Abstract
Objectives
To prospectively validate the association between fetal heart rate (FHR) at the 12‐week scan and the risk of preterm birth (PTB), including spontaneous preterm birth (sPTB).
Methods
This prospective cohort study included 1276 singleton pregnancies undergoing routine first‐trimester screening at 11–13 + 6 weeks' gestation and followed until delivery. Associations between FHR and PTB outcomes were assessed using univariable and multivariable logistic regression analyses and receiver operating characteristic (ROC) curves, incorporating clinical, sonographic, and biochemical first‐trimester parameters.
Results
Compared with term births, pregnancies resulting in PTB (n = 34) and sPTB (n = 23) showed significantly higher FHR at the 12‐week scan (163.6 versus 160.1 bpm, p = .007; and 164.1 versus 160.1 bpm, p = .014, respectively). In univariable analyses, FHR was the only parameter consistently associated with PTB, PTB <34 weeks, sPTB, and sPTB <34 weeks (odds ratios per bpm increase ranging from 1.08 to 1.12). Free β‐human chorionic gonadotropin (free‐βhCG) was associated with PTB <34 weeks and showed borderline significance for other PTB outcomes. In multivariable models, FHR showed the highest predictive performance for sPTB <34 weeks (AUC 0.73; detection rate 25% at a 10% false‐positive rate), which improved when combined with free‐βhCG (AUC 0.81; detection rate 43% at a 10% false‐positive rate).
Conclusion
Elevated FHR at the 12‐week scan is associated with sPTB, particularly before 34 weeks' gestation. FHR, especially when combined with free‐βhCG, may contribute to early first‐trimester screening strategies for sPTB.
Keywords: fetal heart rate, first trimester, free‐βhCG, preterm birth, spontaneous preterm birth
Abbreviations
- AIC
Akaike information criterion
- AUC
area under the curve
- CRL
crown–rump length
- DR
detection rate
- FHR
fetal heart rate
- FPR
false‐positive rate
- GA
gestational age
- IQR
interquartile range
- NT
nuchal translucency
- PAPP‐A
pregnancy‐associated plasma protein‐A
- PTB
preterm birth
- ROC
receiver operating characteristic
- sPTB
spontaneous preterm birth
Spontaneous preterm birth (sPTB) is a heterogeneous inflammatory syndrome that results in delivery at an early gestational age (GA) and remains a leading cause of neonatal morbidity and mortality worldwide. 1 Although sPTB can be triggered by multiple mechanisms, inflammation, often related to local or distant infection, is considered a central pathway initiating the cascade leading to preterm labor. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 Current screening strategies for sPTB rely mainly on mid‐pregnancy assessment, particularly transvaginal measurement of cervical length at approximately 20 weeks' gestation. 10 , 11 However, at this stage, the biological processes leading to preterm labor may already be established, potentially limiting the effectiveness of preventive interventions. This limitation underscores the need to identify reliable first‐trimester markers that allow for earlier risk stratification and timely primary prevention.
In a recent retrospective study conducted in a tertiary referral population, we reported an association between first‐trimester fetal heart rate (FHR) and preterm birth (PTB) across different GA thresholds. 12 Given the simplicity, reproducibility, and universal availability of FHR measurement during routine first‐trimester ultrasound, validation of this finding in a prospective and independent population is essential.
The aim of the present study was therefore to prospectively validate the previous association between FHR at the 12‐week scan and the risk of PTB and sPTB in a regional hospital setting, incorporating not only clinical and sonographic parameters but also biochemical markers routinely used for first‐trimester aneuploidy screening.
Study Design and Population
This prospective cohort study included 1276 singleton pregnancies undergoing routine first‐trimester evaluation at Hospital Universitario Francisco de Borja (Gandía, Spain). All pregnancies were examined between 11 and 13 + 6 weeks' gestation and followed until delivery.
The first‐trimester assessment included measurement of crown–rump length (CRL) for pregnancy dating, nuchal translucency (NT), and FHR, as well as biochemical analysis of pregnancy‐associated plasma protein‐A (PAPP‐A) and free β‐human chorionic gonadotropin (free‐βhCG), obtained approximately 2 weeks earlier as part of the combined screening for aneuploidy. Maternal characteristics recorded included age, pre‐pregnancy weight and height, parity, GA at examination, and fetal sex.
Ultrasound examinations were performed using a General Electric Voluson® E8 system with 2–8 MHz transabdominal convex probes.
Exclusion Criteria
Multiple pregnancies, pregnancies with a history of previous PTB, maternal chronic conditions predisposing to PTB, and pregnancies complicated by major fetal structural anomalies or chromosomal abnormalities were excluded (Figure 1).
Figure 1.
Flow chart illustrating the inclusion and exclusion of participants in the study population.
Follow‐Up and Outcome Assessment
Pregnancies were managed according to local hospital protocols 10 and followed until delivery. Outcome data collected included GA at birth, birthweight, birthweight centile, mode of labor onset (spontaneous, induction, or cesarean section), mode of delivery, Apgar score, and umbilical arterial pH.
Definitions of Outcomes
Preterm birth (PTB) was defined as delivery before 37 weeks' gestation, and PTB <34 weeks as delivery before 34 weeks, irrespective of the mode of onset or medical indication.
sPTB and sPTB <34 weeks were strictly defined as deliveries occurring spontaneously before 37 and 34 weeks' gestation, respectively, excluding all cases of medically indicated induction or cesarean delivery for maternal or fetal complications.
Statistical Analysis
Continuous variables are presented as median and interquartile range (IQR), and categorical variables as number and percentage. Comparisons between groups were performed using the Mann–Whitney U test or Kruskal–Wallis test for continuous variables and the χ 2 test for categorical variables.
Univariable logistic regression analyses were conducted to assess the association of each first‐trimester parameter with PTB, sPTB, PTB <34 weeks, and sPTB <34 weeks. Variables showing statistical significance or borderline significance were entered into multivariable logistic regression models. Model performance was assessed using receiver operating characteristic (ROC) curves, area under the curve (AUC), detection rate (DR), false‐positive rate (FPR), and Akaike information criterion (AIC). A difference of ≥2 units in AIC was considered significant.
Statistical analyses were performed using StatPlus® (version 7) and GraphPad Prism® (version 9). Statistical significance was set at p < .05.
Ethical Approval
The study was approved by the ethics committees of Hospital Universitario Francisco de Borja (registry number 8/2021) and Hospital Universitario y Politécnico La Fe (registry number 2022‐555‐1).
Results
Study Population
Baseline characteristics of the study population are summarized in Table 1. The mean maternal age was 31.2 years, mean pre‐pregnancy weight 71.1 kg, mean height 163 cm, mean parity 0.72, and mean GA at delivery was 39.6 weeks. Overall, 16.9% of women reported smoking during pregnancy, 6.3% conceived by assisted reproductive techniques, 49.0% were nulliparous, and 15.4% had hypothyroidism diagnosed during pregnancy.
Table 1.
