Two definitions of preterm preeclampsia—preterm-onset and preterm-delivery preeclampsia: A mini-review

Abstract

Aim: Currently, the medical term “preterm preeclampsia (PE)” is not included in the Japan Society of the Study of Hypertension in Pregnancy (JSSHP) classification of hypertensive disorders of pregnancy.

Methods: We searched PubMed for studies using the term “preterm PE” on October 1, 2024, with the following combination of keywords: “preterm preeclampsia” OR “preterm pre-eclampsia.”

Results: A total of 479 articles were identified. The term “preterm PE” first appeared in 1994. From 2011 to 2023, the number of studies using the term “preterm PE” gradually increased, reaching 62 in 2023. The studies using the term “preterm PE” involved prediction of preterm PE (i.e., preterm-delivery PE). Current studies predicting preterm PE focus on competing risks models using maternal factors, biophysical markers, and biomarkers in the first trimester, and an established competing risks model for predicting preterm PE is available on the website of the Fetal Medicine Foundation (FMF). However, the term “preterm PE” has been used with different meanings (preterm-onset vs. preterm-delivery PE).

Conclusions: Both definitions of preterm PE have merits and demerits. Therefore, not only preterm-delivery PE but also preterm-onset PE should be evaluated simultaneously as primary outcomes when predicting preterm PE.

Introducion

In 2018, the Japan Society of the Study of Hypertension in Pregnancy (JSSHP) revised the definition and classification of hypertensive disorders of pregnancy (HDP), whereby HDP was redefined as early- or late-onset type excluding chronic hypertension (CH) developing earlier than or after 34 weeks of gestation, respectively.¹⁾ However, the medical term “preterm preeclampsia (PE)” is not included in the current classification of HDP. The 2018 JSSHP definition and classification of HDP (JSSHP 2018) were mostly based on the definition and classification of HDP proposed by the International Society of the Study of Hypertension in Pregnancy (ISSHP) in 2014 (ISSHP 2014).²⁾ In the ISSHP 2014 guideline, the following statement is included: “Early (<34 weeks) and late (P34 weeks) onset PE may have different hemodynamics”; however, there is no description regarding the definition of preterm PE.²⁾ Prior to the publication of the ISSHP 2014 guideline, there was a discrepancy in the literature regarding the definitions of severe and early-onset PE. Thus, 26 members of the International Committee of ISSHP answered a questionnaire focused on early-onset and preterm PE. The results of this questionnaire revealed that 73.0%, 18.0%, and 9.0% regarded early-onset PE as that occurring before 34 weeks, 32 weeks, and 28 weeks of gestation, respectively, and 73.0% agreed to define preterm PE as that occurring before 37 weeks of gestation.³⁾ So far, the ISSHP has twice revised the classification and diagnosis of HDP and management recommendations for international practice (2018 and 2021)^4,5); however, early-onset PE and preterm PE have not been clearly defined.

In the present study, we searched PubMed for articles that contained the keyword “preterm PE” with the aim of summarizing the current evidence on the usage of this term.

Materials and methods

We searched PubMed for studies using the term “preterm PE” on October 1, 2024, with the following keywords: “preterm preeclampsia” OR “preterm pre-eclampsia.” A total of 479 articles were identified. We read the abstracts of all articles and subsequently read the full texts if we considered the content to be relevant.

Results and discussion

Appearance of the term “preterm PE” in PubMed

Martin JN et al.⁶⁾ first used the term “preterm PE” in 1994. Figure 1 summarizes the number of reports containing the term “preterm PE” in the abstract by year. From 2011 to 2023, the number of reports containing the term “preterm PE” gradually increased, reaching 62 in 2023.

Figure 1. Number of articles related to “preterm preeclampsia” in PubMed from 1994 to 2023.

We searched PubMed for studies using the term “preterm PE” on October 1, 2024, with the following keywords: “preterm preeclampsia” OR “preterm pre-eclampsia.” A total of 479 articles were identified. Preterm preeclampsia first appeared in 1994. From 2011 to 2023, the number of articles gradually increased, reaching 62 in 2023.

Two definitions of preterm PE: preterm-onset and preterm-delivery PE

The first author used “preterm PE” to refer to a disease concept, as in preterm-onset PE, defined specifically as PE with onset at <37 weeks of gestation.⁶⁾ However, Salafia et al.,⁷⁾ who subsequently used the term “preterm PE” in 1995, defined this disease concept as preterm-delivery PE—specifically, PE with delivery at <37 weeks of gestation. Since then, the simple term “preterm PE” has been used to mean both preterm-onset PE and preterm-delivery PE, without clear distinction.

