added value of measuring angiogenic biomarkers for placental insufficiency, sFlt‐1/PlGF or PlGF, at presentation in a targeted group referred with suspected FGR (sFGR), to predict preterm birth and birthweight < 3rd centile.
2. Materials and Methods
This is a post hoc subgroup analysis of a prospective single‐centre cohort study conducted at a tertiary NZ hospital with 6000 births per annum [9]. The NZ Health and Disability Ethics Committees approved the study, reference number 18/STH/120; Australian New Zealand Clinical Trials Registry, ACTRN12620001186943. Inclusion criteria were age ≥ 18 years, and a live singleton pregnancy between 20 and 36 + 6 weeks' gestation referred with sFGR. Exclusion criteria were known fetal chromosomal or major congenital anomaly, inability to provide written informed consent, suspected preeclampsia defined as the presence of new onset hypertension ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic, or worsening of pre‐existing hypertension, after 20 weeks' gestation, with or without renal, haematological, liver, neurological involvement or pulmonary oedema. Eligible participants were sequentially recruited from hospital outpatient clinics, having been referred with sFGR on ultrasound scan (USS) from September 2018 to December 2020 and followed until birth. Only the sFlt‐1/PlGF and USS and Doppler parameters measured in‐hospital at recruitment were used for analyses. Clinicians and investigators were blinded to sFlt‐1/PlGF results, which were batch analysed after all participants had birthed. Elecsys assays for sFlt‐1 and PlGF (Roche Diagnostics International Ltd) were performed following one freeze–thaw cycle, at a local laboratory holding International Accreditation New Zealand (IANZ) accreditation. A sFlt‐1/PlGF > 38 and PlGF < 100 pg/mL were classified as angiogenic biomarker positive [1, 2, 9, 10].
Pregnancies were dated by USS ≤ 13 weeks gestation. The 2023 NZ FGR criteria [8] were applied retrospectively, defined as
Early‐onset FGR < 32 weeks gestation at diagnosis:
Estimated fetal weight (EFW) customised or abdominal circumference (AC) < 3rd centile; or umbilical artery Doppler (UA) with absent or reversed end‐diastolic flow; or EFW customised or AC < 10th centile plus ≥ 1 of UA Doppler pulsatility index (PI) > 95th centile, uterine artery (UtA) Doppler mean PI > 95th centile or bilateral notching (perform only once at the time of diagnosis).
Late onset FGR ≥ 32 weeks gestation at diagnosis:
EFW customised or AC < 3rd centile; or ≥ 2 of EFW customised or AC < 10th centile, decline in EFW or AC of > 30 centiles from 28+0 weeks' gestation onwards, UA Doppler PI > 95th centile, cerebroplacental ratio (CPR) < 5th centile, or UtA mean PI > 95th centile or bilateral notching (perform only once at the time of diagnosis).
Customised birthweight centiles were calculated using the GROW Bulk Centiles Calculator (GROW version 6.7.8_NZ, 2021, Gestation Network, https://www.gestation.net). Outcome data were collected from electronic and paper hospital records and managed using REDCap (Research Electronic Data Capture, https://www.projectredcap.org). Data entries were checked for accuracy by two researchers. The statistical software package Stata 17 (StataCorp LLC, College Station, TX, USA) was used for analysis. Data were analysed using the 2‐tailed Fisher's exact test, unpaired T‐test or Mann–Whitney U test, as appropriate, p < 0.05 was considered statistically significant, and odds ratios were calculated for significant results when all fields were greater than zero. As this is a small exploratory study, adjustments for multiple comparisons were not conducted.
3. Results
Included were 77 pregnancies with sFGR, ethnicity was self‐reported as Māori n = 7 (9.1%), Indian n = 15 (19.5%), other Asian n = 11 (14.3%), European n = 41(53.2%) and other n = 3 (3.9%); median (IQR) age 31.5 (26.8–35.2) years, body mass index 24 (21.6–30.4) kg/m2, and median parity 1 (range 0–3).
Outcomes are reported in Tables 1 and 2. For sFGR presenting < 32 weeks, positive angiogenic biomarkers were associated with a higher risk ratio for birth < 37 weeks gestation and customised birthweight < 3rd centile than FGR criteria. For sFGR presenting ≥ 32–37 weeks gestation, no meaningful differences in risk prediction were found.
TABLE 1.