Description of the Study Population (N = 1276) and the Population Presenting Any Preterm (N = 34), Spontaneous Preterm (N = 23), and Term Births (N = 1242)
| Parameter | 1. All Pregnancies (N = 1276) | 2. Any Preterm Birth (N = 34) | 3. Spontaneous Preterm Birth (N = 23) | 4. Term Birth (N = 1242) | 2 vs 4 | 3 vs 4 |
|---|---|---|---|---|---|---|
| Mean (SD); median (1st, 3rd quartile) | Mean (SD); median (1st, 3rd quartile) | Mean (SD); median (1st, 3rd quartile) | Mean (SD); median (1st, 3rd quartile) | p‐Value a | p‐Value a | |
| Maternal age (year) | 31.2 (5.96); 32.0 (27.0, 35.0) | 31.06 (5.4); 30.5 (27.75, 36.25) | 31.1 (5.2); 30.0 (28.0,36.0) | 31.16 (5.9); 32 (27, 35) | .7701 | .7754 |
| Maternal pre‐pregnancy weight (kg) | 71.1 (14.9); 69.5 (60, 79) | 75.12 (20.5); 70.5 (58.7, 90.2) | 70.4 (16.1); 67.2 (58.5, 87.3) | 71 (14.7); 69.5 (60.1, 79) | .4704 | .6555 |
| Maternal height (cm) | 163.0 (5.9); 163 (159, 167) | 163.3 (6.4); 163 (157, 168) | 163.2 (6.4); 163.0 (157.0, 168.0) | 163.0 (5.9); 163 (159, 167) | .7468 | .9726 |
| Parity | 0.72 (0.87); 1 (0, 1) | 0.62 (0.85); 0 (0, 1) | 0.69 (0.92); 0 (0, 1) | 0.73 (0.87); 1 (0, 1) | .3874 | .7311 |
| Gestational age at ultrasound scan (week) | 12.44 (0.44); 12.28 (12.0, 12.71) | 12.4 (0.46); 12.28 (12.0, 12.71) | 12.34 (0.39); 12.28 (12.0, 12.57) | 12.44 (0.44); 12.28 (12, 12.71) | .6726 | .4604 |
| PAPP‐A (mU/mL) | 3.575 (2.187); 3.11 (1.96, 4.71) | 3.39 (2.592); 2.70 (1.57, 4.178) | 3.89 (2.93); 3.04 (1.73, 5.73) | 3.58 (2.18); 3.12 (1.98, 4.72) | .2349 | .9267 |
| Free‐βhCG (mU/mL) | 44.9 (267.9); 29.7 (19.32, 46.32) | 46.6 (41.27); 34 (20.6, 58.86) | 49.2 (47.9); 33.2 (21.4, 57.3) | 37.0 (27.95); 29.56 (19.25, 45.89) | .1316 | .2253 |
| Leukocytes count (μL) | 8357 (1991); 8200 (7000, 9500) | 8434 (1545); 8450 (7325, 9275) | 8473 (1673); 8450 (7200, 9350) | 8355 (2001); 8200 (7000, 9500) | .5851 | .6275 |
| Neutrophils count (μL) | 5311 (1603); 5200 (4200, 6200) | 5316 (1019); 5250 (4550, 5775) | 5286 (1080): 5200 (4475, 5700) | 5311 (1616); 5200 (4200, 6300) | .7393 | .8990 |
| Lymphocytes count (μL) | 2304 (1190); 2200 (1800, 2600) | 2334 (661); 2250 (1800, 2600) | 2377 (707); 2350 (1775, 2800) | 2303 (1201); 2200 (1800, 2600) | .7096 | .5452 |
| Nuchal translucency (mm) | 1.55 (0.39); 1.50 (1.30, 1.75) | 1.61 (0.32); 1.58 (1.39, 1.74) | 1.68 (0.34); 1.70 (1.40, 1.90) | 1.55 (0.39); 1.50 (1.30, 1.76) | .2568 | .0788 |
| Crown rump length (mm) | 63.3 (16.0); 62.5 (58.1, 67.3) | 62.5 (6.6) 62.6 (56.8, 67.0) | 62.2 (6.28); 62.5 (56.8, 66.1) | 63.35 (16.23); 62.5 (58.1, 67.3) | .6377 | .5389 |
| Fetal heart rate (bpm) | 160.2 (7.07); 160 (156, 164) | 163.6 (1.12); 163.5 (158.8, 167.3) | 164.1 (6.8); 164 (159, 168) | 160.1 (7.06); 160.0 (155.0, 164.0) | .0072 | .0144 |
| Gestational age at delivery (week) | 39.6 (1.6); 39.8 (38.8, 40.6) | 33.74 (3.5); 35.07 (33.03, 36.04) | 33.56 (3.7); 35.0 (32.7, 36.0) | 39.76 (1.12); 39.85 (39, 40.57) | <.0001 | <.0001 |
| Birth weight (g) | 3337 (502.8); 3340 (3046, 3660) | 2246 (696.7); 2397 (1879, 2688) | 2236 (737); 2394 (1860, 2670) | 3367 (461.8); 3350 (3065, 3670) | <.0001 | <.0001 |
| Birth weight centile | 51.1 (30.8) 51 (24, 79) | 46.91 (31.25); 44.5 (17.25, 78.25) | 48.3 (31.5); 46.0 (25.0, 82.0) | 51.24 (30.8); 51.0 (24.0, 79.0) | .4124 | .6633 |
| N/total (%) | N/total (%) | N/total (%) | N/total (%) | p‐Value b | p‐Value b | |
|---|---|---|---|---|---|---|
| Nulliparity | 626/1276 (49.0) | 20/34 (58.8) | 13/23 (56.5) | 606/1242 (48.8) | .2977 | .4625 |
| Fetal male sex | 678/1276 (53.1) | 22/34 (64.7) | 15/23 (65.2) | 688/1242 (55.4) | .2998 | .3475 |
| Smoking | 215/1274 (16.9) | 4/34 (11.8) | 3/23 (13.0) | 211/1242 (17) | .6408 | .6170 |
| Assisted reproduction c | 81/1276 (6.3) | 2/34 (5.9) | 1/23 (4.3) | 79/1242 (6.4) | 1.0000 | .6943 |
| Hypothyroidism d | 197/1276 (15.4) | 7/34 (20.6) | 7/23 (30.4) | 190/1242 (15.3) | .4671 | .0473 |
| Rh‐ | 176/1276 (13.8) | 4/34 (11.8) | 4/23 (17.4) | 172/1242 (13.8) | 1.0000 | .6267 |
| Blood antigen A | 580/1276 (45.4) | 16/34 (47.0) | 13/23 (56.5) | 564/1242 (45.4) | .8631 | .2891 |
| Blood antigen B | 225/1276 (17.6) | 8/34 (23.5) | 5/23 (21.7) | 217/1242 (17.5) | .3618 | .5940 |
| Type of labor onset | ||||||
| Cesarean section | 109 /1276 (8.5) | 2/34 (5.9) | 0/23 (0%) | 107/1242 (8.6) | .7630 | .1412 |
| Induction of labor | 442/1276 (34.6) | 9/34 (26.5) | 0/23 (0%) | 702/1242 (56.5) | .0007 | <.0001 |
| Spontaneous onset of labor | 725/1276 (56.8) | 23/34 (67.6) | 23/23 (100%) | 433/1242 (34.9) | .0002 | <.0001 |
| Mode of birth | ||||||
| Cesarean section | 370/1276 (29) | 8/34 (23.5) | 3/23 (13.0) | 362/1242 (29.1) | .5683 | .0912 |
| Assisted vaginal delivery | 184/1276 (14.4) | 4/34 (11.8) | 4/23 (17.4) | 180/1242 (14.5) | .8077 | .6960 |
| Spontaneous vaginal delivery | 722/1276 (56.6) | 22/34 (64.7) | 16/23 (69.6) | 700/1242 (56.4) | .3832 | .2055 |
| Apgar at 5 minutes <7 | 5/1260 (0.40) | 4/34 (11.8) | 3/23 (13) | 1/1226 (0.1) | <.0001 | <.0001 |
| Arterial pH <7.10 | 6/1036 (0.58) | 2/25 (5.9) | 2/17 (11.8) | 4/1011 (0.4) | .0079 | <.0001 |
Mann–Whitney U test.
