Describing and interpreting 24-hour blood pressure patterns

physiologic pregnancy

. In

Pietro Cugini, MD: Loredana Di Palma, MD: Paola Battisti, MD: Giuseppe Leone, MD: Antonio Pachi, MD: Rosalba Paesano, MD: Cristiana Masella, MD,b Giovanni Stirati, MD,c Alessandro Pierucci, MD,c Anna Rachele Rocca, MD,c and Santo Morabito, MDc

Rome, Italy

The time course of blood pressure in clinically healthy (pregnant and nonpregnant) women was followed by automatic ambulatory monitoring. Chronobiologic methods revealed the time course of dynamic rhythm characteristics as a function of gestational age. Differences were found between nonpregnant and pregnant women with an overall lowering during pregnancy of the rhythm-adjusted midline estimating statistic of rhythm (mesor). (AM J OBSTET GVNECOL 1992;166:54-60.)

Key words: Blood pressure, chronobiology, hypertension, pregnancy

The physiologic pattern of blood pressure consists of 80,000 to 140,000 tensions that take place beat to beat during the day-night cycle. Thus, so-called casual measurements' should be replaced by noninvasive au­tomated monitoring to improve clinical assessment of the constitutive sequence of the 24-hour blood pressure pattern. However, the automated monitoring has to be biometrically interpreted, considering that blood pres­sure is a rhythmic variable showing a circadian-depen­dent periodicity.2.8 Interpretation criteria are particu­larly crucial for pregnancy because blood pressure shows changes peculiar to each stage of gestation.9

.'6

On the other hand, the designation of normotensive or hypertensive pregnancies may be important for mothers and babies, whose 24-hour blood pressure pat­tern shows a chronobiologic separation according to the positive or negative family history.'7

Our study was designed to approach the 24-hour blood pressure pattern in physiologic pregnancy by de­scribing and interpreting time-qualifIed variability with particular reference to the periodic pattern.

Material and methods

Subjects and protocol. Thirty pregnant women and thirty nonpregnant women were investigated (Table I). These subjects were stratified from a large sample of randomly investigated individuals. Their participa­tion was allowed because they were classified a posteriori

From the Departments of Endocrine Pathophysiology (Chronobiology Untt),' Obstetrics and Gynaecology,b and Nephrology,' Untversity of Rome "La Sapzenza." Supported In part fry a grant from Mlntstero Pubblica IstTuzwne. Received for publzcatwnJanuary 10,1990; revised June 8,1990; accepted June 17,1991. Reprznt requests: Professor Pietro Cugtni, c/o II Clinica Medica, Policlinico Umberto 1,00161 Rome, Ital~. 6/1/31814 -

54

Table I. Clinical data in nonpregnant and pregnant women

Characterzstics

No. observations Age (yr) Height (cm) Weight (kg) Casual blood pressure

Systolic (mm Hg) Diastolic (mm Hg)

Nonpregtzant women

30 20-25

176 ± 4 58 ± 4

110-170 70-80

Blood pressure values given as range. *Before pregnancy.

Pregtzant women

30 20-26

166 ± 5 57 ± 5*

105-115 65-75

to be clinically healthy subjects in accordance with ex­tensive clinical checkups. Furthermore, the preg­nant women were all primiparous women not at risk of hypertension and with no history of familial an.d personal high blood pressure. The pregnant women had uneventful gestations and were vaginally delivered of term infants with Apgar scores >7.

The 24-hour blood pressure monitoring in pregnant women was repeated in each trimester of pregnancy at 8 to 10, 18 to 20, and 32 to 34 gestational weeks, re­spectively. Both the nonpregnant women and pregnant women were hospitalized to be synchronized to light­dark alternation (lights on 7 AM; lights off 11 PM) and meal-timing schedule (breakfast 8:30 AM; lunch noon; dinner 6:30 PM) by using a noninvasive ambulatory au­tomated recorder (Space Labs, ICR, Redmont, Wash­ington) that took measurements (oscillometric tech­nique) for systolic and diastolic blood pressure at pro­grammable intervals.

Biometric analysis. Individual time data series were analyzed with methods of noninferential and inferen­tial biometry.