Performance of angiogenic biomarkers in risk stratification for preterm birth and birthweight < 3rd customised centile in pregnancies with suspected fetal growth restriction.
| Risk ratio [95% CI] | Sensitivity [95% CI] | Specificity [95% CI] | PPV [95% CI] | NPV [95% CI] | ||
|---|---|---|---|---|---|---|
| 20 to < 32 weeks at presentation | ||||||
| Prediction birth < 37 weeks | NZ FGR criteria | 2.19 [0.89–5.37] | 66.7% [38.4–88.2] | 62.1% [42.3–79.3] | 47.6% [33.6–62.1] | 78.3% [62.5–88.6] |
| Angiogenic biomarkers | 5.32 [2.04–13.88] | 73.3% [44.9–92.2] | 86.2% [68.3–96.1] | 73.3% [51.3–87.8] | 86.2% [72.7–93.6] | |
| NZ FGR criteria including angiogenic biomarkers | 4.09 [1.05–15.93] | 86.7% [59.5–98.3] | 51.7% [32.5–70.6] | 48.2% [37.7–58.7] | 88.2% [66.3–96.6] | |
| Prediction birthweight < 3rd customised centile | NZ FGR criteria | 1.83 [0.92–3.63] | 60.9% [38.5–80.3] | 66.7% [43.0–85.4] | 66.7% [50.1–79.9] | 60.8% [46.2–73.8] |
| Angiogenic biomarkers | 2.11 [1.24–3.58] | 52.2% [30.6–73.2] | 85.7% [63.7–97.0] | 80.0% [56.7–92.5] | 62.1% [50.8–72.2] | |
| NZ FGR criteria including angiogenic biomarkers | 2.27 [1.04–4.96] | 78.6% [56.3–92.5] | 57.1% [34.0–78.2] | 66.7% [53.9–77.4] | 70.6% [50.4–85.0] | |
| 32 to < 37 weeks at presentation | ||||||
| Prediction birth < 37 weeks | NZ FGR criteria | 6.38 [0.86–47.28] | 85.7% [42.1–99.6] | 61.5% [40.6–79.8] | 37.5% [25.3–51.5] | 94.1% [71.8%–99.0%] |
| Angiogenic biomarkers | 3.07 [0.84–11.25] | 57.1% [18.4–90.1] | 76.9% [56.4–91.0] | 40.0% [20.5–63.3] | 87.0% [73.4–94.2] | |
| NZ FGR criteria including angiogenic biomarkers | 8.33 [1.10–63.35] | 85.7% [42.1–99.6] | 53.9% [33.4–73.4] | 33.3% [23.0–45.5] | 93.3% [68.8–98.9] | |
| Prediction birthweight < 3rd customised centile | NZ FGR criteria | 1.06 [0.38–2.94] | 50.0% [18.7–81.3] | 52.2% [30.6–73.2] | 31.3% [17.6–49.1] | 70.6% [53.6–83.3] |
| Angiogenic biomarkers | 1.53 [0.55–4.27] | 40.0% [12.2–73.8] | 73.9% [51.6–89.8] | 40.0% [19.3–65.0] | 73.9% [61.8–83.2] | |
| NZ FGR criteria including angiogenic biomarkers | 1.25 [0.43–3.62] | 60.0% [26.2–87.8] | 47.8% [26.8–69.4] | 33.3% [20.9–48.7] | 73.3% [53.5–86.8] |
Abbreviations: CI, confidence intervals; NPV, negative predictive value; NZ FGR Criteria, New Zealand fetal growth restriction criteria; PPV, positive predictive value.
TABLE 2.
Birth outcomes in pregnancies complicated with suspected fetal growth restriction stratified by NZ fetal growth restriction and angiogenic biomarker criteria.
