Usefulness of brain-type natriuretic peptide (BNP) levels in pregnancy

Abstract

Background

Natriuretic peptides, such as active brain-type natriuretic peptide (BNP) and inert N-terminal pro-B-type natriuretic peptide (NT-proBNP), are hormones secreted by the heart in response to increased intraventricular pressure and circulating blood volume. Physiological cardiovascular adaptations during pregnancy result in an increase in BNP secretion. In non-pregnant populations, these peptides are well-established markers for diagnosing heart failure and assessing cardiac risk; however, their clinical usefulness in pregnancy and cardiovascular risk assessment is limited. This paper aims to summarise the possible uses of BNP in pregnancy based on the available literature and research.

Materials and methods

We searched Medline, PUBMED, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for English-language studies published regarding BNP and pregnancy.

Result

BNP and NT-proBNP are valuable markers for diagnosing and predicting cardiac complications in pregnancy, including heart failure, pre-eclampsia, and peripartum cardiomyopathy, and for risk stratification in women with adverse pregnancy outcomes. Recommended upper limits are 50 pg/ml for BNP across all trimesters and 200 pg/ml (first and second trimester) and 150 pg/ml (third trimester) for NT-proBNP. A BNP >100 pg/ml demonstrates high diagnostic accuracy (sensitivity 98%, specificity 92%, PPV 92%, NPV 97%) for cardiac complications. In addition, BNP used in conjunction with sFlt-1/PlGF ratio tests, has improved the predictive capability of delivery in pre-eclampsia (p = 0.011).

Discussion

BNP and NT-proBNP are widely used in emergency settings to differentiate cardiac from non-cardiac causes of dyspnoea and heart failure, but their use in pregnancy-specific conditions remains. The fluctuation of BNP levels with pre-existing cardiac, renal disease and obesity needs further evaluation to identify a useful cut-off for the use of BNP in pregnancy.

Keywords

BNP pregnancy complications cardiovascular pre-eclampsia peripartum cardiomyopathy heart failure

Introduction

Natriuretic peptides are proteins involved in the regulation and improvement of blood circulation. There are different types of natriuretic peptides, namely, brain-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal Pro-B-type natriuretic peptide (NT-proBNP). Serum BNP is currently being used highly effectively in predicting the onset of several cardiac issues, including heart failure, hypertension and cardiomyopathy in the general population.^1,2

Pregnancy imposes substantial physiological and haemodynamic changes on the maternal cardiovascular system, including a marked increase in blood volume and cardiac output.³ In response to the increase in volume and intraventricular pressure, BNP is secreted.³ While these adaptations are essential for supporting fetal development, they can unmask or precipitate cardiac dysfunction in susceptible individuals.

During pregnancy, BNP levels rise but generally remain within normal limits, offering a potential early indicator of maternal cardiovascular compromise.^4–6

Elevated BNP and NT-proBNP have also been associated with pregnancy-specific complications such as pre-eclampsia, gestational hypertension, gestational diabetes and preterm labour.

This review summarises current evidence on the clinical utility of BNP and NT-proBNP in pregnancy, highlighting their role in predicting adverse maternal and neonatal outcomes with particular focus on peripartum cardiomyopathy, hypertensive disorders and preterm birth.

Brain-type natriuretic peptide and N-terminal Pro-B-type natriuretic peptide

BNP is a protein that is cleaved from pro-BNP, which is secreted by the cardiac ventricular myocytes in response to increased circulating blood volume and intraventricular pressure.³ The remaining N terminal has no active function and is called NT-proBNP. The half-life of BNP in serum is 60 min while NT-proBNP lasts about 120 min hence NT-proBNP remains longer in the blood and can be used to predict cardiac health over a prolonged period.⁷

BNP is cleared by binding to natriuretic peptide receptor type C and through proteolysis by neutral endopeptidases found in the liver, lung, kidney, and vascular endothelium.^3,8 NT-proBNP is cleared only by the kidney.⁸

BNP released from cardiomyocytes acts on the cardiovascular system in 4 main ways:

Increases vascular compliance and causes venous dilation, thereby lowering venous return and reducing cardiac preload.

Induces arterial dilation, which decreases systemic vascular resistance and afterload, reducing blood pressure.

