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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology and Physiology, University of Oulu, Oulu, Finland.
Address reprint requests to: Kaarin Mäkikallio, MD Department of Obstetrics and Gynecology University of Oulu Oulu, 90220 Finland E-mail: kmakikal{at}cc.oulu.fi
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Abstract |
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Methods: Umbilical artery plasma N-terminal peptide of proatrial natriuretic peptide concentrations were measured in neonates by radioimmunoassay. The control group consisted of 50 neonates with uncomplicated gestation and labor. In group 1, there were 22 newborns of hypertensive pregnancies. Doppler ultrasonography showed abnormal umbilical artery blood velocity waveform in five cases and normal nonpulsatile umbilical vein blood velocity profile in every case. Group 2 consisted of five newborns of pregnancies complicated by maternal hypertensive disorder. Atrial pulsations in the umbilical vein and retrograde diastolic blood velocity pattern in the umbilical artery were detected in every case. Group 3 was composed of 27 newborns of uncomplicated pregnancies with fetal acidemia (pH 7.10 or less) during labor.
Results: In groups 1–3, N-terminal peptide of proatrial natriuretic peptide concentrations were higher (P < .001) than in the control group. In group 1, neonates with abnormal umbilical artery blood velocity pattern had higher N-terminal peptide of proatrial natriuretic peptide concentrations than neonates with normal umbilical artery Doppler findings (P < .006). N-terminal peptide of proatrial natriuretic peptide concentrations were higher in group 2 (P < .002) than in groups 1 and 3.
Conclusion: Maternal hypertensive disorder and fetal acidemia during labor stimulate fetal atrial natriuretic peptide production, which was greatest in fetuses with severe placental insufficiency and signs of congestive heart failure.
The N-terminal peptide of proatrial natriuretic peptide is released in equimolar amounts with atrial natriuretic peptide from atrial myocytes of the heart. The half-life of N-terminal peptide of proatrial natriuretic peptide is longer than that of atrial natriuretic peptide, which is reflected in the proportionately larger increase in plasma N-terminal peptide of proatrial natriuretic peptide levels compared with those of atrial natriuretic peptide in subjects with congestive heart failure. Therefore it is often used to characterize endogenous secretion of atrial natriuretic peptide.1,2 The predominant signal responsible for atrial natriuretic peptide release is atrial wall stretch or atrial distension in response to increased volume.3 In addition, increased atrial natriuretic peptide release has been found during hypoxemia.4 In adults with congestive heart failure, elevated circulating N-terminal peptide of proatrial natriuretic peptide concentrations has been proposed as a marker of symptomless left ventricular dysfunction.5 Pregnancy itself increases maternal plasma N-terminal peptide of proatrial natriuretic peptide concentrations.6 Maternal plasma atrial natriuretic peptide and N-terminal peptide of proatrial natriuretic peptide concentrations were significantly higher in preeclamptic women than in healthy pregnant controls.7,8
Abnormal placental function and fetal growth restriction (FGR) are common findings in preeclampsia. Severe placental insufficiency triggers compensatory mechanisms in the fetus to maintain adequate oxygen and nutritional supply to the most vital fetal organs, the heart and the brain.9,10 One of these protective mechanisms is redistribution of cardiac output. Right ventricular cardiac output decreases, while left ventricular cardiac output usually remains unchanged. Further deterioration in placental function and oxygen supply results in decreased left ventricular cardiac output.
Doppler ultrasonography is useful for examining placental function. Placental insufficiency with a decreased number of villar arterioles is associated with decreased, absent, or even reversed diastolic blood flow velocity pattern in the umbilical artery.11,12 Deterioration of placental function and decreased cardiac output might lead to increased fetal systemic venous pressure, which is detected as an increased atrial contraction wave in the hepatic veins, ductus venosus, and inferior vena cava, as well as atrial pulsations in the portal and umbilical veins.
We hypothesized that maternal hypertensive disorder during pregnancy and fetal acidemia during labor induce the atrial natriuretic peptide system, detected as an increase in newborn plasma N-terminal peptide of proatrial natriuretic peptide concentrations. The specific aims of this study were to investigate newborn N-terminal peptide of proatrial natriuretic peptide levels in pregnancies complicated by maternal hypertensive disorder without signs of increased fetal systemic venous pressure; in hypertensive pregnancies with an increase in fetal systemic venous pressure; and in uneventful pregnancies complicated by fetal acidemia during labor.