| Suspected fetal growth restriction < 32 weeks gestation | ||||||
|---|---|---|---|---|---|---|
| 20 to < 32 weeks at presentation, n = 44 | NZ FGR criteria positive, n = 21 | Angiogenic biomarker criteria positive, n = 15 | p OR (95% CI) | Both criteria positive, n = 9 | Both criteria negative, n = 17 | p OR (95% CI) |
| Smoking | 3 (14.3%) | 3 (20.0%) | 0.67 | 1 (11.1%) | 4 (23.5%) | 0.51 |
| Preeclampsia | 5 (23.8%) | 8 (53.3%) | 0.09 | 5 (55.6%) | 0 | < 0.01 |
| Gestation at birth (weeks) median (IQR) | 37.1 (31.6–38.1) | 32.6 (28.6–36.2) | 0.18 | 29 (27–32) | 39.1 (38.4–40.1) | < 0.001 |
| Birth gestation < 32 weeks | 6 (28.6%) | 6 (40%) | 0.50 | 6 (66.7%) | 0 | < 0.001 |
| Caesarean section | 14 (66.7%) | 11 (73.3%) | 0.69 | 8 (88.9%) | 5 (29.4%) | < 0.01 OR 19.2 (1.9–196.5) |
| Customised birthweight centile median (IQR) | 0.9 (0.3–4.9) | 0.5 (0.1–1.65) | 0.70 | 0.3 (0–0.5) | 9.2 (1.8–26.7) | 0.02 |
| Customised birthweight centile < 3rd | 15 (71.4%) | 12 (80.0%) | 0.59 | 8 (88.9%) | 5 (29.4%) | < 0.01 OR 19.2 (1.9–196.5) |
| Neonatal unit admission | 9 (42.9%) | 12 (80.0%) | 0.03 OR 5.3 (1.2–24.7) | 8 (88.9%) | 2 (11.8%) | < 0.001 OR 60 (4.7–767.7) |
| Neonatal unit length of stay (days) median (IQR) | 62 (27–98) | 62 (27–98) | 93 (68–104) | 28 (20–36) | ||
| Suspected fetal growth restriction ≥ 32 to < 37 weeks gestation | ||||||
|---|---|---|---|---|---|---|
| 32 to < 37 weeks at presentation, n = 33 | NZ FGR criteria positive, n = 16 | Angiogenic biomarker criteria positive, n = 10 | p OR (95% CI) | Both criteria positive, n = 8 | Both criteria negative, n = 15 | p OR (95% CI) |
| Smoking | 3 (18.8%) | 0 | 0.22 | 0 | 5 (33.3%) | 0.09 |
| Preeclampsia | 1 (6.3%) | 1 (10.0%) | 0.80 | 1 (12.5%) | 1 (6.7%) | 0.70 |
| Gestation at birth (weeks) median (IQR) | 38.0 (36.6–38.3) | 37.6 (36.5–38.4) | 0.93 | 37.0 (36.3–38.2) | 39.3 (38.1–40.2) | < 0.01 |
| Caesarean section | 8 (50.0%) | 5 (50.0%) | 0.99 | 4 (50.0%) | 3 (20.0%) | 0.18 |
| Customised birthweight centile median (IQR) | 5.4 (2.5–9.9) | 5.4 (1.5–10.7) | 0.92 | 5.4 (2.3–9.9) | 12.2 (3.0–40.2) | 0.09 |
| Customised birthweight centile < 3rd | 5 (31.3%) | 4 (40.0%) | 0.67 | 3 (37.5%) | 4 (26.7%) | 0.62 |
| Neonatal unit admission | 5 (31.3%) | 4 (40.0%) | 0.67 | 4 (50.0%) | 1 (7.0%) | 0.03 OR 14 (1.2–163.3) |
| Neonatal unit length of stay (days) median (IQR) | 27 (17–30) | 22 (16–32) | 22 (16–32) | 10 | ||
Abbreviations: IQR, interquartile range; NZ FGR Criteria, New Zealand fetal growth restriction criteria; OR, odds ratio (95% confidence limits).
Angiogenic biomarkers were positive when NZ FGR criteria were negative in seven people, reflecting additional participants with placental insufficiency at recruitment. Five presented < 32 weeks and 2 presented between 32 and 37 weeks: four had customised birthweight centiles < 3rd, one was on 3rd centile, two were < 24th centile; 3 developed preeclampsia; 3 birthed at 32–35 weeks gestation and 4 babies were admitted to the neonatal unit, for 20–36 days.
In sFGR presenting < 32 weeks gestation, both angiogenic biomarkers and NZ FGR criteria were negative in 17 participants, and both were positive in 9 participants. Comparing these groups, there were no cases of preeclampsia in participants with dual negative criteria, and a greater odds of caesarean section, birthweight < 3rd customised centile and neonatal unit admission in those with dual positive criteria.