Chi‐square test, SD: standard deviation.
Any assisted reproduction treatment.
Pregestational or gestational hypothyroidism, PAPP‐A, pregnancy‐associated plasma protein‐A; free‐βhCG, free β‐human chorionic gonadotropin; bpm, beats per minute.
Most pregnancies had spontaneous onset of labor and vaginal delivery. Cesarean section was performed in 29.8% of cases, of which 8.5% were elective. Adverse neonatal outcomes were infrequent, with umbilical arterial pH <7.0 or Apgar score <7 at 5 minutes occurring in fewer than 1% of cases.
Among the 1276 pregnancies, 34 (2.7%) resulted in PTB and 23 (1.8%) in sPTB.
Fetal Heart Rate and Preterm Birth
Pregnancies ending in PTB and sPTB showed significantly higher FHR at the 12‐week scan compared with term pregnancies (163.6 versus 160.1 bpm, p = .007, and 164.1 versus 160.1 bpm, p = .014, respectively; Table 1, Figure 2). This difference remained evident when restricting the analysis to births before 34 weeks.
Figure 2.
Violin plots showing the fetal heart rate of fetuses presenting term, preterm, and spontaneous preterm births.
A higher prevalence of maternal hypothyroidism was observed in the sPTB group compared with term pregnancies (30.4% versus 15.3%, p = .047), whereas no significant differences were found for other maternal or sonographic variables.
Univariable Analysis
Results of the univariable logistic regression analyses are shown in Tables 2 and 3. Fetal heart rate was the only parameter consistently associated with all PTB outcomes, including PTB, PTB <34 weeks, sPTB, and sPTB <34 weeks, with odds ratios per bpm increase ranging from 1.08 to 1.12.
Table 2.
Univariable Logistic Regression Analysis for the Prediction of Any Cause of Preterm Birth Before 37 and 34 Weeks Using the Parameters Available at the 12‐Week Screening Scan
| Parameter | Intercept | Estimate | Stand Error | OR (95% CI) | p‐Value |
|---|---|---|---|---|---|
| Preterm birth <37 weeks | |||||
| Maternal data | |||||
| Maternal age | −3.5072 | −0.0029 | 0.0291 | 0.9971 (0.9417, 1.0557) | .9201 |
| Maternal pre‐pregnancy weight | −4.8589 | 0.0169 | 0.0119 | 1.0171 (0.9936, 1.0411) | .1545 |
| Maternal height | −4.8754 | 0.0077 | 0.0329 | 1.0077 (0.9447, 1.0749) | .8152 |
| Parity | −3.4920 | −0.1579 | 0.2162 | 0.8539 (0.5589, 1.3045) | .4649 |
| Smoking | −3.5351 | −0.4304 | 0.5376 | 0.6502 (0.2267, 1.8651) | .4233 |
| Assisted reproduction a | −3.5930 | −0.0833 | 0.7381 | 0.9200 (0.2165, 3.9093) | .9102 |
| Hypothyroidism b | −3.7003 | −12.0414 | 917.4394 | 0.0000 (0,0000, N/A) | .9895 |
| Ultrasound data | |||||
| Fetal heart rate | −16.4128 | 0.0791 | 0.0267 | 1.0824 (1.0271, 1.1406) | .0031 |
| Nuchal translucency | −4.1844 | 0.3706 | 0.4135 | 1.4485 (0.6440, 3.2579) | .3702 |
| Crown rump length | −3.0317 | −0.0090 | 0,0252 | 0,9910 (0,9431, 1,0413) | .7210 |
| Fetal sex male | −3.8918 | 0.4998 | 0,3633 | 1,6483 (0.8086, 3.3599) | .1690 |
| Blood test data | |||||
| PAPP‐A | −3.4597 | −0.0402 | 0.0867 | 0.9606 (0.8105, 1.1385) | .6429 |
| Free β‐hCG | −3,9291 | 0.0080 | 0.0043 | 1.0081 (0.9996, 1.0166) | .0631 |
| Leukocytes count | −3.8087 | 0.0199 | 0.0890 | 1.0201 (0,8568, 1.2145) | .8231 |
| Neutrophils count | −3.6516 | 0.0019 | 0,1116 | 1.0019 (0.8049, 1.2469) | .9867 |
| Lymphocytes count | −3.6851 | 0.0187 | 0.1268 | 1.0189 (0.7946, 1.3065) | .8829 |
| Rh‐ | −3.5733 | −0.1879 | 0.5386 | 0.8287 (0.2884, 2.3815) | .7272 |
| Blood antigen A | −3.6288 | 0.0663 | 0.3483 | 1.0685 (0.5399, 2.1148) | .8490 |
| Blood antigen B | −3.6743 | 0.3739 | 0.4111 | 1.4534 (0.6492, 3.2536) | .3631 |
| Preterm birth <34 weeks | |||||
| Maternal data | |||||
| Maternal age | −4.0845 | −0.0186 | 0.0482 | 0.9816 (0.8932, 1.0788) | .6998 |
| Maternal pre‐pregnancy weight | −3.3222 | −0.0189 | 0.0237 | 0.9813 (0,9368, 1.0279) | .4241 |
| Maternal height | −5,5858 | 0,0059 | 0.0537 | 1.0059 (0.9054, 1.1175) | .9131 |
| Parity | −4.8404 | 0.2245 | 0.2959 | 1.2517 (0.7009, 2.2354) | .4479 |
| Smoking | −4.5567 | −0.8092 | 1.0472 | 0.4452 (0.0572, 3.4667) | .4396 |
| Assisted reproduction a | −4.6788 | 0.2967 | 1.0508 | 1,3454 (0,1715, 10,5525) | .7776 |
| Hypothyroidism b | −4,7782 | 0.6089 | 0.6712 | 1.8385 (0.4933, 6.8519) | .3643 |
| Ultrasound data | |||||
| Fetal heart rate | −19.2057 | 0.0897 | 0.0445 | 1.0938 (1.0024, 1.1936) | .0440 |
| Nuchal translucency | −5.3366 | 0.4279 | 0.6799 | 1.5339 (0.4046, 5.8157) | .5292 |
| Crown rump length | −4.7811 | 0.0019 | 0.0118 | 1.0019 (0.9791, 1.0253) | .8685 |
| Fetal sex male | −4.7791 | 0.2192 | 0.5882 | 1.2451 (0.3931, 3.9441) | .7094 |
| Blood test data | |||||
| PAPP‐A | −4.9513 | 0.0708 | 0.1241 | 1.0734 (0,8416, 1.3690) | .5682 |
| Free β‐hCG | −5.1877 | 0.0114 | 0.0056 | 1.0115 (1.0004, 1.0227) | .0427 |
| Leukocytes count | −5.9009 | 0.1359 | 0.1401 | 1.1457 (0.8705, 1.5078) | .3318 |
| Neutrophils count | −5.3442 | 0.1131 | 0.1769 | 1.1198 (0.7915, 1.5841) | .5227 |
| Lymphocytes count | −4.8665 | 0.0591 | 0.1379 | 1.0609 (0,8096, 1.3902) | .6680 |
| Rh‐ | −4.4659 | −0.2254 | 0.7789 | 0.7982 (0.1734, 3.6736) | .7722 |
| Blood antigen A | −4.7449 | 0.1841 | 0.5801 | 1.2021 (0.3856, 3.7474) | .7510 |
| Blood antigen B | −4.8704 | 0.8585 | 0.6168 | 2.3597 (0.7044, 7.9053) | .1639 |
OR, odds ratio; Stand Error, standard error; CI, confidence interval.