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Materials and Methods |
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In group 1, 22 women with pregnancy-induced hypertension or preeclampsia were included. According to ACOG guidelines,13 one woman had pregnancy-induced hypertension, and 16 women had mild and five had severe preeclampsia. Cesarean delivery was performed because of suspected fetal distress in five cases: in two cases the indication for cesarean delivery was maternal hypertension and severe headache, and in one case, previous cesarean delivery. Doppler ultrasonographic examination (Sequoia 512; Acuson, Mountain View, CA) of the umbilical artery showed normal blood flow velocity waveforms (systolic-diastolic ratio [S/D] less than 3.5) in 17 cases, decreased diastolic blood flow velocity component (S/D over 3.5) in three cases, absent diastolic blood flow velocity pattern in one case, and retrograde diastolic blood flow velocity pattern in one case. In this group, all fetuses had normal nonpulsatile venous blood velocity profiles in the intraabdominal portion of the umbilical vein. The interval between the last Doppler ultrasonographic examination and delivery was 0–10 days, with a median of 2 days.
Group 2 consisted of five patients with preeclampsia or hypertensive disorder. Pregnancy-induced hypertension was diagnosed in one case, and three women had mild preeclampsia and one had severe preeclampsia. In every case, cesarean delivery was performed because of signs of fetal distress by nonstress tests. A retrograde diastolic blood flow velocity component in the umbilical artery was detected in all five cases, and every fetus had atrial pulsations in the intraabdominal portion of the umbilical vein, reflecting increased systemic venous pressure. The interval between the last Doppler ultrasonographic examination and delivery ranged from 0 to 1 day.
Group 3 consisted of 27 patients with uneventful pregnancy combined with fetal acidemia during labor, which was defined as newborn umbilical artery pH of 7.10 or less. All subjects had normal fetal heart rate (FHR) tracings when admitted to the labor unit. In five cases, cesarean delivery was performed during the first stage of labor because of signs of acute fetal distress in FHR tracings; for the same reason vacuum extraction was done during the second stage of labor in four cases. In the control group and groups 1 and 2, the newborn umbilical artery pH values were above 7.10. Subjects who met the criteria for study groups were enrolled consecutively. All subjects were white. Perinatal data are presented in Table 1
. The research protocol was approved by the Ethics Committee of Oulu University, and all women gave written informed consent.
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-globulin antiserum in the presence of 8% polyethyleneglycol 6000. Synthetic human proatrial natriuretic peptide79–98 was used as a standard. The sensitivity of the assay was 40 pmol/L. The antiserum crossreacted 100% with the purified human proatrial natriuretic peptide1–126, whereas it did not recognize atrial natriuretic peptide itself (crossreactivity less than 0.01%). In the radioimmunoassay, the intraassay and interassay coefficients of variation were less than 10% and less than 15%, respectively.14 Statistical analysis was done using analysis of variance when comparisons were made between the four groups and the data were normally distributed. If statistical significance was shown, the Scheffé F test was used in further analysis. If the data was not normally distributed, nonparametric Kruskal-Wallis test was used. Between two groups, comparisons were made by using Student t test if the data were normally distributed, otherwise, the Mann Whitney U test was chosen. Linear regression analysis was used to show the relationship between umbilical vein and artery, and maternal cubital vein N-terminal peptide of proatrial natriuretic peptide concentrations. P < .05 was considered statistically significant. A sample size of 22 patients could detect a 232 pmol/L mean difference between groups with a power of 80%; and a sample size of five patients, a mean difference of 487 pmol/L.