Volume 166 Number I, Part I

Blood pressure patterns in physiologic pregnancy 55

Table II. Reference limits for cumulative values of 24-hour systolic and diastolic blood pressure pattern in nonpregnant and pregnant women

SBP (mm Hg) DBP (mm Hg)

Groups Mean I 90% TL Mean I 90% TL

Nonpregnant women 118 93; 143 69 50; 88 Pregnant women

First trimester 102* 87; 117 64* 44; 84 Second trimester 105* 81; 129 64* 44; 84 Third trimester 109* 85; 133 66* 49; 83

TL, Tolerance limits; SBP, systolic blood pressure; DBP, diastolic blood pressure. *p < 0.001 by t test in contrast to nonpregnant women.

Table III. Summary of outcomes by frequency distribution analysis for 24-hour systolic and diastolic blood pressure pattern in nonpregnant and pregnant women

Nonpregnant women

First

Parameters SBP DBP SBP I Median (mm Hg) 110 70 101* Mode (mm Hg) 120 70 98 Lower value 70 35 57

(mmHg) Higher value 172 105 177

(mmHg) Range (mm Hg) 95 70 120 Variation coefficient 12 16 14

(%) Ql Lower quartile 110 62 91

(mmHg) Q3 Upper quartile 130 79 110

(mmHg) Quartile range 20 17 19

(mmHg) 97th percentile 148 90 131

(mmHg) Classes (5 mm Hg

interval) Number 19 14 21 Lower class 70 35 55 (mmHg) Upper class 165 105 175 (mmHg) Class range 95 70 120 (mmHg)

SBP, Systolic blood pressure; DBP, diastolic blood pressure. *p < 0.001 by median test in contrast to nonpregnant women.

tp < 0.01. tp = 0.005.

Noninferential biometry refers to the analysis of the distribution for blood pressure values estimated inde­pendently of their temporal qualification (macroscopic cumulative biometry) or qualified by their daily tem­porality (macroscopic temporal biometry). Inferential biometry (microscopic temporal biometry) refers to the analysis of the circadian rhythmicity with the Single Cosinor methodl8 and the Single Cosint (combination of cosine and integration) procedure. lY

Pregnant women by tnmester

Second Third

DBP SBP I DBP SBP r DBP

61* 112* 70t 125t 70* 57 105 60 105 70 38 70 40 70 40

120 150 95 175 95

82 80 55 105 55 19 12 18 13 15

57 97 56 100 59

71 111 72 118 74

14 14 16 18 15

90 131 87 139 83

16 16 11 21 11 35 70 40 70 40

120 150 95 175 95

85 80 55 105 55

The single cosinor method is a periodic regression analysis fitting a 24-hour cosine curve to raw data and defining the optimal waveform by means of the least squares method. The cosinor procedure uses this equation:

Yt = M + A . cos (w . t + <1» (1)

where M (mesor, acronym of midline estimating statis­tic of rhythm) is the rhythm-adjusted mean; A (am-

56 Cugini et al. January 1992 Am J Obstet Gynecol

Table IV. Time-qualified measures of central location (mean) and dispersion (SD) and 90% tolerance intervals for 24-hour systolic and diastolic blood pressure pattern in nonpregnant and pregnant women

Nonpregnant women Pregnant women by trimester

SBP DBP First

SBP DBP Time

(clock hr) Mean SD 90% TI Mean SD 90% TI Mean 1 SD 1 90% TI Mean 1 SD 1 90% TI

01 112 12 20 64 12 19 89 7 14 63 14 27 02 III 14 23 68 II 19 93 10 21 58 6 II 03 113 13 23 69 II 18 91 14 27 60 8 16 04 112 14 24 68 10 17 93 8 15 52 6 10 05 114 14 24 70 II 18 87 5 10 53 6 12 06 115 14 24 71 II 18 91 14 26 52 8 15 07 II7 15 26 73 10 17 96 II 20 57 7 14 08 119 15 26 72 10 17 103 8 14 66 II 22 09 122 18 30 72 10 16 99 12 24 68 12 25 10 120 16 27 73 13 22 103 9 17 69 7 13 II 122 16 27 74 II 18 106 II 21 73 12 23 12 123 17 28 75 II 18 110 10 19 70 16 30 13 121 13 21 72 10 17 105 10 18 65 12 22 14 120 12 21 69 10 16 103 13 24 62 II 20 15 120 15 26 72 II 18 102 19 34 63 8 14 16 123 14 24 74 II 19 102 17 32 66 14 26 17 125 IS 25 74 10 16 104 13 24 67 14 26 18 122 13 22 73 II 18 105 6 II 64 8 16 19 122 15 25 71 II 19 107 15 28 65 10 17 20 120 13 21 70 10 17 108 10 19 63 13 23 21 120 16 21 70 10 18 102 9 16 62 10 18 22 118 14 23 71 12 20 101 14 25 67 17 31 23 II6 12 21 70 II 15 103 14 26 61 9 18 24 lIS 13 21 68 II 19 96 8 16 54 10 20

