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Obstetrics & Gynecology 2005;105:621-625
© 2005 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

The Influence of Pregnancy on Arterial Compliance

Ira M. Bernstein, MD*, Amy Thibault, MD*, Joan A. Mongeon, MS{dagger} and Gary J. Badger, MS{dagger}

From the Departments of *Obstetrics and Gynecology and {dagger}Medical Biostatistics, University of Vermont College of Medicine, Burlington, Vermont.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To examine the effect of pregnancy and the interval between pregnancies on arterial compliance as measured by mean arterial pressure (MAP) and pulse pressure.

METHODS: We conducted a 3-month chart review of deliveries at a tertiary care hospital (index pregnancies). Data collected included demographics, obstetric history, blood pressures, prepregnancy weight, weight gain, and neonatal outcome. If a subject's first delivery occurred at our institution, these records were reviewed in a similar fashion. Mean antepartum MAP and pulse pressure were calculated and compared for each trimester between index and first pregnancies. Statistical methods employed included repeated measures analysis of variance, repeated measures analysis of covariance, and correlation analysis.

RESULTS: Two hundred eighty-five charts were reviewed. Forty-seven women had complete data covering both index and first pregnancy. Mean arterial pressure was significantly higher in all trimesters of first compared with index pregnancies (first pregnancy-first trimester 82.0 ± 8.1 mm Hg, index pregnancy-first trimester 79.4 ± 7.6 mm Hg, P = .032; first-second trimester 81.6 ± 6.7 mm Hg, index-second trimester 78.7 ± 6.6 mm Hg, P = .016; first-third trimester 83.9 ± 6.9 mm Hg, index-third trimester 81.6 ± 6.9 mm Hg, P = .047). Repeated measures analysis of covariance confirmed that pregnancy order contributed independently to differences in MAP. The interval between pregnancies was found to be inversely related to the difference in MAP from first to index pregnancies by trimester (r = –0.41, P = .004) and the change in MAP within pregnancy from first to third trimester (r = –0.31, P = .046).

CONCLUSION: Mean arterial pressure is reduced in subsequent pregnancies compared with first pregnancies. This raises the possibility that pregnancy plays a role in modifying cardiovascular compliance. Consistent with this, the effect has temporal limitations in that the shorter the interval between pregnancies, the greater the reduction in MAP.

LEVEL OF EVIDENCE: II-3

Preeclampsia is a disorder of pregnancy whose etiology remains unknown. Familial occurrence has been demonstrated and specific genetic traits have been associated with preeclampsia in some populations.1,2 Epidemiologically, preeclampsia is primarily a disorder of first pregnancies and most often does not recur in subsequent pregnancies.3 Genetic and familial predispositions do not adequately address the issue of nonrecurrence.

We have hypothesized that preeclampsia occurs pathophysiologically as a result of an intolerance to the volume expansion of pregnancy.4 We have suggested that some women are at risk for this intolerance based on low prepregnancy plasma volume and that this low plasma volume, which is well compensated for before pregnancy, contributes to vascular adaptations that limit the ability of the vasculature to accommodate the volume loading of pregnancy.5 The hypothesis that preeclampsia is primarily a disorder of inadequate vascular compliance in pregnancy is consistent with the increased risk of preeclampsia observed with multiple gestation where there is an increased plasma volume expansion beyond that observed for singleton pregnancy,5,6 and with the reduced risk for preeclampsia associated with smoking where evidence suggests that plasma volume expansion is reduced.7,8 The hypothesis is also supported by the findings of both Easterling et al9 and Bosio et al,10 who have demonstrated that cardiac output is higher in women destined to develop preeclampsia and that this difference can be observed as early as the first trimester.