Any assisted reproduction treatment.
Pregestational or gestational hypothyroidism, PAPP‐A, pregnancy associated plasma protein‐A; free β‐hCG, free beta human chorionic gonadotropin.
Table 3.
Univariable Logistic Regression Analysis for the Prediction of Spontaneous Preterm Birth Before 37 and 34 Weeks Using the Parameters Available at the 12‐Week Screening Scan
| Parameter | Intercept | Estimate | Standard E | OR (95% CI) | p‐Value |
|---|---|---|---|---|---|
| Spontaneous preterm birth <37 weeks | |||||
| Maternal data | |||||
| Maternal age | −3.9327 | −0.0021 | 0.0353 | 0.9979 (0.9312, 1.0694) | .9527 |
| Maternal pre‐pregnancy weight | −3.7514 | −0.0032 | 0.0158 | 0.9968 (0.9663, 1.0282) | .8381 |
| Maternal height | −4.9935 | 0.0062 | 0.0391 | 1.0062 (0.9319, 1.0864) | .8737 |
| Parity | −3.9686 | −0.0410 | 0.2463 | 0.9598 (0.5922, 1.5554) | .8677 |
| Smoking | −3.9502 | −0.3077 | 0.6237 | 0.7351 (0.2165, 2.4962) | .6218 |
| Assisted reproduction a | −3.9763 | −0.4057 | 1.0289 | 0.6665 (0.0887, 5.0081) | .6933 |
| Hypothyroidism b | −4.1963 | 0.8951 | 0.4599 | 2.4477 (0.9936, 6.0295) | .0516 |
| Ultrasound data | |||||
| Fetal heart rate | −18.4048 | 0.0889 | 0.0324 | 1.0929 (1.0256, 1.1647) | .0062 |
| Nuchal translucency | −5.1729 | 0.7285 | 0.4671 | 2.0720 (0.8294, 5.1763) | .1188 |
| Crown rump length | −2.9943 | −0.0160 | 0.0312 | 0,9841 (0,9257, 1,0462) | .6078 |
| Fetal sex male | −4.3041 | 0.5184 | 0.4414 | 1,6793 (0.7069, 3.9892) | .2403 |
| Blood test data | |||||
| PAPP‐A | −4.2116 | 0.0614 | 0.0898 | 1.0633 (0.8917, 1.2678) | .4942 |
| Free β‐hCG | −4.3709 | 0.0092 | 0.0048 | 1.0093 (0.9999, 1.0187) | .0518 |
| Leukocytes count | −4.2712 | 0.0293 | 0.1063 | 1.0297 (0.8361, 1.2683) | .7827 |
| Neutrophils count | −3.9726 | −0.0098 | 0.1349 | 0.9902 (0.7602, 1.2899) | .9421 |
| Lymphocytes count | −4.1101 | 0.0366 | 0.1268 | 1.0373 (0.8091, 1.3299) | .7725 |
| Rh‐ | −3.7612 | −0.2800 | 0.5562 | 0.7558 (0.2541, 2.483) | .6147 |
| Blood antigen A | −4.2283 | 0.4529 | 0.4244 | 1.5728 (0.6845, 3.6138) | .2859 |
| Blood antigen B | −4.0498 | 0.2657 | 0.5109 | 1.3043 (0.4791, 3.5506) | .6031 |
| Spontaneous preterm birth < 34 weeks | |||||
| Maternal data | |||||
| Maternal age | −4.9251 | −0.0045 | 0.0594 | 0.9955 (0.8861, 1.1184) | .9393 |
| Maternal pre‐pregnancy weight | −3.8133 | −0.0149 | 0.0259 | 0.9851 (0.9363, 1.0364) | .5627 |
| Maternal height | −11.2947 | 0.0393 | 0.0594 | 1.0401 (0.9258, 1.1686) | .5079 |
| Parity | −5.3283 | 0.3072 | 0.3469 | 1.3597 (0.6889, 2.6834) | .3757 |
| Smoking | −4.8781 | −15.1961 | 945,5379 | 0 (0, N/A) | .9872 |
| Assisted reproduction a | −5.1341 | 0.7521 | 1.0753 | 2.1214 (0,2578, 17,4548) | .4843 |
| Hypothyroidism b | −5.3697 | 1.2005 | 0.7344 | 3.3216 (0.7874, 14.0130) | .1021 |
| Ultrasound data | |||||
| Fetal heart rate | −23.3101 | 0.1121 | 0.0548 | 1.1187 (1.0047, 1.2455) | .0407 |
| Nuchal translucency | −6.7011 | 0.9968 | 0.7392 | 2.7097 (0.6363, 11.5389) | .1775 |
| Crown rump length | −5.1698 | 0.0016 | 0.0154 | 1.0016 (0.9719, 1.0323) | .9153 |
| Fetal sex male | −5.2933 | 0.3939 | 0.7325 | 1.4829 (0.3529, 6.2314) | .5907 |
| Blood test data | |||||
| PAPP‐A | −5.6367 | 0.1266 | 0.1407 | 1.1350 (0,8613, 1.4957) | .3685 |
| Free β‐hCG | −5,6372 | 0.0113 | 0.0069 | 1.0113 (0.9978, 1.0251) | .1014 |
| Leukocytes count | −5.8794 | 0.0972 | 0.1680 | 1.1021 (0.7928, 1.5321) | .5628 |
| Neutrophils count | −5.3320 | 0.0529 | 0.2149 | 1.0543 (0.6919, 1.6065) | .8055 |
| Lymphocytes count | −5.1651 | 0.0500 | 0.1775 | 1.0513 (0,7423, 1.4889) | .7782 |
| Rh‐ | −4.4659 | −0.7399 | 0.8206 | 0.4771 (0.0955, 2.3830) | .3672 |
| Blood antigen A | −5.4424 | 0.6975 | 0,7325 | 2.0087 (0.4779, 8.4413) | .3409 |
| Blood antigen B | −5.1600 | 0.4459 | 0.8198 | 1.5620 (0.3132, 7.7899) | .5864 |
OR, odds ratio; Stand Error, standard error; CI, confidence interval.
Any assisted reproduction treatment.
Pregestational or gestational hypothyroidism, PAPP‐A, pregnancy associated plasma protein‐A; free β‐hCG, free beta human chorionic gonadotropin.
Free‐βhCG was significantly associated with PTB <34 weeks and showed borderline significance for PTB and sPTB. Maternal hypothyroidism showed borderline significance only for sPTB and was not associated with other outcomes.
Multivariable Analysis and Model Performance
Multivariable models including variables with significant or borderline significance in univariable analyses are presented in Table 4 and Figures 3 and 4.
Table 4.