Prediction of preterm PE (preterm-delivery PE)

The majority of studies using “preterm PE” mainly involve the prediction of preterm PE (preterm-delivery PE). Aquilina et al.⁸⁾ used the term “preterm PE” for the first time in 2000; they investigated several serum biomarkers in the second trimester to predict preterm (i.e., preterm-delivery) PE. Vatten et al.⁹⁾ used the term “preterm PE” for the first time in 2006; they investigated serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in the first and second trimesters to predict preterm (i.e., preterm-delivery) PE, and found that low PlGF levels not only in the second trimester but also in the first trimester were associated with the subsequent occurrence of preterm (i.e., preterm-delivery) PE. Interestingly, low PlGF levels in the first trimester were not found to be significantly correlated with the later occurrence of term (i.e., term-delivery) PE. Romero et al.¹⁰⁾ used the term “preterm PE” for the first time in 2008; they investigated serum placental protein 13 (PP13) in the first trimester to predict preterm (i.e., preterm-delivery) PE, and found that low PP13 levels in the first trimester could be used to predict early (delivery at <34 weeks) and preterm (delivery at <37 weeks) PE, as well as severe term PE (severe PE with delivery at ≥37 weeks) but not mild term PE (mild PE with delivery at ≥37 weeks). Skråstad et al.,¹¹⁾ also for the first time, used the term “preterm PE” in 2014; they investigated serum pregnancy-associated plasma protein A (PAPP-A) in the first trimester to predict preterm (i.e., preterm-delivery) PE.

Establishment of the Fetal Medicine Foundation (FMF) competing risks model for predicting preterm-delivery PE

Current studies on the prediction of preterm PE focus on competing risks models using maternal factors, biophysical markers, and biomarkers in the first trimester. Poon et al.¹²⁾ found low serum levels of PlGF at 11–13 weeks of gestation to be associated with the later occurrence of both early PE (PE with delivery at <34 weeks) and late PE (PE with delivery at ≥34 weeks). They also constructed the original competing risks models for predicting early PE, late PE, and gestational hypertension (GH) using maternal factors (body mass index [BMI], race, family history of PE, combination of parity and previous history of PE), the uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum multiples of the median (MoM) of pregnancy-associated plasma protein-A (PAPP-A), and serum MoM of PlGF based on 7,797 singleton pregnancies in 2009. Sensitivities at a 5% false positive rate (FPR) for predicting early PE, late PE, and GH using the respective algorithms were 93.1%, 44.9%, and 34.1%, respectively. Subsequently, Wright et al.,¹³⁾ for the first time, constructed competing risks models for predicting early PE (PE with delivery at <34 weeks), preterm PE (PE with delivery at <37 weeks), and all PE (PE with delivery at <42 weeks) using maternal factors (maternal age, weight, height, race, and medical history [chronic hypertension (CH), type I diabetes mellitus (DM), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS)], conception by in vitro fertilization, family history of PE, parity, and previous PE), UtA-PI at 11–13 weeks of gestation, and MAP based on 58,884 singleton pregnancies in 2012. Sensitivities at a 10% FPR for predicting early PE, preterm PE, and all PE were 89.7%, 71.5%, and 56.6%, respectively. These competing risks models were later modified by adding either PlGF or PAPP-A by O’Gorman et al.¹⁴⁾ in 2016, with a superior sensitivity (75% vs. 70% using only maternal factors, UtA-PI, and MAP) at a 10% FPR for predicting preterm PE using maternal factors (maternal age, BMI, race, medical history [CH, DM, SLE, APS], cigarette smoking, family history of PE, combination of parity and previous PE), UtA-PI, MAP, and PlGF at 11–13 weeks of gestation based on 35,948 singleton pregnancies. Currently, an established competing risks model for predicting preterm PE is available on the FMF website.¹⁵⁾ Maternal factors used in this competing risks model include singleton or twins, height, weight, race, smoking during pregnancy, family history (mother of the patient) of PE, conception methods (spontaneous, ovulation drugs, in vitro fertilization), medical history (CH, type I DM, type II DM, SLE, APS), and parity. Figures 2 and 3 show examples of input and output formats for calculating the risk of preterm PE using the FMF model, respectively.

Figure 2. Example of input format for Fetal Medicine Foundation (FMF) preterm preeclampsia (PE) risk assessment.

The input format for calculating the risk of preterm PE. Maternal factors used in the FMF competing risks model for predicting the occurrence of preterm PE were as follows: singleton or twins, height, weight, race, smoking during pregnancy, family history (mother of the patient) of PE, conception methods (spontaneous, ovulation drugs, in vitro fertilization), medical history (chronic hypertension [CH], type I diabetes mellitus [DM], type II DM, systematic lupus erythematosus [SLE], anti-phospholipid syndrome [APS]), and parity.