In support of the theory that prepregnancy volume status contributes to this intolerance to volume expansion we have shown that nulligravid women who possess a specific angiotensinogen genotype, which has been linked to preeclampsia in some populations, have lower nonpregnant plasma volumes than women with the alternative genotypes.11 It has also recently been demonstrated that low plasma volume in women between pregnancies is a significant risk for recurrent preeclampsia.12

Compliance is a measure of the change in pressure within a physical system relative to the change in volume, and this concept is frequently applied to the cardiovascular system. A highly compliant system is one where large volume changes are associated with small changes in pressure. Indirectly addressing this issue, Clapp and Capeless13 have identified persistent changes in cardiovascular parameters as far as 1 year postpartum when compared with baseline measures obtained before pregnancy. These changes include increased cardiac output, predominantly on the basis of increased stroke volume, with no change in pulse rate or arterial pressure. These findings are consistent with the hypothesis that pregnancy results in increased vascular compliance and that these changes persist beyond the puerperium. We decided to pursue this hypothesis by examining the patterns of changes in blood pressure that accompany a first pregnancy compared with a subsequent pregnancy within individuals. We specifically postulated that mean arterial pressure would be lower in subsequent pregnancies than in first pregnancies when matched by trimester. If we observed differences in mean arterial pressure between pregnancies, we proposed to examine whether there was evidence that these differences would change as a function of the time elapsed between pregnancies.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We performed a chart review of all deliveries occurring at a tertiary care hospital between January 1, 2000, and March 30, 2000. These pregnancies were identified as index pregnancies. We excluded from review all charts registered to the maternal–fetal medicine service and pregnancies with evidence of hypertension, preeclampsia, thrombophilia, or multiple gestation. We also excluded women who were late registrants for prenatal care (defined for our purposes as registration at or beyond 14 completed menstrual weeks of gestation. We screened 285 charts, of which 101 subjects were excluded because of a priori exclusions or incomplete data availability. Of the 184 subject available for analysis, 71 were primiparous and had no previous deliveries for comparison. Of the 113 multiparous subjects, constituting the index pregnancies, 47 had complete data sets available for their first pregnancy, and these women made up the study group. We collected data on demographic and morphometric criteria as well as obstetrical history. Blood pressures were recorded for each prenatal visit. We calculated both mean arterial pressure (MAP) and pulse pressure for each blood pressure recording for each trimester of pregnancy. Trimesters were defined as first (≤ 13 completed weeks of gestation), second (> 13 and ≤ 26 completed weeks of gestation), and third (> 26 weeks gestation). Additional maternal information included prepregnancy height and weight and weight gain during pregnancy. Neonatal information including birth weight, gestational age, and gender were recorded. To examine the impact of the interval between pregnancies on the outcomes of interest, we calculated the interval from the index pregnancy to the previous pregnancy in months. In the majority of cases (81%, 38/47), the pregnancy before the index pregnancy was the first pregnancy. In 9 cases the index pregnancy was a third pregnancy, and the pregnancy before the index pregnancy was a second pregnancy. In these cases blood pressures from the index pregnancy were compared to blood pressures from the subject's first pregnancy, but the interval between pregnancies was the interval between the second and the third pregnancy. This study was reviewed and approved by the University of Vermont Committee for Human Research in the Medical Sciences.

Clinical and demographic characteristics of first and index pregnancies were compared using paired t tests for continuous measures and the McNemar test for correlated proportions on categorical measures. Repeated measures analyses of variance were used to evaluate the significance associated with differences in MAP and pulse pressure between first and index pregnancies. The statistical model included 2 within-subject factors, pregnancy (first versus index) and trimester (first, second, and third), and their interaction. Simple effects (eg, differences between pregnancies within each trimester) were evaluated based on the F test corresponding to the appropriate contrast. The Fisher least significant difference test was used to perform pairwise comparisons. Evaluation of pregnancy differences in MAP and pulse pressure, adjusting for potentially confounded covariates such as prepregnancy body mass index and weight gain during pregnancy, was performed with repeated measures analyses of covariance. Regression and correlation analyses were used to examine the relationship between the length of the interpregnancy interval and changes in MAP and pulse pressure.