Multivariable Logistic Regression Analysis Using Those Parameters that Were Statistically Significant or Borderline Significant in the Univariable Analysis
| Estimate | Standard E | OR (95% CI) | p‐Value | |
|---|---|---|---|---|
| Any cause of preterm birth | ||||
| Preterm birth <37 weeks | ||||
| Fetal heart rate | ||||
| Fetal heart rate | 0.0791 | 0.0267 | 1.0824 (1.0271, 1.1406) | .0031 |
| Intercept | −16.4128 | |||
| AUC = 0.6340, (95% CI = 0.5437, 0.7242), AIC = 308.5, DR = 16% for a FPR of 5% and 20% for a FPR of 10%, p = .0076 | ||||
| Fetal heart rate + free‐βhCG | ||||
| Fetal heart rate | 0.0757 | 0.0277 | 1.0787 (1.0217, 1.1388) | .0062 |
| Free‐βhCG | 0.0077 | 0.0046 | 1.0077 (0.9987, 1.0168) | .0929 |
| Intercept | −16,1894 | |||
| AUC = 0.6492, (95% CI = 0.5561, 0.7422), AIC = 290.8, DR = 19% for a FPR of 5% and 25% for a FPR of 10%, p = .0039 | ||||
| Preterm birth < 34 weeks | ||||
| Fetal heart rate | ||||
| Fetal heart rate | 0.0897 | 0.0445 | 1.0938 (1.0024, 1.1936) | .0439 |
| Intercept | −19.2057 | |||
| AUC = 0.6750, (95% CI = 0.5388, 0.8112), AIC = 135.7, DR = 20% for a FPR of 5% and 25% for a FPR of 10%, p = .0367 | ||||
| Fetal heart rate + free‐βhCG | ||||
| Fetal heart rate | 0.0967 | 0.0471 | 1.1015 (1.0044, 1.2081) | .0401 |
| Free‐βhCG | 0.0118 | 0.0061 | 1.0119 (0.9999, 1.0241) | .0523 |
| Intercept | −20.9344 | |||
| AUC = 0.7489, (95% CI = 0.6169, 0.8808), AIC = 124.1, DR = 18% for a FPR of 5% and 36% for a FPR of 10%, p = .0044 | ||||
| Spontaneous preterm birth | ||||
| Spontaneous preterm birth <37 weeks | ||||
| Fetal heart rate | ||||
| Fetal heart rate | 0.0889 | 0.0324 | 1.0929 (1.0256, 1.1647) | .0062 |
| Intercept | −18,4048 | |||
| AUC = 0.6467, (95% CI = 0.5395, 0.7539), AIC = 226.5, DR = 15% for a FPR of 5% and 21% for a FPR of 10%, p = .0158 | ||||
| Fetal heart rate + free‐βhCG | ||||
| Fetal heart rate | 0.0895 | 0.0334 | 1.0936 (1.0243, 1.1677) | .0074 |
| Free‐βhCG | 0.0091 | 0.0051 | 1.0092 (0.9991, 1.0193) | .0735 |
| Intercept | −18.9001 | |||
| AUC = 0.6800, (95% CI = 0.5716, 0.7885), AIC = 215.4, DR = 18% for a FPR of 5% and 27% for a FPR of 10%, p = .0038 | ||||
| Fetal heart rate + hypothyroidism | ||||
| Fetal heart rate | 0.0879 | 0.0325 | 1.0919 (1.0246, 1.1638) | .0068 |
| Hypothyroidism | 0.8717 | 0.4625 | 2.3909 (0.9657, 5.9195) | .0595 |
| Intercept | −18.4540 | |||
| AUC = 0.6733, (95% CI = 0.5663, 0.02, AIC = 225.4, DR = 26% for a FPR of 5% and 26% for a FPR of 10%, p = .0044 | ||||
| Fetal heart rate + free‐βhCG + hypothyroidism* | ||||
| Fetal heart rate | 0.0879 | 0.0334 | 1.0919 (1.0228, 1.1659) | .0084 |
| Free‐βhCG | 0.0093 | 0.0051 | 1.0093 (0.9992, 1.0195) | .0699 |
| Hypothyroidism | 0.7238 | 0.4906 | 2.0623 (0.7884, 5.3948) | .1401 |
| Intercept | −18.8107 | |||
| AUC = 0.6923, (95% CI = 0.5835, 0.8010), AIC = 215.5, DR = 27% for a FPR of 5% and 32% for a FPR of 10%, p = .0020 | ||||
| Spontaneous preterm birth < 34 weeks | ||||
| Fetal heart rate | ||||
| Fetal heart rate | 0.1121 | 0.0548 | 1.1187 (1.0047, 1.2455) | .0407 |
| Intercept | −23.3101 | |||
| AUC = 0.7298, (95% CI = 0.6139, 0.8457), AIC = 96.77, DR = 20% for a FPR of 5% and 25% for a FPR of 10%, p = .0039 | ||||
| Fetal heart rate + free‐βhCG | ||||
| Fetal heart rate | 0.12964 | 0.05958 | 1.1384 (1.0129, 1.2794) | .0296 |
| Free‐βhCG | 0.01203 | 0.00781 | 1.0121 (0.9967, 1.0277) | .1233 |
| Intercept | −26,84502 | |||
| AUC = 0.8111, (95% CI = 0.7198, 0.9024, AIC = 85.37, DR = 14% for a FPR of 5% and 43% for a FPR of 10%, p = .0045 | ||||
| Fetal heart rate + free‐βhCG + hypothyroidism | ||||
| Fetal heart rate | 0.1266 | 0.0593 | 1.1349 (1.0104, 1.2748) | .0328 |
| Free‐βhCG | 0.0119 | 0.0078 | 1.0119 (0.9966, 1.0276) | .1274 |
| Hypothyroidism | 0.7381 | 0.8502 | 2.0919 (0.3952, 11.0733) | .3853 |
| Intercept | −26.4933 | |||
| AUC = 0.7891, (95% CI = 0.6752, 0.9030, AIC = 86.71, DR = 29% for a FPR of 5% and 29% for a FPR of 10%, p = .0083 | ||||
AIC, Akaike information criteria; AUC, area under the curve; free β‐hCG, free beta human chorionic gonadotropin; OR, odds ratio; PAPP‐A: pregnancy associated plasma protein‐A; *Pregestational or gestational hypothyroidism.
Figure 3.
ROC curves of several models for the prediction of any preterm birth (PTB). In the upper part, the fetal heart rate (FHR) alone before 37 and 34 weeks, and in the lower part, the FHR combined with the free‐bhCG before 37 and 34 weeks.
Figure 4.
ROC curves of several models for the prediction of spontaneous preterm birth (sPTB). In the upper part, the fetal heart rate (FHR) alone before 37 and 34 weeks, in the middle part, the FHR combined with the free‐bhCG before 37 and 34 weeks, and in the lower part, the FHR combined with the maternal thyroid status (hypothyroidism) <34 weeks, and the FHR combined with the free‐bhCG and the maternal thyroid status (hypothyroidism) <37 weeks.
The highest predictive performance of FHR alone was observed for sPTB <34 weeks (AUC 0.73; detection rate 25% at a 10% false‐positive rate). For PTB <34 weeks and sPTB before 37 weeks, model performance was more modest (AUCs 0.65–0.68).
The combination of FHR and free‐βhCG improved predictive performance, particularly for sPTB <34 weeks (AUC 0.81; detection rate 43% at a 10% false‐positive rate). Adding maternal thyroid status to the models did not result in further improvement.
FHR Cut‐off Analysis
The diagnostic performance of different FHR cut‐offs is shown in Table 5. The most favorable balance between sensitivity and specificity was observed for sPTB <34 weeks using a cut‐off of 170 bpm, yielding a detection rate of 25%, a false‐positive rate of 6%, a positive predictive value of 6.3%, and a negative predictive value of 97%.
Table 5.