Figure 3. Example of output format for Fetal Medicine Foundation (FMF) preterm preeclampsia (PE) risk assessment.

The output format showing the probability of preterm PE following the input of maternal data in the first trimester into a risk assessment sheet for preterm PE on the FMF website (Figure 2).

Validation of the FMF competing risks model for predicting preterm-delivery PE

Based on the above-mentioned search regarding usage of the term “preterm PE,” we constructed a list of validation studies on the FMF competing risks model for predicting preterm PE (i.e., preterm-delivery PE) (Table 1).^{14,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36)} Figure 4 shows a scattergram of sensitivity at a 10% FPR for predicting preterm-delivery PE using the FMF model. The median value of sensitivity at a 10% FPR in 16 studies using the FMF competing risks model for predicting preterm-delivery PE was 72.4%.^{14,17,18,19,20,22,23,24,26,27,28,29,30,31,33,34)}

Table 1. Sensitivity, false-positive rate (FPR), and positive likelihood ratio (LR+) in the FMF competing risks model for predicting preterm-delivery PE

Studies	Original or validationa	Included risk factors	Countries	Sample size	Sensitivity	FPR	LR+
O’Gorman et al., 201614) b	Original	MF, MAP, UtA-PI, PlGF	UK	3548	75	10	7.5
					65	5	13.0
O’Gorman et al., 201717) b	Validation	MF, MAP, UtA-PI, PlGF	UK, Spain, Belgium, Greece, Italy	8775	75	10	7.5
					61	5	12.2
Tan et al., 201818) b	Validation	MF, MAP, UtA-PI, PlGF	UK	16451	81.7	10	8.2
Tan et al., 201819) b	Validation	MF, MAP, UtA-PI, PlGF	UK, Spain, Belgium, Italy, Greece	61174	74.8	10	7.5
Guizani et al., 201820) b	Validation	MF, MAP, UtA-PI, PlGF	Belgium	3239	80.6	10	8.1
Rezende et al., 201921) b	Validation	MF, MAP, UtA-PI	Brazil	1531	46.1	13.9	3.3
Lobo et al., 201922) b	Validation	MF, MAP, UtA-PI, PlGF, PAPP-A	Brazil	617	66.7	10	6.7
					27.8	5	5.6
Chaemsaithong et al., 201923) b	Validation	MF, MAP, UtA-PI, PlGF	Hong Kong SAR, Japan, China, Thailand, Taiwan, India, Singapore	10935	75.8	20	3.8
					71.8	15	4.8
					64	10	6.4
					48.2	5	9.6
Khan et al., 202024) c	Validation	MF, MAP, UtA-PI, PlGF	UK	66964	74	10	7.4
Rezende et al., 202125) b	Validation	MF, MAP, UtA-PI	Brazil	1695	59	18	3.3
Zwertbroek et al., 202126) b	Validation	MF, MAP, UtA-PI, PlGF, PAPP-A	Netherlands	362 (high risk women)	70	25	2.8
					30	10	3.0
					20	5	4.0
Prasad et al., 202127) b	Validation	MF, MAP, UtA-PI, PlGF	India	1863	77.5	10	7.8
Goto et al., 202128) b	Validation	MF, MAP, UtA-PI, PlGF	Japan	913	91	20	4.6
					91	10	9.1
					73	5	14.6
Hu et al., 202129) b	Validation	MF, MAP, UtA-PI, PlGF	China	10899	46.4	20	2.3
					33.9	10	3.4
					29	5	5.8
Mendoza et al., 202130) c	Validation	MF, MAP, UtA-PI, PlGF at 8–10 wk	Spain	1675	37.5	10	3.8
					31.3	5	6.3
		MF, MAP, UtA-PI, PlGF at 11–13 wk		966	50	10	5.0
					42.9	5	8.6
Chen et al., 202131) c	Validation	MF, MAP, UtA-PI, PlGF	Taiwan	700	62.5	20	3.1
					50	15	3.3
					50	10	5.0
					12.5	5	2.5
Rolnik et al., 202232) b	Validation	MF, MAP, UtA-PI, PlGF, PAPP-A	Australia	29618	65.2	13.4	4.9
Riishede et al., 202333) b	Validation	MF, MAP, UtA-PI, PlGF	Denmark	8156	68.5	10	6.9
Cuenca-Gómez et al., 202334) b	Validation	MF, MAP, UtA-PI, PlGF	Spain	10110	70.8	10	7.1
Rezende et al., 202435) c	Validation	MF, MAP, UtA-PI	Brazil	2749	71.4	24.4	2.9
Guerby et al., 202436) c	Validation	MF, MAP, UtA-PI, PlGF, PAPP-A	Canada	7325	63.1	15.8	4.0