Promotes natriuresis and diuresis by increasing glomerular filtration rate and inhibiting sodium reabsorption in the renal tubules.

Suppresses renin release, thereby reducing circulating angiotensin II and aldosterone, further enhancing natriuresis and diuresis.

Through these mechanisms, BNP/NT-ProBNP functions as a counter-regulatory system to the renin-angiotensin-aldosterone axis, maintaining cardiovascular homeostasis.

BNP and NT-proBNP values in standard and pregnant populations

BNP and NT-proBNP are valuable biomarkers, widely used in prediction and diagnosis of heart failure in the general population, as evidenced by multiple studies^9–12 as well as guidelines listed in Table 1. This has also been adopted and recommended by the National Institute of Health and Care Excellence (NICE) as a biomarker for the prediction of patients presenting with acute heart failure.¹³

Table 1.

Reference ranges for diagnosis of HF in standard population.

Standard population reference intervals:
Reference	Analyse	Cut off
NICE¹³	NT-proBNP	>400pg/ml or 46pmol/litre
PRIDE Study⁹	NT-proBNP	<300pg/ml
ICON-RELOADED study ¹⁰	NT-proBNP	<300pg/ml
ESC 2021 Guidelines ¹	NT-proBNP	>125pg/ml
Mueller ¹¹	BNP	<100pg/ml
Wieczorek ¹²	BNP	<100pg/ml

However, BNP and NT-proBNP values have not been validated for routine use in pregnancy, and research in this cohort remains limited. Physiological changes during pregnancy, including increased blood volume and haemodynamic adaptations, influence circulating concentrations of these peptides. For this reason, several studies have proposed trimester-specific reference intervals as listed in Table 2.

Table 2.

Reference ranges of BNP/NT-proBNP in pregnant population.

Pregnancy-specific reference intervals:
Reference	Analyse	Ranges (1^st trimester)	Ranges (2^nd trimester)	Ranges (3^rd trimester)
Oxford ¹⁴	BNP	10–51.8pg/ml	10–59.8pg/ml	10–51.5pg/ml
Oxford ¹⁴	NT-proBNP	21.5–200.6pg/ml	17.7–198.2pg/ml	9.6–171pg/ml
University of California ¹⁵	BNP	10–115pg/ml	10–112pg/ml	10–143pg/ml
Postgraduate Institute of Medical Education and Research, Chandigarh ¹⁶	BNP	50.4–88.2pg/ml		51.9–84.9pg/ml

Franz et al. and Kale et al. demonstrated that NT-proBNP levels are higher in pregnant women compared to non-pregnant controls, reflecting the cardiovascular adaptations of gestation.^17,18 Dockree et al. reported an upper reference limit for BNP of 50 pg/mL, with no significant trimester-related variation, whereas NT-proBNP was 200 pg/mL in the first and second trimesters and 150 pg/mL in the third trimester.¹⁴ The observed fall in the third trimester was attributed to haemodilution from plasma volume expansion. Importantly, NT-proBNP may represent a more reliable biomarker in pregnancy, as it is not degraded by neprilysin. In contrast, BNP is subject to neprilysin-mediated degradation, and neprilysin levels are elevated in pregnancy due to placental release, potentially leading to underestimation of BNP values.

These key observations and cut-offs for use in pregnancy are summarised in Tables 3 and 4.

Table 3.

Reference ranges of BNP/NT-proBNP levels in pregnancy.

Test	Normal pregnancy range	Suggestive of cardiac dysfunction
BNP	Usually <100 pg/mL	>100 pg/mL (consider >200 significant)
NT-proBNP	Usually <125 pg/mL (1st/2nd trimester) <200 pg/mL (3rd trimester)	>300 pg/mL (suggests cardiac dysfunction)

Table 4.

Key observations for use of BNP and NT-proBNP in pregnancy.

Key observations for use of BNP and NT-proBNP in pregnancy:

Approximately twice the range observed in the non-pregnant population – related to 50% increase in circulating blood volume and left ventricular pressure in pregnancy.

BNP levels – usually stable across trimesters, upper limit = 50pg/ml.

NT-proBNP levels – higher in the first trimester compared to the third trimester (haemodilution effect) = upper limit 200pg/ml (1^st/2^nd trimester), 200pg/ml (3^rd trimester).

