Our study identified two pivotal findings related to NT-proBNP levels and their association with HDP. First, patients with HDP had significantly lower NT-proBNP levels during the early-pregnancy phase than those without HDP. The logistic regression models showed that higher early-pregnancy NT-proBNP levels were associated with a lower HDP risk. Second, the current study revealed that a cutoff point of ≥ 60.5 pg/mL for early-pregnancy NT-proBNP levels for ruling out HDP had a high NPV and sensitivity.
First, patients with HDP had significantly lower early-pregnancy NT-proBNP levels compared with those without HDP. The logistic regression analyses showed that higher early-pregnancy NT-proBNP levels were associated with a lower HDP risk. There are numerous studies on elevated NT-proBNP levels immediately before and at HDP onset18–20. However, only a few studies focused on the early stages of pregnancy. To date, only one report that used logistic regression models has focused on the association between early-pregnancy NT-proBNP levels and HDP in nulliparous women. This study showed that higher early-pregnancy NT-proBNP concentrations were associated with a significantly lower risk of HDP and a lower risk of incident hypertension 2–7 years after delivery21. Hence, this is the first study that evaluated multiparous women with HDP who had low early-pregnancy NT-proBNP levels compared with those without HDP. The logistic regression models showed that higher early-pregnancy NT-proBNP levels were associated with a lower HDP risk.
Incidentally, the detailed mechanism underlying the transition in NT-proBNP levels during pregnancy remains unclear. Considering that maternal conditions significantly occur in the early-pregnancy stages, our evaluation focused on early-pregnancy NT-proBNP levels. In fact, the average early-pregnancy NT-proBNP levels of women without HDP were approximately more than twice as high as that of those in nonpregnant Asian young women from a previous report (81.0 vs. 34.9)22. This change occurred in women without HDP immediately after pregnancy. Therefore, a transient increase in early-pregnancy NT-proBNP levels can be important for maintaining hemodynamic homeostasis during pregnancy. In addition, our study showed that the early-pregnancy NT-proBNP levels of the HDP group was approximately half as low as those of the without HDP group. Lower NT-proBNP levels can indicate impaired early vascular adaptation to pregnancy, resulting in later-onset HDP. In normal pregnancies, decreased peripheral vascular resistance caused by elevated NT-proBNP levels and vascular sensitivity to the presser effects of angiotensin II and norepinephrine as compensatory mechanisms can facilitate adequate blood flow to the utero-placental circulation to ensure adequate intravascular volume during rapid hemodynamic changes that occur in the early stages of pregnancy. Therefore, a healthy maternal–fetal interface should be developed23,24. However, in patients with HDP who do not present with elevated NT-proBNP levels during early gestation, resulting in insufficient blood supply to the uteroplacental circulation, subsequent maternal hypertension can be a compensatory response to increased placental blood flow.
Further studies should be performed to discuss the detailed mechanisms underlying the source of NT-proBNP. High NT-proBNP levels are commonly associated with increased left ventricular end-diastolic dimension25. In contrast, the cardiac load increases toward the late term of pregnancy. The effect of this factor in early pregnancy is negligible. Thus, we focused on two possible factors, which are endogenous hormones related to pregnancy and organ development during pregnancy. In terms of endogenous hormones, hCG, which is released from the placenta and increases rapidly in early pregnancy, is one of the candidate hormones. Its peak is at approximately 10 weeks of gestation, and its production decreases toward late pregnancy. The beta subunit of hCG has structural homology with thyroid stimulating hormone; therefore, hCG can weakly stimulate its receptor, leading to the increased production of thyroidal hormone26. Hyperthyroidism increase BNP and NT-proBNP levels, and transient hyperthyroidism during early pregnancy is usually observed during prenatal checkups. Moreover, a previous study showed that the beta subunit of hCG in early pregnancy was significantly lower in pregnant women who subsequently develop preeclampsia27, which can be a reason for low early-pregnancy NT-proBNP levels in women with HDP. Taken together, early-pregnancy hCG levels can be a factor affecting NT-proBNP levels. The placenta is a unique organ that develops during pregnancy. Corin is an enzyme that converts BNP prohormone into BNP and NT-proBNP28. Previous rodent and human studies have revealed that NT-proBNP is secreted from the placenta, in addition to the ventricular muscle, to maintain pregnancy. In mouse placenta, BNP mRNA is expressed in the peripheral margin of the decidual layer29. In addition, corin mRNA was detected in the mouse uterus, umbilical cord, and placenta30. Moreover, corin-deficient mice developed high blood pressure and proteinuria late in gestation. However, their blood pressure and protein levels normalized after delivery31. In humans, the transcripts of corin and proBNP/NT-proBNP mRNA and their proteins have been observed in maternal spiral arteries and syncytiotrophoblasts in placental tissues17,28,30,32–35. Considering that the placenta is an endocrine organ that synthesizes and secretes hormones that maintain pregnancy status, NT-proBNP levels in maternal blood might be partly attributed to the placental release of the peptides.