Abbreviations: FPR, false-positive rate; FMF, Fetal Medicine Foundation; PE, preeclampsia; LR+, positive likelihood ratio; MF, maternal factors; MAP, mean arterial pressure; UtA-PI, pulsatility index of uterine artery flow velocity waveform; PlGF, placental growth factor; PAPP-A, pregnancy-associated plasma protein A; wk, weeks of gestation

Numbers in bold indicate that the sensitivity, FPR, and LR+ fulfilled the following conditions: 1) ≥75% sensitivity at around 15% FPR; 2) ≥50% sensitivity at around 10% FPR; and 3) ≥25% sensitivity at around 5% FPR, assuming that LR+ (sensitivity/[1 – specificity]) ≥5.0 would be required for an ideal screening test for the later occurrence of preterm PE. The pairs of sensitivity and LR+ at 10% FPR are shown within gray shaded fields.

a.   “Original” indicates that the study was an initial study in which the FMF competing risks model for predicting preterm PE was developed, whereas “validation” indicates that the study was a validation study using an FMF competing risks algorithm for predicting preterm PE.

b.   These 16 articles appeared in a systematic review by Tiruneh et al.¹⁶⁾

c.   These 3 articles were added following our literature search for preterm PE in PubMed.

Figure 4. Sensitivities for predicting preterm-delivery preeclampsia (PE) at a 10% false-positive rate (FPR).

We constructed a list of validation studies for the Fetal Medicine Foundation (FMF) competing risks model for predicting preterm PE (preterm-delivery PE) (Table 1). This figure shows a scattergram of sensitivity at a 10% FPR for predicting preterm-delivery PE using the FMF model. The median value of sensitivity at a 10% FPR in 16 studies using the FMF competing risks model for predicting preterm-delivery PE was 72.4%.

Two definitions of preterm PE: preterm-onset and preterm-delivery PE

Although the disease concept of “preterm PE” has been increasingly used in the prediction and prevention of PE in recent years, two different definitions of “preterm PE” are still found in the literature: “preterm-onset PE,” with onset at <37 weeks of gestation,^{37,38,39,40,41)} and “preterm-delivery PE,” with delivery at <37 weeks of gestation.^{42,43,44,45,46)}

Need of primary outcome of preterm PE (preterm-onset PE) as well as preterm PE (preterm-delivery PE) for clinical investigation to predict preterm PE in the first trimester

A survey of preterm-delivery PE is very straightforward because researchers can easily obtain data on birth weeks from the database. In comparison, a survey of preterm-onset PE is more complicated and requires researchers to investigate the onset of symptoms and signs (i.e., de novo hypertension and/or de novo proteinuria, maternal organ dysfunction, and placental dysfunction) based on original medical charts, which are often unavailable from the database alone. Moreover, the day of delivery in women with PE at 34–36 weeks of gestation may be artificially controlled according to institutional policy, whereby practitioners implement earlier or later induction of labor for those with PE at 34–36 weeks of gestation.³⁹⁾ However, the timing of diagnosis of preterm-onset PE/SPE is not affected by institutional policy. As such, the two definitions of preterm PE (i.e., preterm-delivery PE and preterm-onset PE) have merits and demerits, and thus, both preterm-delivery PE/SPE and preterm-onset PE should be evaluated simultaneously as primary outcomes when predicting preterm PE.

Keikkala et al.,³⁸⁾ for the first time, evaluated the use of hyperglycosylated hCG (hCG-h), PlGF, and PAPP-A at 8–13 weeks of gestation to predict early-onset PE (with onset at <34 weeks) and preterm PE (i.e., preterm-onset PE). Ohkuchi et al.,⁴¹⁾ for the second time, evaluated risk factors for the later occurrence of preterm-onset PE using maternal factors and blood pressure levels in the first trimester. To the best of our knowledge, only two studies have used preterm-onset PE as the primary outcome in the prediction of PE during the first trimester, whereas 18 studies validating the FMF competing risks model for predicting preterm PE in 2016–2023 used preterm-delivery PE as the primary outcome (Table 1, Figure 4).^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36)} Notably, no study has reported first trimester screening for the later occurrence of preterm-onset PE and preterm-delivery PE simultaneously.