NT-proBNP is preferred over BNP – as not degraded by neprilysin (placentally derived hence elevated in pregnancy).

Influence of BMI: Higher BMI is associated with lower BNP (enhanced clearance by excess neprilysin from adipose tissue) and NT-proBNP levels (haemodilution). Use lower reference limits in obesity. European Society of Cardiology guidelines suggest a 50% reduction in cut points for BNP with obesity.

Usefulness of BNP/NT-ProBNP in the prediction, prevention and management of adverse pregnancy outcomes

As the increased levels of BNP and NT-proBNP predict an increased likelihood of cardiovascular compromise, their clinical usefulness as a biomarker to predict and monitor the development of hypertensive and cardiovascular complications in pregnancy has been evaluated in several studies. A primary focus has been on the following conditions, as represented in the summary Table 5 and detailed analysis below:

Peripartum cardiomyopathy

Pre-eclampsia

Gestational hypertension

Gestational diabetes mellitus

Placenta praevia/accreta

Pre-term labour

Table 5.

Usefulness of BNP and NT-proBNP in different pregnancy-specific conditions.

Condition	BNP/NT-proBNP	Clinical utility
Peripartum cardiomyopathy	Markedly ↑, diagnostic	Early detection, monitoring, prognosis
Pre-eclampsia	↑ (correlates with severity)	Prediction & severity assessment
Gestational hypertension	Mild ↑	Differentiate from pre-eclampsia
Gestational diabetes mellitus	Possible mild ↑	Subclinical cardiac dysfunction marker, research, not routine
Placenta praevia/accreta	Limited evidence	Research only, not routine
Pre-term labour	Possible association	Research only

Peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening cause of heart failure with reduced left ventricular ejection fraction (<45%), occurring in the absence of another identifiable cause, typically in late pregnancy or the months following delivery, termination, or miscarriage. It is a diagnosis of exclusion requiring urgent management.¹⁹ According to the European Society of Cardiology (ESC), diagnostic criteria of PPCM includes:

Development of heart failure in the last month of pregnancy or the first 5 months postpartum.

Absence of a determinable aetiology for cardiac failure.

Absence of known heart disease prior to the last month of pregnancy.

Left ventricular systolic dysfunction is demonstrated by classic echocardiographic criteria such as depressed shortening fraction or ejection fraction (EF).

Cardiac disease is still the most common indirect cause of maternal mortality in the UK (MBRRACE 2024).²⁰ Clinicians therefore need to identify asymptomatic patients who are at risk of PPCM. Risk factors for PPCM include African descent, Multiparity, Age, Multiple gestation, Hypertensive disorders complicating pregnancy, and a high BMI (>30 kg/m²).

Biomarkers such as BNP and NT-proBNP have shown promise in predicting cardiac complications. A systematic review conducted by Sheikh et al. involving 13 studies has shown that serum BNP >100 ng/L has been shown to have a positive predictive value of 92%, a negative predictive value of 97%, a sensitivity of 98% and a specificity of 92% of diagnosing cardiac complications such as cardiac failure and pre-eclampsia, although the review was not specific to PPCM.²¹

Tanous et al. compared the BNP levels in 66 patients with heart disease and 12 healthy pregnant patients.²² BNP levels remained stable throughout pregnancy in healthy individuals. Among patients with cardiac disease, 38% of patients had a raised BNP, with 10% of patients showing an increase in BNP in the first trimester. About 13% of patients with cardiac disease had an adverse outcome such as stroke, cardiac failure or arrest or a decline in cardiac function, with 88% of these individuals having a rise in BNP that predated the adverse event, highlighting its predictive value.

In PPCM specifically, NT-proBNP has been shown to correlate with recovery. In a study of 35 patients those with initial BNP >900 pg/mL had no improvement in cardiac function after 12 months (p = 0.028), whereas patients with BNP <900 pg/mL demonstrated more consistent recovery.²³ BNP can therefore guide postpartum follow-up intensity and cardiology involvement.