Behavior of the Fetal Heart Rate as a Marker of Preterm Birth and Spontaneous Preterm Birth in Our Pregnancy Population According to 3 Different Cut‐Offs
| Cut‐off | PTB (N) | AUC | S (DR) (%) | Sp (%) | FPR (%) | FNR (%) | PPV (%) | NPV (%) |
|---|---|---|---|---|---|---|---|---|
| Any preterm birth | ||||||||
| <37 weeks | ||||||||
| >170 bpm | 34 | 0.63 | 18 | 93 | 7 | 82 | 6 | 98 |
| >167 bpm | 34 | 0.63 | 23 | 85 | 15 | 77 | 4 | 98 |
| >165 bpm | 34 | 0.63 | 32 | 78 | 22 | 68 | 4 | 78 |
| <34 weeks | ||||||||
| >170 bpm | 12 | 0.67 | 25 | 94 | 6 | 75 | 4 | 94 |
| >167 bpm | 12 | 0.67 | 25 | 85 | 15 | 75 | 2 | 99 |
| >165 bpm | 12 | 0.67 | 25 | 78 | 22 | 75 | 1 | 99 |
| Spontaneous preterm birth | ||||||||
| <37 weeks | ||||||||
| >170 bpm | 23 | 0.65 | 17 | 94 | 6 | 82 | 5 | 98 |
| >167 bpm | 23 | 0.65 | 26 | 85 | 15 | 74 | 3 | 98 |
| >165 bpm | 23 | 0.65 | 35 | 78 | 22 | 65 | 3 | 98 |
| <34 weeks | ||||||||
| >170 bpm | 8 | 0.73 | 25 | 94 | 6 | 75 | 2 | 99 |
| >167 bpm | 8 | 0.73 | 25 | 85 | 15 | 75 | 1 | 99 |
| >165 bpm | 8 | 0.73 | 25 | 72 | 28 | 75 | 1 | 99 |
In the interest of clarity, percentages were rounded to the nearest unit, and AUCs were expressed with 2 decimals. AUC, area under the curve; S, (sensitivity); DR, detection rate; Sp, specificity; FPR, false positive rate (1‐specificity); FNR, false negative rate (1‐sensitivity); PPV, positive predictive value; NPV, negative predictive value.
Discussion
Principal Findings
This prospective validation study demonstrates that elevated FHR at the 12‐week scan is associated with an increased risk of PTB, particularly sPTB before 34 weeks' gestation. Among all clinical, sonographic, and biochemical parameters assessed during first‐trimester screening, FHR emerged as the only variable consistently associated with all PTB outcomes. Moreover, combining FHR with free‐βhCG substantially improved predictive performance for early sPTB.
Comparison with Existing Literature
Efforts to identify first‐trimester predictors of sPTB have focused on maternal characteristics, biochemical markers, and early sonographic parameters (Table 6). Models based on maternal demographic and obstetric history alone have generally shown limited predictive ability, with moderate performance only for early sPTB outcomes. 13 , 14 , 15 , 16 , 17 , 18
Table 6.
Review of Recently Studied Individual Markers for the Prediction of Preterm Birth and Spontaneous Preterm Birth Before 37 and 34 Weeks
| Author and Reference | Parameter Investigated | Year | N | Outcome | % of PTB | GA Exam | AUC |
|---|---|---|---|---|---|---|---|
| Maternal factors | |||||||
| Beta J et al 13 | Maternal factors | 2011 | 33070 | sPTB <34 | 353 (1.1) | 11–14 | 0.67 |
| Beta J et al 13 | Maternal factors (nulliparous women) | 2011 | 33070 | sPTB <34 | 353 (1.1) | 11–14 | 0.61 |
| Beta J et al 13 | Maternal factors (multiparous women) | 2011 | 33070 | sPTB <34 | 353 (1.1) | 11–14 | 0.71 |
| Greco E et al 14 | Maternal factors | 2012 | 9974 | sPTB <34 | 104 (1) | 11–13 | 0.71 |
| Greco E et al 14 | Maternal factors | 2012 | 9974 | sPTB 34–37 | 213 (2.1) | 11–13 | 0.56 |
| Feng Q et al 15 | Maternal factors | 2025 | 3658 | sPTB <34 | 19 (0.5) | 11–14 | 0.70 |
| Feng Q et al 15 | Maternal factors | 2025 | 3658 | sPTB <37 | 154 (4.2) | 11–14 | 0.58 |
| Becking EC et al 16 | Maternal factors | 2025 | 56110 | sPTB <37 | 1891 (3.4) | 11–14 | 0.63 |
| Goetzinger et al 17 | Maternal factors | 2012 | 578 | PTB <37 | 78 (13.5) | 11–14 | 0.69 |
| Goetzinger et al 17 | Maternal factors | 2012 | 578 | PTB <34 | 36 (6.2) | 11–14 | 0.73 |
| Goetzinger et al 17 | Maternal factors | 2012 | 578 | sPTB <34 | 36 (6.2) | 11–14 | 0.78 |
| Becerra Mojica CH et al 18 | History of PTB | 2024 | 667 | sPTB <34 | 12 (1.8) | 11–14 | 0.58 |
| Becerra Mojica CH et al 18 | History of PTB | 2024 | 667 | sPTB <37 | 61 (9.2) | 11–14 | 0.57 |
| Biochemical markers | |||||||
| Goetzinger et al 17 | ADAM12 | 2012 | 578 | PTB <37 | 78 (13.5) | 11–14 | 0.60 |
| Goetzinger et al 17 | PAPP‐A | 2012 | 578 | PTB <37 | 78 (13.5) | 11–14 | 0.59 |
| Goetzinger et al 17 | ADAM12 | 2012 | 578 | PTB <34 | 36 (6.2) | 11–14 | 0.63 |
| Goetzinger et al 17 | PAPP‐A | 2012 | 578 | PTB <34 | 36 (6.2) | 11–14 | 0.62 |
| Weiner CP et al 19 | Plasma RNA apolipoprotein A1 (APOA1) | 2023 | 60 | sPTB <32 | 40 (66) | 12–14 | 0.72 |
| Weiner CP et al 19 | Plasma RNA proteasome activator subunit 2 (PSME2) | 2023 | 60 | sPTB <32 | 40 (66) | 12–14 | 0.65 |
| Mavreli et al 20 | miRNA‐125 | 2022 | 68 | sPTB 32–37 | 34 (50) | 11–13 | 0.89 |
| Mavreli et al 21 | Vascular cell adhesion molecule 1 (VCAM1) | 2023 | 68 | sPTB 32–37 | 34 (50) | 11–13 | 0.82 |
| Mavreli et al 21 | Serum amyloid A‐1 protein (SAA1) | 2023 | 68 | sPTB 32–37 | 34 (50) | 11–13 | 0.96 |
| Mavreli et al 21 | Cytoskeletal protein Talin‐1 | 2023 | 68 | sPTB 32–37 | 34 (50) | 11–13 | 0.89 |
| Becking EC et al 16 | Fetal fraction | 2025 | 56110 | PTB <37 | 1891 (3.4) | 11–14 | 0.63 |
| Becerra‐Mojica CH et al 23 | Complement factor H | 2024 | 355 | PTB <37 | 27 (7.6) | 11–14 | NR |
| Broekhuis A et al 24 | Ferritin | 2024 | 2044 | PTB <37 | 100 (4.9) | 12 | NR |
| Swierzc G et al 25 | PAPP‐A | 2024 | 1164 | PTB <37 | 84 (7.2) | 11–14 | 0.64 |
| Swierzc G et al 25 | PAPP‐A | 2024 | 1164 | sPTB <37 | 64 (5.5) | 11–14 | 0.60 |
| Swierzc G et al 25 | Free‐β‐hCG | 2024 | 1164 | PTB <37 | 84 (7.2) | 11–14 | 0.59 |
| Swierzc G et al 25 | Free‐β‐hCG | 2024 | 1164 | sPTB <37 | 64 (5.5) | 11–14 | 0.61 |
| Yildiz E et al 26 | Myosin‐binding protein C (MyBP‐C) | 2023 | 628 | PTB <37 | 45 (7.2) | 11–14 | 0.73 |
| Sonographical markers | |||||||
| Greco E et al 14 | Cervical length | 2012 | 9974 | sPTB <34 | 104 (1) | 11–13 | 0.78 |
| Greco E et al 14 | Cervical length | 2012 | 9974 | sPTB (34–37) | 213 (2.1) | 11–13 | 0.55 |
| Feng Q et al 15 | Cervical angle E | 2025 | 3658 | sPTB <34 | 19 (0.5) | 11–14 | 0.74 |
| Feng Q et al 15 | Cervical angle D1 | 2025 | 3658 | sPTB <37 | 154 (4.2) | 11–14 | 0.57 |
| Feng Q et al 15 | Cervical angle D2 | 2025 | 3658 | sPTB <37 | 154 (4.2) | 11–14 | 0.57 |
| Goetzinger et al 17 | Uterine artery Doppler | 2012 | 578 | PTB <37 | 78 (13.5) | 11–14 | 0.54 |
| Becerra Mojica CH et al 18 | Cervical consistency index <10th centile | 2024 | 667 | sPTB <37 | 61 (9.2) | 11–14 | 0.55 |
| Becerra Mojica CH et al 18 | Cervical consistency index <10th centile | 2024 | 667 | sPTB <34 | 12 (1.2) | 11–14 | 0.62 |
| Becerra Mojica CH et al 18 | Cervical length | 2024 | 667 | sPTB <37 | 61 (9.2) | 11–14 | 0.50 |
| Becerra Mojica CH et al 18 | Cervical length | 2024 | 667 | sPTB <34 | 12 (1.8) | 11–14 | 0.41 |
PTB, preterm birth; PTB <34, PTB before 34 weeks; sPTB, spontaneous PTB; sPTB <34, spontaneous PTB <34 weeks; PAPP‐A, pregnancy‐associated plasma protein‐A; free‐βhCG, free beta human chorionic gonadotropin; NR, no reported; %PTB, percentage of PTB in the study; GA Exam, gestational age at exam; AUC, area under the curve.