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Results |
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). In addition, in group 3, the umbilical artery pH values were lower (P < .001) than in the control group and groups 1 and 2. There was no significant difference in umbilical artery pH values between the control group and groups 1 and 2. There was a significant correlation between umbilical artery and vein N-terminal peptide of proatrial natriuretic peptide concentrations (r = 0.71, P < .001) (Figure 1). Conversely, umbilical artery N-terminal peptide of proatrial natriuretic peptide concentrations were not correlated with maternal cubital vein N-terminal peptide of proatrial natriuretic peptide values (r = -0.07, P = .75) (Figure 2). The N-terminal peptide of proatrial natriuretic peptide concentrations in the umbilical artery and vein did not differ significantly (P = .07). However, the median (range) umbilical artery (580 pmol/L [226–3000 pmol/L]) and vein (679 pmol/L [210–2730 pmol/L]) N-terminal peptide of proatrial natriuretic peptide concentrations were higher (P < .02) than in the maternal cubital vein (479 pmol/L [229–1359 pmol/L]).
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, Table 1). In group 1, the subgroup of five neonates with abnormal umbilical artery blood flow velocity patterns during the fetal period had higher (P < .006) N-terminal peptide of proatrial natriuretic peptide concentrations than those with normal blood velocity waveforms in the umbilical artery. In group 2, in which an increase in fetal systemic venous pressure was evident, the umbilical artery N-terminal peptide of proatrial natriuretic peptide concentrations were significantly higher (P < .002) than in groups 1 and 3. The umbilical artery N-terminal peptide of proatrial natriuretic peptide values did not differ significantly between groups 1 and 3 (Figure 3).
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Discussion |
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In pregnancies complicated by maternal hypertensive disorder, the afterload faced by the fetal right ventricle is higher, and these fetuses tend to be hypertensive.16 This is especially obvious in cases with signs of placental insufficiency, ie, abnormal umbilical artery blood velocity waveforms. The present study found that in hypertensive pregnancies, fetuses with abnormal umbilical artery blood velocity waveform patterns had higher N-terminal peptide of proatrial natriuretic peptide concentrations than those with normal umbilical artery blood flow velocity patterns, indicating increased activity of the atrial natriuretic peptide system in that subgroup of fetuses. These results demonstrate that atrial natriuretic peptide is secreted in the fetal heart in response to an increase in afterload. Immunohistochemical examination of the human fetal heart has shown that atrial natriuretic peptide is present in the atria, the ventricular impulse-conducting system, and in working ventricular cardiocytes.17 Similarly, proatrial natriuretic peptide is expressed in human fetal ventricles, in which the myofibers containing atrial natriuretic peptide granules are more abundant in the subendocardial than in the subepicardial region.18 Previously, we showed that in pregnancies complicated by preeclampsia and placental insufficiency, newborn cardiac-specific troponin-T concentrations, which reflect myocardial cell damage, were not higher than those in uncomplicated pregnancies. However, in the presence of atrial pulsations in the umbilical vein associated with severe placental insufficiency, troponin-T levels were above the clinically significant level (0.10 ng/mL) in every case, suggesting that in those cases myocardial cell damage occurred during pregnancy.19
The optimal timing of delivery in pregnancies complicated by severe placental insufficiency is still a controversial issue. Fetuses who have severe placental insufficiency and have evidence of increased systemic venous pressure show signs of cardiac dysfunction and myocardial cell damage. Based on these findings, we speculate that the optimal timing of delivery should be before the appearance of atrial pulsations in the umbilical vein.
Capponi et al20 measured fetal atrial natriuretic peptide concentrations in blood samples obtained by funicentesis. In growth-restricted fetuses with abnormal umbilical artery and inferior vena cava Doppler ultrasonographic findings, atrial natriuretic peptide levels were significantly higher than those in fetuses with abnormal umbilical artery and normal inferior vena cava blood velocity waveforms. Atrial natriuretic peptide levels in growth-restricted fetuses with abnormal umbilical artery and normal inferior vena cava Doppler ultrasonographic findings did not differ from those in appropriately grown fetuses. In the present study, we found elevated N-terminal peptide of proatrial natriuretic peptide concentrations in neonates with abnormal umbilical artery and normal nonpulsatile umbilical vein blood flow velocity patterns. One explanation for the discrepancy is that we measured N-terminal peptide of proatrial natriuretic peptide, which is released in equimolar amounts with atrial natriuretic peptide. The half-life of N-terminal peptide of proatrial natriuretic peptide is longer than that of atrial natriuretic peptide, which is manifested as a larger increase in the concentration of N-terminal peptide of proatrial natriuretic peptide compared with that of atrial natriuretic peptide.