In a multicentre cohort study, women with median NT-proBNP <2585 pg/mL at diagnosis had significantly better event-free survival compared with those with higher levels (p = 0.018), demonstrating its prognostic utility. Interestingly, although PPCM typically manifests late in pregnancy or postpartum, a small study found that first-trimester NT-proBNP levels were higher in women who later developed PPCM (n = 4) (median 115.5 pg/mL) compared with healthy pregnancies (median 37–56 pg/mL) after adjusting for demographics, blood pressure, and weight gain. These findings suggest that subclinical myocardial stress may be detectable early, indicating a potential role for NT-proBNP in early risk stratification, though evidence remains limited.⁶

Pre-eclampsia and eclampsia

The pre-eclampsia is defined by NICE as the onset of blood pressure > 140/90 mmHg after 20 weeks of gestation and one of the following²⁴:

Proteinuria (Urine PCR: 30 mg/mmol, albumin:creatinine ratio of 8 mg/mmol, l g/litre, 2 + on dipstick testing).

Renal insufficiency (creatinine 90micromol/litre).

Liver involvement (elevated transaminases) with/ without right upper quadrant pain.

Neurological complications – altered mental status, blindness, stroke, clonus, headaches.

Haematological complications – thrombocytopenia (platelet count <150,000/microlitre).

Uteroplacental dysfunction – fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, or stillbirth.

As per the MBRRACE report 2024, cardiac disease is the second most frequent indirect cause of maternal death.²⁰ The incidence of pre-eclampsia and eclampsia continue to be higher than the lowest rates observed in 2012–2014.²⁰ Early identification allows obstetricians to tailor antenatal care and improve both maternal and fetal outcomes.

BNP and NT-proBNP in pre-eclampsia

Biomarkers such as BNP and NT-proBNP have been investigated for their predictive and monitoring utility in pre-eclampsia. A systematic review conducted by Afshani et al. including 12 studies reported that 10 out of the 11 studies reported higher BNP/NT-proBNP levels in pre-eclamptic patients than in normal patients.²⁵ Out of these, one study managed to identify that NT-proBNP levels were markedly higher in pre-eclamptic patients than patients with chronic hypertension.²⁶ It is to be noted that these studies had small sample sizes and there was no statistical analysis conducted to ensure heterogenicity and publication bias. Nevertheless, multiple studies not included in this systematic review have also concluded similar findings.¹⁸^26–33

Comparisons with established biomarkers for pre-eclampsia such as sFlt-1/PlGF ratio, studies have shown that NT-proBNP can enhance prediction.^34,35

Sabriá et al. demonstrated that NT-proBNP levels increase approximately one week before delivery in women with pre-eclampsia, showing a significant difference compared to normotensive pregnancies (p < 0.05). These findings suggest that NT-proBNP may help identify patients at risk of disease progression and earlier delivery. Compared with the sFlt-1/PlGF ratio test, which predicts the likelihood of delivery within two weeks, NT-proBNP appeared to provide superior short-term predictive value. The study was adequately powered to account for potential confounders, including gestational diabetes, chronic hypertension, parity, IVF conception, and obesity. Overall, the authors noted that while NT-proBNP has limited value for long-term prediction of pre-eclampsia, it may serve as a useful biomarker for monitoring disease progression in established cases.

Another study combined sFlt-1, PlGF, NT-proBNP and uric acid in a machine-learning model (MLM) to predict pre-eclampsia and compare its performance to the sFlt-1/PlGF ratio alone. In 597 women with suspected PE (936 serum samples, 24–36 + 6 weeks gestation), the MLM outperformed the sFlt-1/PlGF ratio alone in predicting preterm pre-eclampsia within six weeks (PPV 83.1% vs 72.8%, specificity 94.9% vs 91%) and early-onset pre-eclampsia within one week (AUC 0.954 vs 0.914). This combined approach addresses cardiovascular and renal contributions to pre-eclampsia and may improve clinical precision, reduce false positives and guide management, though further validation and research are needed to assess its cost-effectiveness and utility in a diverse population.

Chronic/gestational hypertension

Hypertension in pregnancy is classified into²⁴:

Chronic hypertension – BP elevated before 20 weeks or pre-existing antihypertensive therapy.

Gestational hypertension – new-onset BP elevation after 20 weeks without significant proteinuria.