Several studies have investigated first‐trimester biochemical markers associated with subsequent PTB, including circulating RNA, microRNAs, inflammatory proteins, and placental‐derived molecules. 19 , 20 , 21 , 22 , 23 , 24 , 25 While some markers have shown promising predictive accuracy, most require specialized laboratory techniques and are not yet suitable for routine clinical use.
First‐trimester sonographic markers have also been explored, particularly cervical length and cervical morphology and consistency. 14 , 15 , 18 , 26 However, these measurements are technically challenging early in pregnancy, demonstrate variable reproducibility, and generally yield modest predictive performance, limiting their widespread implementation, especially in low‐resource settings.
In contrast, FHR is routinely measured during first‐trimester ultrasound, requires no additional training or equipment, and is highly reproducible. In the present study, FHR alone showed moderate predictive accuracy for sPTB <34 weeks, which increased substantially when combined with free‐βhCG. This combination aligns with the concept of leveraging routinely collected first‐trimester data to enhance early risk stratification.
Possible Biological Mechanisms
The pathophysiological mechanisms linking elevated FHR at the 12‐week scan with subsequent sPTB are likely multifactorial and remain incompletely understood. One plausible pathway involves early exposure to maternal or placental inflammatory mediators, including cytokines and chemokines, which may influence fetal autonomic regulation and increase heart rate. 27 Subclinical intra‐amniotic infection or mild inflammatory activation has been associated with abnormal FHR patterns, and such early inflammatory stimuli could initiate a cascade leading to premature activation of labor pathways. 28 , 29 , 30 , 31
Biochemical markers, such as elevated free β‐human chorionic gonadotropin (free‐βhCG), may reflect underlying placental dysfunction or early stress responses, which could amplify fetal autonomic perturbations. Together, elevated FHR and abnormal free‐βhCG levels may indicate a fetal‐placental environment under stress, integrating inflammatory, endocrine, and metabolic signals that increase the risk of early spontaneous labor.
In addition, maternal endocrine or metabolic alterations, including hypothyroidism, pregestational diabetes, 27 or oxidative stress, could modulate fetal autonomic tone and contribute to subtle dysregulation of the sympathetic‐parasympathetic balance. FHR itself is a marker of early fetal autonomic maturation, and elevated rates may reflect fetal adaptation to intrauterine stressors, which could predispose to preterm labor.
Although we assessed indirect markers of inflammation, such as leukocyte counts, more sensitive biomarkers (eg, interleukin‐6, TNF‐α) were not available in this cohort and warrant further investigation. 32 Understanding the interplay between early FHR elevation, placental signals such as free‐βhCG, and maternal‐fetal stress responses may help clarify the biological basis of early sPTB and identify additional predictive markers for integrated first‐trimester screening strategies.
Clinical Implications
In clinical practice, prediction is rarely based on a single parameter, and screening strategies usually combine markers obtained at different stages of pregnancy. In this context, FHR should not be considered an independent trigger for intervention but rather an early marker of increased risk that may contribute to first‐trimester risk stratification. Moreover, elevated FHR could help identify a subgroup of pregnancies that might benefit from targeted second‐trimester surveillance, particularly cervical length measurement at around 20 weeks' gestation. Such a 2‐step screening strategy, combining first‐trimester FHR with second‐trimester cervical assessment, could improve the early identification of pregnancies at risk while avoiding unnecessary interventions.
However, given the modest detection rate and the limited number of cases in our cohort, FHR alone should not currently guide preventive treatment decisions. Further studies are needed to confirm these findings and to determine the potential role of FHR in combined screening models for sPTB.
If confirmed in larger populations, incorporating FHR into first‐trimester screening algorithms could enable earlier identification of women at increased risk of sPTB, allowing timely preventive interventions or closer surveillance. Importantly, FHR measurement is simple, inexpensive, and universally available during routine first‐trimester ultrasound, making it a particularly attractive marker for widespread clinical implementation, including in low‐resource settings.
This approach may further support the concept of the “inverted pyramid” of prenatal care proposed by Nicolaides 33 by enabling simultaneous first‐trimester screening for chromosomal abnormalities, early preeclampsia, and sPTB using parameters that are already routinely collected.
Strengths and Limitations
Key strengths of this study include its prospective design, strict definition of sPTB, validation in an independent regional population, and robust statistical methodology. Limitations include the relatively small number of PTB events, the absence of additional biochemical or inflammatory markers that could enhance predictive accuracy, and the inability to definitively elucidate the underlying biological mechanism linking elevated FHR to sPTB.
Conclusion
Elevated FHR at the 12‐week scan is independently associated with sPTB, particularly before 34 weeks' gestation. Given its simplicity, reproducibility, and universal availability during routine first‐trimester ultrasound, FHR represents a promising early marker that might complement biochemical parameters such as free‐βhCG in future multimodal screening strategies for sPTB.