Another pivotal finding was that a cutoff point of ≥ 60.5 pg/mL for early-pregnancy NT-proBNP levels had high NPV and sensitivity for ruling out HDP. Moreover, the HDP group had a significantly high ratio of NT-proBNP levels from the third to the first trimester. If we focus on the predictive markers of HDP onset during the first trimester, there are conflicting findings regarding its usefulness. That is, some studies have shown that it is valuable. Meanwhile, other studies have claimed that it lacks predictive power because there are extremely few relevant studies36–43. Indeed, only one study including nulliparous women has been reported to date. In this study, NT-proBNP levels in the first trimester were significantly lower in patients with term preeclampsia43, which is consistent with our results. To the best of our knowledge, this is the first study that evaluated the predictive value of early-pregnancy NT-proBNP levels in both multiparous and nulliparous women. Hence, a cutoff point of ≥ 60.5 pg/mL for early-pregnancy NT-proBNP levels had a high NPV and sensitivity for ruling out HDP. Moreover, the observed PPV for ruling in subsequent HDP using a third-to-first-trimester NT-proBNP ratio of ≥ 0.93 was 40.4%. NT-proBNP can be a predictive marker of HDP development in early pregnancy. Thus, it is helpful in HDP screening and risk stratification in pregnant women at an extremely early stage of pregnancy. Furthermore, cautious and close observation is required for patients presenting with low NT-proBNP levels during early gestation and high third-to-first-trimester NT-proBNP ratios before HDP diagnosis.
The current study had several strengths. For example, it used a novel approach for evaluating the predictive value of early-pregnancy NT-proBNP levels in both nulliparous and multiparous women. This reinforces the findings of previous studies that investigated early-pregnancy NT-proBNP levels only in nulliparous women21,43. The abovementioned data emphasized the increased early-pregnancy NT-proBNP levels, suggesting the purpose of adjusting to pregnancy and indicating that NT-proBNP can be a possible predictor of HDP.
The current study also had several limitations that should be acknowledged. This was a single-center retrospective cohort study with a small sample size and limited ethnicity (Japanese patients). These factors might have affected the study results. In addition, our clinic is at a primary care hospital. Hence, unlike a perinatal medical center, we could not handle cases of early-onset or severe HDP, which might contribute to some discrepancies. Previous studies have revealed that maternal insufficiency of blood perfusion may be more critical in early-onset preeclampsia than in late-onset preeclampsia. Moreover, early-onset preeclampsia is more significantly affected by placental factors4,44; thus, the outcomes can be more impressive when focusing on early-onset preeclampsia and using first- and additional second-trimester NT-proBNP levels to predict HDP risk. Therefore, a larger, multicenter study involving perinatal medical centers that may have managed several early-onset preeclampsia cases should be performed to validate our findings. Moreover, further research on the use of NT-proBNP levels and other examinations, such as assessment of predictive biomarkers and ultrasonography, must be conducted to enhance predictive power.
In conclusion, high early-pregnancy NT-proBNP levels were associated with a lower HDP risk. Further, a cutoff point of ≥ 60.5 pg/mL for early-pregnancy NT-proBNP levels had a high NPV and sensitivity for ruling out HDP, thereby emphasizing its potential as a predictive marker of HDP onset. These findings can set the stage for a deeper exploration of the detailed mechanisms and clinical implications of the associations between NT-proBNP levels and HDP.