Pre-eclampsia (as discussed above)

Both chronic and gestational hypertension increase the risk of intrauterine growth restriction (IUGR), pre-eclampsia, placental abruption, preterm birth, and caesarean delivery, emphasising the importance of early identification and management.^24,36

There is limited evidence of BNP/NT-proBNP in hypertensive pregnancies. Two studies on patients with chronic hypertension and they have shown that patients with chronic hypertension do not have raised BNP/NT-proBNP.^26,29 This likely because the cardiovascular system has adapted to a sustained high-pressure state. A small study found that elevated BNP in chronic hypertension inversely correlated with fetal growth,³⁷ suggesting potential utility in monitoring for fetal growth restriction, but further research is needed to investigate the prognostic value of BNP and IUGR pregnancies.

Conversely, in gestational hypertension, there is a new introduction of a raised pressure state, increasing the workload on the heart, which will result in the increased production of BNP.^26,28,29 However, the results are inconsistent with some studies showing that the BNP levels in gestational hypertension were higher than those in normal pregnancy, while others considered that there was no significant difference in BNP levels between them. Hence, further large-scale studies are needed to clarify BNP's diagnostic value in gestational hypertension.

Gestational diabetes mellitus (GDM)

Gestational diabetes is a recognised risk factor for future cardiovascular disease. Unlike pre-eclampsia and hypertensive disorders, NT-proBNP levels are not increased in women with GDM. This allows for standard upper cut-off values can therefore be used in this group of patients.^31,38 However, caution should be taken in interpreting these values in women with insulin dependent GDM as these women were found to have lower concentrations of circulating NT-proBNP than women with diet controlled GDM or unaffected pregnancies. These differences amongst women with insulin-dependent gestational diabetes may be due to differences in BMI, glomerular filtration rate and haemodynamics, suggesting NT-pro BNP be an insensitive marker for early cardiac complications in this subgroup, with potential risk of false negatives.

Later studies in 2015, however, found that serum ANP and BNP levels in GDM are significantly lower than in healthy controls and no difference was observed in BNP levels between diet-controlled and insulin dependent gestational diabetes.³⁹

In contrast, type 2 diabetes has been associated with elevated NT-proBNP. Unfortunately, the work carried out by Andreas et al. did not take into consideration physiological cardiovascular changes that occur in pregnancy.³⁸

Early pregnancy is associated with transient rise in NT-proBNP which normalises by 24 weeks’ gestation, with limited evidence that the left ventricular mass may be augmented in even normotensive women with GDM, indicating that there may be cardiovascular changes in women with GDM that are not detected during routine screening.³⁸

De Souza et al. investigated the relationship between previous gestational glucose tolerance and NT-proBNP. He found that serum NT-proBNP is related to current glucose tolerance rather than previous gestational dysglycaemia, with the lowest levels found in diabetic women compared to women with normal glucose tolerance. This study also suggested a relationship between BNP and adiponectin, potentially implicating early cardiovascular alterations.⁴⁰

Overall, the current evidence is contradictory, and further work needs to be carried out to further establish the relationship between NT-proBNP and GDM, and its implications in pregnancy and its role in predicting future cardiovascular risk.

Placenta praevia/accreta

Evidence examining NT-proBNP in placenta praevia and accreta is extremely limited. The only study, conducted by Esroy, looked at 54 pregnant patients with placenta praevia and found that NT-proBNP and troponin I levels were significantly higher than in groups with normally implanted placenta.^41,42However, correlation analysis between serum NT-proBNP levels and the AIP (abnormally invasive placenta) degrees of invasion showed a trend but was not significant. The authors propose the use of serum VEGF (vascular endothelial growth factors) instead, as it provides a better correlation.

Given the low incidence of AIP,⁴³ larger studies are challenging but necessary to determine whether NT-proBNP is useful in predicating and monitoring placenta accreta/praevia.

Pre-term labour

Preterm labour is an area of emerging interest for BNP as a potential biomarker. During most of a pregnancy, the myometrial smooth muscle cells remain in a state of active relaxation, known as myometrial quiescence, which is crucial for prolonging gestation. The mechanisms responsible for this are not well understood, however, it has been suggested that proteins produced by fetal membranes (the chorion and amnion) act in a paracrine fashion to inhibit myometrial contractions.