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
First and index pregnancies on 47 subjects were included in the analyses. All pregnancies were singletons, and the majority of the subjects were white women, 94% (44/47). Clinical and demographic characterizations for the 2 pregnancies are outlined in Table 1. Birth weight percentiles were based on local hybrid curves derived from a combination of ultrasound-estimated fetal weight and live birth weight for singletons.14,15 The interval between the index pregnancy and the prior pregnancy was 33 ± 11 months (mean ± standard deviation), with a range of 11–62 months. The interval between the index pregnancy and the first pregnancy was 38 ± 13 months, with a range of 13–67 months. The interval between pregnancies was defined as the interval between dates of deliveries.


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  		Table 1. Clinical and Demographic Features of Pregnancy

 

Mean arterial pressure was significantly lower in index pregnancies than in first pregnancies (main effect of pregnancy, F1,46 = 15.2, P < .001) (Table 2). When differences between first and index pregnancies were examined within each trimester, significant reductions were identified in the first (P = .032), second (P = .016), and third trimesters (P = .047). There was no evidence that reductions were different across the 3 trimesters (pregnancy by trimester interaction, F2,92 = 1.7, P = .92). Mean arterial pressure was significantly different across trimesters independent of the pregnancy being examined (main effect of trimester, F2,92 = 11.4, P < .001) Third-trimester MAP was significantly higher than that of both first and second trimester (Fisher least significant difference test, P < .05). Repeated measures analyses of covariance was used to determine whether reductions in mean arterial pressure between first and index pregnancies remained significant after considering potentially confounding covariates. The covariates considered in this analysis included maternal prepregnancy body mass index, total weight gain in pregnancy, and neonatal gender. After adjusting for these covariates, the difference in MAP from first to index pregnancies remained highly significant (main effect of pregnancy, F1,43 = 10.1, P = .003), with estimated reductions of 3.53 mm Hg, 3.88 mm Hg, and 3.32 mm Hg, respectively for the first, second, and third trimesters. In contrast to the findings of significant changes in MAP, there was no evidence of differences in pulse pressure between first and index pregnancies (main effect of pregnancy, F1,46 = 1.18, P = .28): first trimester, first pregnancy 43.5 ± 9.1 mm Hg (mean ± standard deviation), index pregnancy 42.6 ± 8.2, P = .59; second trimester, first pregnancy 45.3 ± 8.0, index pregnancy 44.1 ± 7.5, P = .47; third trimester, first pregnancy 45.9 ± 7.6, index pregnancy 44.9 ± 5.9, P = .55. There was evidence of differences in pulse pressure between trimesters independent of the pregnancy being examined (F2,92 = 4.06, P = .02). Mean pulse pressure during the second and third trimesters was significantly increased compared with the first trimester (Fisher least significant difference test, P < .05)


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  		Table 2. Differences in Mean Arterial Pressure between First and Subsequent Pregnancy

 

Based on correlation and regression analyses, we examined the association between the length of the interval between pregnancies and the differences observed in MAP between pregnancies. Figure 1 illustrates how the difference in third-trimester MAP between first and index pregnancies relates to the interval between pregnancies. A significant inverse relationship was observed (r = –.41, P = .004), demonstrating that longer intervals between pregnancies were associated with smaller reductions in third-trimester MAP between pregnancies. Similarly, we examined how the length of the interpregnancy interval relates to differences in MAP changes during pregnancy (from first to third trimester). Figure 2 illustrates that shorter interpregnancy intervals are associated with greater differences in first- to third-trimester changes in MAP (r = –.31, P = .03). That is, index pregnancies corresponding to shorter interpregnancy intervals are associated with smaller increases in MAP between the first and third trimester than first pregnancies. As the interval between pregnancies lengthens, the increase in MAP that occurs during the index pregnancies is more similar to that of first pregnancies.



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  		Fig. 1. The difference between first and index pregnancies in average mean arterial pressure in the third trimester is plotted against the interval between pregnancies. A positive value on the Y axis reflects higher mean arterial pressure in the first pregnancy. The relationship demonstrates a significant negative function (r = –0.41, P = .004).

Bernstein. Pregnancy and Arterial Compliance. Obstet Gynecol 2005.