The authors would like to thank the auxiliary staff of the Department of Obstetrics for their valuable assistance. The authors report no conflicts of interest. No funds were needed for this study. Patient consent was not required as all the data obtained were part of the routine 12‐week scan, already included in the hospital protocol. Our study does not include any individual person's data in any form. Therefore, individual consent for publication is not required.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- 1. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014; 345:760–765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Spencer NR, Radnaa E, Baljinnyam T, et al. Development of a mouse model of ascending infection and preterm birth. PLoS One. 2021; 16:e0260370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Kumar M, Murugesan S, Singh P, et al. Vaginal microbiota and cytokine levels predict preterm delivery in Asian women. Front Cell Infect Microbiol. 2021; 11:639665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Yan C, Hong F, Xin G, Duan S, Deng X, Xu Y. Alterations in the vaginal microbiota of patients with preterm premature rupture of membranes. Front Cell Infect Microbiol. 2022; 12:858732. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Musilova I, Andrys C, Drahosova M, et al. Cervical fluid interleukin 6 and intra‐amniotic complications of preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2018; 31:827–836. [DOI] [PubMed] [Google Scholar]
- 6. Budal EB, Bentsen MHL, Kessler J, et al. Histologic chorioamnionitis in extremely preterm births, microbiological findings and infant outcome. J Matern Fetal Neonatal Med. 2023; 36:2196599. [DOI] [PubMed] [Google Scholar]
- 7. Ren H, Du M. Role of maternal periodontitis in preterm birth. Front Immunol. 2017; 8:139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Mohanty T, Doke PP, Khuroo SR. Effect of bacterial vaginosis on preterm birth: a meta‐analysis. Arch Gynecol Obstet. 2023; 308:1247–1255. [DOI] [PubMed] [Google Scholar]
- 9. Morales‐Roselló J, Loscalzo G, Martínez‐Varea A, Álamo BN, Nieto‐Tous M. Primary prevention with vaginal chlorhexidine before 16 weeks reduces the incidence of preterm birth: results of the preterm labor prevention using vaginal antiseptics study. AJOG Glob Rep. 2023; 3:100277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Berghella V, Palacio M, Ness A, Alfirevic Z, Nicolaides KH, Saccone G. Cervical length screening for prevention of preterm birth in singleton pregnancy with threatened preterm labor: systematic review and meta‐analysis of randomized controlled trials using individual patient‐level data. Ultrasound Obstet Gynecol. 2017; 49:322–329. [DOI] [PubMed] [Google Scholar]
- 11. Coutinho CM, Sotiriadis A, Odibo A, et al. ISUOG practice guidelines: role of ultrasound in the prediction of spontaneous preterm birth. Ultrasound Obstet Gynecol. 2022; 60:435–456. [DOI] [PubMed] [Google Scholar]
- 12. Morales‐Roselló J, Loscalzo G, Perez G, Payá AS, Jakaitė V, Perales‐Marín A. Association of first trimester fetal heart rate and nuchal translucency with preterm birth. J Matern Fetal Neonatal Med. 2022; 35:5572–5579. [DOI] [PubMed] [Google Scholar]
- 13. Beta J, Akolekar R, Ventura W, Syngelaki A, Nicolaides KH. Prediction of spontaneous preterm delivery from maternal factors, obstetric history and placental perfusion and function at 11‐13 weeks. Prenat Diagn. 2011; 31:75–83. [DOI] [PubMed] [Google Scholar]
- 14. Greco E, Gupta R, Syngelaki A, Poon LC, Nicolaides KH. First‐trimester screening for spontaneous preterm delivery with maternal characteristics and cervical length. Fetal Diagn Ther. 2012; 31:154–161. [DOI] [PubMed] [Google Scholar]
- 15. Feng Q, Chen Y, Wong JSY, et al. First trimester cervical angles for the prediction of spontaneous preterm birth. Eur J Obstet Gynecol Reprod Biol. 2025; 307:21–28. [DOI] [PubMed] [Google Scholar]
- 16. Becking EC, Bekker MN, Henrichs J, et al. Fetal fraction of cell‐free DNA in the prediction of adverse pregnancy outcomes: a Nationwide retrospective cohort study. BJOG. 2025; 132:318–325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Goetzinger KR, Cahill AG, Kemna J, Odibo L, Macones GA, Odibo AO. First‐trimester prediction of preterm birth using ADAM12, PAPP‐A, uterine artery Doppler, and maternal characteristics. Prenat Diagn. 2012; 32:1002–1007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Becerra‐Mojica CH, Parra‐Saavedra MA, Martínez‐Vega RA, et al. Performance of the first‐trimester cervical consistency index to predict preterm birth. J Clin Med. 2024; 13:3906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Weiner CP, Zhou H, Cuckle H, Syngelaki A, Nicolaides KH. Maternal plasma RNA in first trimester Nullipara for the prediction of spontaneous preterm birth ≤ 32 weeks: validation study. Weiss ML, Dong Y. Biomedicines. 2023; 11:1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Mavreli D, Theodora M, Avgeris M, et al. First trimester maternal plasma aberrant miRNA expression associated with spontaneous preterm birth. Int J Mol Sci. 2022; 23:14972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Mavreli D, Theodora M, Lambrou G, et al. First trimester maternal plasma proteomic changes predictive of spontaneous moderate/late preterm delivery. J Matern Fetal Neonatal Med. 2023; 36:2232074. [DOI] [PubMed] [Google Scholar]
- 22. Becerra‐Mojica CH, Mora‐Guevara E, Parra‐Saavedra MA, Martínez‐Vega RA, Díaz‐Martínez LA, Rincón‐Orozco B. Low levels of complement factor H in the first trimester of pregnancy are associated with spontaneous preterm birth. Int J Mol Sci. 2024; 25:10549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Broekhuis A, Koenen SV, Broeren MAC, Krabbe JG, Pop VJM. High first trimester ferritin levels differ according to parity and are independently related to preterm birth: a prospective cohort study. Acta Obstet Gynecol Scand. 2024; 103:1437–1443. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Swiercz G, Zmelonek‐Znamirowska A, Szwabowicz K, et al. Evaluating the predictive efficacy of first trimester biochemical markers (PAPP‐A, fβ‐hCG) in forecasting preterm delivery incidences. Sci Rep. 2024; 14:16206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Yildiz E, Gencer FK, Timur B, Timur H. Serum myosin‐binding protein c levels: a new marker for exclusion of preterm birth? Turk J Med Sci. 2023; 53:1498–1504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Berghella V, Talucci M, Desai A. Does transvaginal sonographic measurement of cervical length before 14 weeks predict preterm delivery in high‐risk pregnancies? Ultrasound Obstet Gynecol. 2003; 21:140–144. [DOI] [PubMed] [Google Scholar]
- 27. Sirico A, Sarno L, Zullo F, et al. Pregestational diabetes and fetal heart rate in the first trimester of pregnancy. Eur J Obstet Gynecol Reprod Biol. 2019; 232:30–32. [DOI] [PubMed] [Google Scholar]
- 28. Salafia CM, Mangam HE, Weigl CA, et al. Abnormal fetal heart rate patterns and placental inflammation. Am J Obstet Gynecol. 1989; 160:140–147. [DOI] [PubMed] [Google Scholar]
- 29. Salafia CM, Ghidini A, Sherer DM, et al. Abnormalities of the fetal heart rate in preterm deliveries are associated with acute intra‐amniotic infection. J Soc Gynecol Investig. 1998; 5:188–191. [DOI] [PubMed] [Google Scholar]
- 30. Buhimschi CS, Abdel‐Razeq S, Cackovic M, et al. Fetal heart rate monitoring patterns in women with amniotic fluid proteomic profiles indicative of inflamma‐ tion. Am J Perinatol. 2008; 25:359–372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Gleicher N, Runowicz CD, Brown BL. Sinusoidal fetal heart rate pattern in association with amnionitis. Obstet Gynecol. 1980; 56:109–112. [PubMed] [Google Scholar]
- 32. Chang Y, Li W, Shen Y, Li S, Chen X. Association between interleukin‐6 and preterm birth: a meta‐analysis. Ann Med. 2023; 55:2284384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther. 2011; 29:183–196. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.