BNP has been detected in both chorion and amnion, with receptor binding sites present in the placenta and myometrium.^44–47 In vitro studies indicate BNP is more potent than any of the other natriuretic peptides at inhibiting contractions. It has been hypothesised that a premature decrease in BNP levels may identify women at increased risk of preterm labour. This is thought to be via the cAMP-PKA pathway.^46,47

Currently, the diagnosis of pre-term labour is by testing for the presence of fetal fibronectin as well as the measurement of cervical length (NICE Guidelines NG25). Using the cut off > 50 ng/ml, FFN has a negative predictive value of 99.2% and a positive predictive value of only 40% for delivery within 14 days. Measurement of BNP levels in cervicovaginal fluid could be another marker to improve the prediction and management of patients at risk of preterm labour, and further research could be done in this field.

Proposed use of BNP in obstetric patients with cardiac disease

BNP/NT-proBNP are now recommended to be used in pre-pregnancy and during pregnancy, both for individuals with known heart disease and for those presenting with new cardiac symptoms (e.g. dyspnoea, palpitations, chest pain, oedema, etc) even if they do not have a prior cardiac history (MBRRACE 2024 and the European Society of Cardiology (ESC) guidelines for the management of cardiovascular disease in pregnancy 2025).^20,48

For patients with established cardiac disease, assessing baseline and trimester-specific trends in BNP or NT-proBNP levels can help monitor cardiac function throughout pregnancy. Rising levels, as illustrated in Figure 1, should prompt further investigation and specialist referral to identify early signs of cardiac deterioration, thereby facilitating timely intervention and improving maternal and fetal outcomes.

Figure 1.

Proposed use of BNP/NT-proBNP in pregnant and non-pregnant individuals with cardiac disease or symptoms.

Individuals with no history of cardiac disease but presenting with cardiac symptoms, understanding normal BNP levels during pregnancy would be useful to rule out cardiac-related symptoms. If BNP levels exceed normal pregnancy ranges at different trimesters, further investigations would be warranted as described in Figures 1 and 2. BNP and NT-proBNP have notably a high negative predictive value, and elevated results warrant further evaluation.⁴⁹

Figure 2.

Interpretation of BNP/ NT-proBNP in pregnancy.

It is important to acknowledge that there are also other factors that can influence BNP levels. According to the European Society of Cardiology Guidelines and NICE guidelines on heart failure^13,48,50:

Conditions such as renal failure can increases BNP levels

Obesity can lower BNP levels by up to 50%

Flash pulmonary oedema can also reflect artificially lower BNP levels, as compared to clinical presentation.^46,47

High creatinine and low haemaglobin levels can lead to an increase in BNP/NT-proBNP concentrations.⁵¹

The results should never be used as a standalone test and must be complimented with patient's clinical presentation and history.

Figures 1 and 2 show the practical flow charts to illustrate their clinical use.

Conclusion

BNP is a useful marker for evaluating cardiac failure. Its clinical use in pregnancy has been limited to research studies. Few studies have looked at cut-off reference ranges for BNP in pregnancy. This paper describes the role of BNP/NT-proBNP as a readily available predictive test to evaluate cardiac function in pregnancy, improve early detection and intervention and assess the recovery in conditions like PPCM. Additionally, these markers potentially have an important clinical role as a screening test in the assessment and diagnosis of pre-eclampsia, either alone or in combination with sFlt-1/PlGF ratio tests. Furthermore, in resource-limited settings where sFlt-1/PlGF ratio testing may not be readily available the clinical utility of these markers may be even greater. The fluctuation of BNP levels with pre-existing cardiac and renal disease, as well as obesity, needs further studies to determine clinically useful cut-off for the use of BNP in pregnancy with these co-morbidities.

Footnotes

Acknowledgements

The authors would like to thank their respective institutions for supporting this collaborative work.

ORCID iDs

Stuart Quek

Rabia Zill-e-Huma

Mark Andrews

Maria Mouyis

Author contributions

Dr Stuart Quek led the review and manuscript preparation. Dr R Zill-e-Huma, Dr M Andrews and Dr M Mouyis provided supervision, critical revisions and topic-specific guidance.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Guarantor

Dr. Stuart Quek.

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