 


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  		Fig. 2. The difference between first and index pregnancies in the increase in mean arterial pressure from the first to the third trimester is plotted against the interval between pregnancies. A positive value on the Y axis reflects a greater increase in mean arterial pressure between the first and third trimester in the first pregnancy. The relationship demonstrates a significant negative function (r = –0.31, P = .046).

Bernstein. Pregnancy and Arterial Compliance. Obstet Gynecol 2005.

 

The relationship of the differences in pulse pressure between index and first pregnancies and the interval between pregnancies was also examined. Although similar in direction, no significant relationship was observed between the length of the interpregnancy interval and the difference in third-trimester pulse pressure (r = –0.20, P = .18). A significant association was observed between the length of the interpregnancy interval and pregnancy differences in the rise in pulse pressure from first to third trimester (r = –.29, P = .046).


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Pregnancy is a physiologic condition associated with profound intravascular volume expansion.5 Significant elevations of blood pressure during the course of pregnancy are routinely observed under normal conditions.16 This raises the possibility that normal pregnancy physiology operates at the limits of compliance of the maternal cardiovascular system. By examining the changes in blood pressure through pregnancy we are, in effect, examining the compliance of the cardiovascular system. Comparing the changes in blood pressure between pregnancies within women, we can begin to evaluate whether these blood pressure patterns suggest a change in the compliance of the cardiovascular system between pregnancies and whether pregnancy itself might play a role in altering compliance.

A comparison of these blood pressure changes between pregnancies can be revealing, relative to compliance, if the volume expansion that occurs in pregnancy is similar between first and subsequent pregnancies. There is, however, significant evidence that volume expansion may be different in parous women compared with women in their first pregnancy. The evidence suggests that the volume load experienced in pregnancy is greater in parous women. Clapp and Capeless,13 in a cross-sectional analysis, have shown that cardiac output throughout pregnancy is raised more above baseline in multiparous women when compared with women in their first pregnancy. At its peak the increase in cardiac output over baseline is approximately 60% higher in multiparous subjects than in those in their first pregnancy, and this increase is most directly attributable to an augmented stroke volume. Letsky5 has estimated that the increase is plasma volume for multiparous subjects is 20% higher than in primiparous subjects. These observations are consistent with the larger fetal weights in parous women, a finding that we also observed in this study, and with the previously observed direct associations of maternal plasma volume and cardiac output with birth weight.5,17 As a result, the highly statistically significant, but biologically modest, changes in MAP that we observed in this study may reflect a more profound change in compliance that might only be revealed by direct measures of plasma volume, cardiac output, and arterial pressures followed longitudinally in sequential pregnancies.

The influence of the duration of interpregnancy interval on changes in MAP is certainly of interest. We found a significant inverse relationship of the interpregnancy interval both with the differences in MAP between pregnancies and in the rise in MAP from the first through the third trimester, comparing first and subsequent pregnancies. Recent publications suggest that the interval between pregnancies is an important determinant of recurrence risk for preeclampsia and that prolonged interpregnancy interval may account for much of the effect previously attributed to new paternity.18,19 We have observed that a short interval between pregnancies is associated with an apparent increase in compliance. However, this increased compliance appears to be limited temporally. The differences in third-trimester MAP between pregnancies were noted to approach zero at 4–5 years following a previous pregnancy. Although the relationship of pregnancy interval with difference in MAP was best represented by linear modeling for the acquired data, we did not have enough subjects with long (> 5 years) interpregnancy intervals to determine whether the relationship beyond that point would maintain a linear relationship or become curvilinear, suggesting a return to the baseline compliance observed in the first pregnancy. The lack of an observed change in pulse pressure between pregnancies may represent a lack of statistical power to detect differences. With a sample size of 47 subjects, we had sufficient power (0.80) to detect a 6% drop in pulse pressure. Overall, we believe that the current observations are consistent with the hypothesis that pregnancy results in a transient improvement in cardiovascular compliance and that this change may be an important factor contributing to a reduction in the risk of preeclampsia when the interpregnancy interval is short. Nevertheless, because of the retrospective nature of this study, the limited number of patients evaluated, and the patient selection criteria, the conclusions of this study may not be fully generalizable.