SBP, Systolic blood pressure; DBP, diastolic blood pressure; TI, tolerance interval.

plitude) represents the extent of oscillatory wave from mesor; <I> (acrophase) is the timing of the wave with reference to local midnight; t is a fraction of the time period (T); 00 is the angular frequency given by 2-rr1T. The dispersion limits for mesor, amplitude, and acrophase are computed with the population-mean cosinor.20 The confidence limits are estimated as SEM for mesor and 95% confidence limits for amplitude and acrophase. The Single Cosint method is an integral periodic analysis that estimates the parameter aesor (acronym of area estimating statistic of rhythm), that is, the surface covered by the sinusoidal wave of a given biologic rhythm. The cosint method uses this formula:

,24

Aesor = J [M + A . cos (00 . t + <1»] dt (2) ,0

where the coefficients have the same meaning as in equation 1. The overall aesor estimates the baric impact as the total number of millimeters of mercury that re­late to the systolic and diastolic blood pressure circadian cycle!l The aesor may be estimated in a fraction of the circadian time such as diurnal and nocturnal hours (partial aesor). The diurnal and nocturnal aesors differ in relation to the acrophase location. The dispersion limits for the aesor were estimated as SEM.

The sample-related estimates in both the noninfer-

ential and inferential procedures were further analyzed to derive the reference limits as 90% tolerance limits (90% TL), herein intended as the reference inter­vals that include 90% of distribution with 90% of probability. The 90% TL were computed with this formula:

90% TL = M + SD· t(Ol)(df) (3)

where M and SD are respectively the mean and stan­dard deviation of the sample distribution, and t is the integral of Student's distribution for a probability (1 - a) of 0.1. df is the symbol of the degrees of free­dom given by n - 1 observations.22-24

Comparative statistics. The statistical differences be­tween nonpregnant women and pregnant women were analyzed by different procedures such as the Student t test, median test, discriminant analysis, and parameter test, respectively, for the equality of the means, medi­ans, gaussian distribution, and rhythmometric param­eters.

Results

Macroscopic cumulative biometry. The analysis of cumulative means and their reference limits for both the 24-hour systolic and diastolic blood pressure pat­terns is displayed in Table II. The biometric estimates document that the overall mean for systolic and dia-

Volume 166 Number I. Part 1

Blood pressure patterns in physiologic pregnancy 57

Pregnant women by trimester

Second Third

SBP DBP SBP DBP

Mean I SD I 90% Tl Mean I SD I 90% Tl Mean I SD I 90% Tl Mean I SD I 90% Tl

98 17 33 56 15 30 103 14 25 62 6 10 101 II 20 58 9 15 104 16 28 62 II 19 100 12 23 57 7 14 100 12 21 64 14 25 99 16 32 62 16 31 III H 78 65 28 50

100 6 12 56 6 12 109 13 24 64 8 15 95 16 31 61 17 37 98 11 21 58 9 15 98 15 27 58 11 21 98 13 22 61 12 21

104 14 26 66 14 28 104 15 27 66 12 21 106 13 23 63 11 21 109 12 21 67 7 12 109 9 17 66 7 13 113 8 15 72 10 17 113 12 23 72 10 18 124 26 46 73 14 24 114 II 21 77 13 24 113 10 18 71 9 15 119 19 34 76 13 23 116 14 25 70 6 II 118 II 20 72 II 20 115 13 23 68 8 14 116 14 24 69 14 25 112 4 27 68 8 15 117 14 27 73 14 25 108 II 20 66 8 14 II 15 27 70 13 23 108 12 21 71 11 18

122 18 33 74 10 19 109 15 26 70 10 17 115 12 22 78 10 17 110 19 34 68 12 20 118 15 27 72 11 20 III 10 18 71 6 II 112 16 28 71 9 17 III 13 24 71 12 21 108 14 20 70 14 25 106 II 19 70 5 9 103 II 19 66 13 23 107 10 18 66 8 14 97 6 12 62 13 25 99 13 23 60 10 18