Candidate research for which preterm-onset PE is an appropriate primary outcome

We found that many studies used preterm PE (i.e., preterm-onset PE) as the primary outcome. In studies measuring circulating protein levels at the onset of PE in pregnant women, preterm-onset PE is more appropriate than preterm-delivery PE.^37,38,47,48) In randomized controlled trials of pregnant women with PE, preterm-onset PE should be used instead of preterm-delivery PE, because the delivery date is undetermined when performing interventions in women with PE.^39,49) In addition, in studies using biomarkers of PE to predict the timing of delivery in pregnant women with PE, preterm-onset PE, not preterm-delivery PE, should be used.⁴⁰⁾ Meanwhile, both preterm-delivery PE and preterm-onset PE should be evaluated simultaneously as primary outcomes for the prediction of preterm PE.

Why do major clinical guidelines of the ISSHP, American College of Obstetricians and Gynecologists (ACOG), and World Health Organization (WHO) emphasize timing-based classification of PE?

Why do major clinical guidelines issued by the ISSHP, ACOG, and WHO emphasize timing-based classification of PE? In the 2014 ISSHP guideline,²⁾ the rationale for introducing the timing-based classification is described as follows: “Distinctions between early and late onset, and mild and severe pre-eclampsia, are useful for research purposes, as described in the accompanying ISSHP paper³⁾; however, for clinical purposes, the condition should be considered as one that is at any time capable of being severe and life-threatening for mother and baby.” Although the ACOG guideline does not formally define early-onset PE, the term “early-onset preeclampsia” is introduced in its commentary.⁵⁰⁾ Similarly, the WHO guideline mentions the term in its commentary, without a definition.⁵¹⁾ In contrast, the National Institute for Health and Care Excellence (NICE) guidelines made no reference to the terms “early-onset preeclampsia” or “early preeclampsia”.⁵²⁾ The increased use of the term “early-onset PE” in various HDP guidelines may reflect the growing body of evidence linking early-onset PE to adverse maternal/neonatal outcomes. A PubMed search conducted on November 27, 2024, using the keywords “early-onset preeclampsia” OR “early-onset pre-eclampsia” identified 1,248 articles. Similarly, a PubMed search conducted on the same day using the keywords “early preeclampsia” OR “early pre-eclampsia” yielded 235 articles.

Why do studies on PE prediction and prevention tend to use the term “preterm PE” rather than “early-onset PE”?

Why do studies on PE prediction and prevention tend to use the term “preterm PE” rather than “early-onset PE”? The goal of preventing preterm PE with low dose aspirin (LDA) is to reduce the incidence of PE requiring delivery at <34 weeks, not 34–36 weeks, of gestation. However, no clinical trials have been designed to explicitly prevent early-onset PE or early PE requiring delivery at <34 weeks. It is well established that the sensitivity for predicting early PE at a 10% FPR in the first trimester is higher than that for predicting preterm PE at the same FPR.⁵³⁾ Despite this, designing a clinical trial with sufficient statistical power to prevent early PE is extremely challenging. For instance, the ASpirin for evidence-based PREeclampsia prevention (ASPRE) trial,⁴²⁾ which evaluated the use of LDA in pregnant women at risk for preterm PE, designated preterm PE as the primary outcome and early PE (delivery at <34 weeks) as the secondary outcome. The trial screened 26,941 singleton pregnancies, identifying 2,971 (11.0%) at high risk for preterm PE. Ultimately, 1,776 (6.6%) participants were enrolled in the trial, which was powered to detect a 50% reduction in the incidence of preterm PE. The findings were noteworthy: while the incidence of early PE decreased by 82%, this reduction was not statistically significant. In contrast, the incidence of preterm PE decreased by 62%, achieving statistical significance. Based on the ASPRE trial experience, we consider it unrealistic to design a trial aimed at preventing early PE, given its low incidence (approximately 0.4%)⁵⁴⁾ and the modest preventive efficacy of LDA for early PE (estimated at 38% in cohort studies).⁵⁵⁾ We speculate that the primary reason why studies on PE prediction and prevention prefer the term “preterm PE” over “early PE” is the practical difficulty of designing clinical trials with early PE as the primary outcome.

Conclusions

Although the disease concept of “preterm PE” has been prevalent in the prediction and prevention of PE in recent years, two different definitions of preterm PE are still used in the literature: “preterm-onset PE,” with onset at <37 weeks of gestation,^{37,38,39,40,41)} and “preterm-delivery PE,” with delivery at <37 weeks of gestation. As the two definitions each have merits and demerits, both preterm-delivery PE and preterm-onset PE should be evaluated simultaneously as primary outcomes when predicting preterm PE.

Conflict of interest

None.

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