   Footnotes
 
This work is supported by grant HL 71944 from the National Institutes of Health to I.M.B.

Address reprint requests to: Ira Bernstein, MD, Department of Obstetrics and Gynecology, Burgess 217, FAHC, 111 Colchester Avenue, Burlington, VT 05401–1435; e-mail: ira.bernstein{at}uvm.edu.

Received August 10, 2004. Received in revised form November 9, 2004. Accepted November 18, 2004.

doi:10.1097/01.AOG.0000152346.45920.45


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Chesley LC, Annitto JE, Cosgrove RA. The familial factor in toxemia of pregnancy. Obstet Gynecol 1968;32:303–11.[Free Full Text]

2. Wilson ML, Goodwin TM, Pan VL, Ingles SA. Molecular epidemiology of preeclampsia. Obstet Gynecol Surv 2003;58:39–66.[Medline]

3. Chesley LC. Epidemiology of preeclampsia-eclamsia. In: Hypertensive disorders in pregnancy. New York (NY): Appleton Century Crofts; 1978. p. 35–55.

4. Bernstein IM, Meyer MC, Osol G, Ward K. Intolerance to volume expansion: a theorized mechanism for the development of preeclampsia. Obstet Gynecol 1998;92:306–8.[Abstract]

5. Letsky EA. The haemotological system. In: Hytten F, Chamberlain G, editors. Clinical physiology in obstetrics. 2nd ed. London (UK): Blackwell Scientific; 1991. p. 39–82.

6. Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders in twins versus singleton gestations Am J Obstet Gynecol 2000;182:938–42.

7. Pirani BBK, MacGillivray I. Smoking during pregnancy: its effect on maternal metabolism and fetoplacental function. Obstet Gynecol 1978;52:257–63.[Abstract/Free Full Text]

8. Bruinse HW, van den Berg H, Haspels AA. Smoking and its effect on maternal plasma volume during and after normal pregnancy. Eur J Obstet Gynecol Reprod Biol 1985;20:215–9.[Medline]

9. Easterling TR, Benedetti TJ, Schmucker BC, Millard SP. Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study. Obstet Gynecol 1990;76:1061–9.[Abstract/Free Full Text]

10. Bosio PM, McKenna PJ, Conroy R, O'Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol 1999;94:978–84.[Abstract/Free Full Text]

11. Bernstein IM, Ziegler W, Stirewalt WS, Brumsted J, Ward K. Angiotensinogen genotype and plasma volume in nulligravid women. Obstet Gynecol 1998;92:171–3.[Abstract]

12. Aardenburg R, Spaanderman MEA, Ekhart TH, van Eijndhoven HW, van der Hrijden OWH, Peeters LLH. Low plasma volume following pregnancy complicated by pre-eclampsia predisposes for hypertensive disease in a next pregnancy. BJOG 2003;110:1001–6.[Medline]

13. Clapp JF, Capeless EL. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol 1997;80:1469–73.[Medline]

14. Bernstein IM, Mohs G, Rucquoi M, Badger G. The case for hybrid "fetal growth curves": a population-based estimation of normal fetal size across gestational age. J Matern Fetal Med 1996;5:124–7.[Medline]

15. Fry AG, Bernstein IM, Badger GJ. Comparison of fetal growth estimates based on birth weight and ultrasound references. J Matern Fetal Neonatal Med 2002;12:247–53.[Medline]

16. MacGillivray I, Rose GA, Rowe D. Blood pressure survey in pregnancy. Clin Sci 1969;37:395–407.[Medline]

17. Desai DK, Moodley J, Naidoo DP. Echocardiographic assessment of cardiovascular hemodynamics in normal pregnancy. Obstet Gynecol 2004;104:20–9.[Abstract/Free Full Text]

18. Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002;346:33–8.[Abstract/Free Full Text]

19. Basso O, Christensen K, Olsen J. Higher risk of preeclampsia after change of partner: an effect of longer interpregnancy intervals. Epidemiology 2001;12:624–9.[Medline]




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