4. Discussion
We found that for sFGR < 32 weeks gestation, measuring angiogenic biomarkers at presentation has the potential to improve risk stratification above the NZ FGR criteria alone, with a higher risk of preterm birth and customised birthweight centile < 3rd centile. Furthermore, 7 participants had positive angiogenic biomarkers at presentation who did not meet NZ FGR criteria and subsequently a high rate of adverse pregnancy outcome. Thus, sFlt‐1/PlGF testing may identify an additional group with placentally mediated FGR missed by standard ultrasonography and Doppler measures performed at first presentation with sFGR. Our data suggest that integration of sFlt‐1/PlGF testing into clinical practice may have added value as an additional criterion for placentally mediated FGR in pregnancies with sFGR < 32 weeks gestation. Thus providing an early indicator of placental insufficiency with increased risk of preterm birth and severe FGR and the opportunity to tailor clinical management.
A strength of this study is that clinicians were blinded to the sFlt‐1 and PlGF results, and thus medical management was not influenced. Growth scans are not routine in NZ, but targeted to those with risk factors, or sFGR, therefore the gestation of onset of FGR may be overestimated. A major weakness is the small sample size, this subgroup analysis is under‐powered to adequately assess differences in test characteristics between NZ FGR and angiogenic biomarker criteria, particularly in sFGR presenting ≥ 32 weeks gestation. In support of our findings, others have found angiogenic factor measurements useful in the assessment of sFGR. A large Spanish study of FGR and small for gestational age (SGA) found the sFlt‐1/PlGF level showed good correlation with the severity of feto‐placental Doppler abnormalities and may be useful to classify FGR severity when Doppler assessment is not feasible [11]. In early‐ and late‐onset FGR, sFlt‐1/PlGF and PlGF predict faster clinical deterioration [7, 12, 13, 14] and FGR secondary to placental dysfunction [10, 15]. sFlt‐1/PlGF also predicts lower birthweight in SGA [16, 17]. Furthermore, in predicting adverse outcomes in FGR, models integrating angiogenic biomarkers outperform models using fetal ultrasound and Doppler parameters alone [4, 18].
It can be difficult to distinguish FGR from a constitutionally small fetus. Abnormalities in sFlt‐1/PlGF and PlGF are seen in several placental vascular bed pathologies associated with early‐onset preeclampsia and FGR [15, 19], including maternal vascular malformation, chronic histiocytic intervillositis (CHI) and massive perivillous fibrinoid deposition (MPVED). Canadian researchers found that a low PlGF was a better predictor of all three placental pathologies than uterine artery Dopplers and better predicted recurrence of CHI and MPVED in subsequent pregnancies [19]. Mounting evidence suggests that ‘obstetrical syndromes’ of FGR, preterm birth, placental abruption and preeclampsia may have a similar underlying pathology, with the failure of deep placentation in the second trimester via the second wave of extravillous trophoblast invasion, which is dependent on adequate PlGF [20]. A low PlGF measured in the early second trimester is a predictor of placental insufficiency [6, 10, 19].
In New Zealand, babies born prematurely with a customised birthweight < 5th centile have substantially higher mortality rates than others [8]. Māori, Indian and Pacific people and those living in areas of high deprivation are particularly at risk of adverse perinatal outcomes [8]. Measurement of sFlt‐1/PlGF is an additional screening tool for placental insufficiency in sFGR, especially when Doppler measurement is unavailable, and may help reduce health outcome disparities by identifying those at higher risk for perinatal related morbidity and mortality.
5. Conclusion
Angiogenic factors show promise in risk stratification of sFGR < 32 weeks gestation. In sFGR, a sFlt‐1/PlGF > 38 or PlGF < 100 pg/mL may also identify an additional group with placentally mediated FGR missed by current NZ FGR criteria. This study is underpowered to fully understand the value of sFlt‐1/PlGF analysis in sFGR, but the results are useful in informing the design of larger trials. We encourage further research in this area, which may ultimately address some of the health outcome inequities related to placental insufficiency and FGR.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
Roche Diagnostics ltd. supported this study, supplying the reagents and consumables required to perform the sFlt‐1/PlGF analysis. The authors received no fees or other monitory support from Roche Diagnostics. We thank Dr. Coleen Caldwell for assisting with the Ethics application and initial study set‐up; Di Leishman research midwife, for assisting in both recruitment and data entry and Dr. Jonathan Williman biostatistician, for statistical support. Open access publishing facilitated by University of Otago, as part of the Wiley ‐ University of Otago agreement via the Council of Australian University Librarians.
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