Neonates with acidemia during labor had higher umbilical artery N-terminal peptide of proatrial natriuretic peptide concentrations than neonates in the control group. In this group, the pregnancy was uncomplicated, and the birth weights of the neonates were within the normal range in every case. In addition, FHR tracings were normal when the mothers were admitted to the labor unit. These findings suggest that relatively rapid changes in fetal acid-base status are manifested in the cardiovascular system as increased atrial natriuretic peptide production. It was shown that newborn umbilical vein atrial natriuretic peptide concentrations are inversely related to umbilical artery pH values, which was thought to indicate fetal cardiac response to the stress of acidosis.21 In addition, in some cases acute fetal hypoxemia might have induced atrial natriuretic peptide production. Studies using animals have shown that atrial natriuretic peptide production in the fetus was increased by acute hypoxemia and an increase in atrial pressure. However, in human fetuses, the connection between acute hypoxemia and increased atrial natriuretic peptide production is not so evident. It has been reported that in neonates oxygen tension did not show an independent relationship with atrial natriuretic peptide concentrations.21 Human fetal atrial natriuretic peptide concentrations increased promptly in response to vascular volume expansion, which was shown during intravascular blood transfusion in utero. That increase in atrial natriuretic peptide concentration was due to acute volume expansion and a sharp increase in the afterload that occurs during intravascular red blood cell transfusion.22 Acute fetal distress with acidemia during labor can trigger fetal cardiac dysfunction.
In this study, N-terminal peptide of proatrial natriuretic peptide measurements were carried out using blood samples collected from umbilical arteries. When umbilical artery and vein blood samples were compared, N-terminal peptide of proatrial natriuretic peptide concentrations did not differ significantly. However, maternal cubital vein N-terminal peptide of proatrial natriuretic peptide concentrations were significantly lower than corresponding neonatal umbilical artery and vein concentrations. In addition, maternal cubital vein N-terminal peptide of proatrial natriuretic peptide values were not correlated with newborn umbilical artery N-terminal peptide of proatrial natriuretic peptide concentrations, whereas a significant correlation was found between newborn umbilical artery and vein concentrations. These findings indicate that N-terminal peptide of proatrial natriuretic peptide measured in newborn umbilical arteries was of fetal origin. Previously, Shilo et al23 found no correlation between maternal and neonatal atrial natriuretic peptide concentrations, which supports the view that it does not cross the human placenta. Studies in rats have also shown that.24 The molecular size of the N-terminal peptide of proatrial natriuretic peptide (98 amino acids) is much greater than that of the atrial natriuretic peptide (28 amino acids), making it likely that it does not cross the placenta either. Our results suggest that there is no significant transplacental passage of N-terminal peptide of proatrial natriuretic peptide.
Earlier studies have shown that mode of delivery did not influence maternal or umbilical artery or vein plasma atrial natriuretic peptide concentrations.21 In addition, it has been shown that gestational age at delivery is not an important determinant of newborn atrial natriuretic peptide concentrations. Analysis of atrial natriuretic factor concentrations in human fetal blood samples obtained by funicentesis has shown that they do not change with gestation.25
Newborn N-terminal peptide of proatrial natriuretic peptide concentrations in hypertensive pregnancies without signs of increased fetal systemic venous pressure were significantly higher than those in normal pregnancies. A subgroup of neonates with evident placental insufficiency during fetal life had significantly higher N-terminal peptide of proatrial natriuretic peptide values than neonates of hypertensive mothers with normal placental function. This finding suggests that in hypertensive pregnancies, atrial wall stretch of the fetal heart is higher than in normal pregnancies and that it increases with further deterioration of placental function. Fetuses with severe placental insufficiency and signs of increased systemic venous pressure had higher neonatal N-terminal peptide of proatrial natriuretic peptide concentrations than those with uncomplicated gestations and hypertensive pregnancies with normal umbilical venous return. We speculate that atrial pulsations in the umbilical vein are a sign of fetal congestive heart failure. In addition, human fetal atrial natriuretic peptide production is stimulated by fetal acidemia during labor.
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Footnotes |
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Received March 6, 2000. Received in revised form June 19, 2000. Accepted July 7, 2000.
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References |
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