Table V. Intertime variability for time-qualified mean levels of 24-hour systolic and diastolic blood pressure pattern in nonpregnant and pregnant women

Nonpregnant women Pregnant women by trimester

First Second Third

Parameters SBP DBP SBP I DBP SBP I DBP SBP I DBP

24-hour mean 119 70 101 63 108 67 109 66 (mmHg)

SD (mm Hg) 4 3 6 6 8 7 6 5 Peak level 126 75 114 75 122 78 124 73

(mmHg) Trough level 111 64 87 49 90 46 98 54

(mmHg) Range 15 11 27 26 32 32 26 19

(mmHg) Variation co- 3 4 6 10 8 II 5 7

efficient (%)

First trimester, 8 to 10 wk; Second trimester, 18 to 20 wk; Third trimester, 32 to 34 wk; values rounded to nearest unit. SBP, Systolic blood pressure; DBP, diastolic blood pressure.

stolic blood pressure is reduced in pregnant women as compared with nonpregnant women. A t test found the gestational reduction of cumulative blood pressure mean level to be statistically significant, even though the values tend to increase during the second and third trimester of pregnancy.

The frequency distribution analysis is illustrated in

Table III. The frequency densities document the over­all distribution of both the systolic and diastolic blood pressure values as being consistently different in preg­nant women as compared with nonpregnant women. The dissimilarity applies to the entire set of descriptive parameters, that is, the median, mode, extremes, range, variation coefficient, 97th percentile, and numerous-

58 Cugini et al. Jan uary 1992 Am J Ohstet Gynecol

I'lIfSTRUAllY·(YCll/liG WQl'£JI

I G[STATIOOl TlIIlESTE' II GESTATlOML TRIIlESTER

Fig. 1. Bivariate representation of the gaussian distribution found in cumulated values that constitute 24-hour systolic (SBP) and diastolic (DBP) blood pressure pattern in nonpregnant and pregnant women.

ness of constitutive frequencies. The class repartition documents that the population of blood pressure values is differently composed in pregnant women as com­pared with nonpregnant women. A median test found the differences in distribution to be statistically signif­icant, even though the medians tend to change during the various trimesters of pregnancy.

The gaussian analysis of the systolic and diastolic blood pressure cumulative distributions is depicted in Fig. I. The bivariate plots document that a gaussian curve is detectable in both populations of cumulative blood pressure values in pregnant women and non­pregnant women. The gestational systolic and diastolic blood pressure values, however, cover a narrower dis­persion in their variability around the mean. A bivariate discriminant analysis found these differences to he sta­tistically significant (P < 0.001) within their distributive normality.

Macroscopic temporal biometry. The analysis of time-qualified mean levels and their reference limits is displayed in Table IV. The estimates document that the time-qualified means for both the 24-hour systolic and diastolic blood pressure patterns are consistently dif­ferent in pregnant women as compared with nonpreg­nant women. The gestational time-qualified dispersion of values is also peculiar. A t test found the time-qual­ified decrease of gestational blood pressure values to be statistically significant at each time point (significance ranging from p < 0.01 to p < 0.001).

More details on the intertime variability of the 24-hour blood pressure patterns are given in Table V. The estimates indicate that the 24-hour mean level of both the 24-hour systolic and diastolic blood pressure pat­terns is noticeably reduced in pregnant women as com­pared with nonpregnant women. The differences in time-qualified variability are also well demonstrated by the variation coefficient. A t test found the gestational decrease of 24-hour systolic and diastolic blood pres­sure mean level to be statistically significant (P < 0.001 in each trimester).

Microscopic temporal biometry Cosinor analysis. The analysis of rhythm properties

and their reference limits is reported in Table VI. The p values indicate that the sinusoidality testing validated the occurrence of a circadian rhythm for the 24-hour systolic blood pressure and diastolic blood pressure pat­terns in both pregnant women and nonpregnant women. However, the gestational systolic and diastolic blood pressure circadian rhythms exhibit a less pro­nounced mesor and a greater amplitude of oscillation. The first trimester of pregnancy is, additionally, char­acterized by a consistent shift of the acrophase. The parameter test found the mesor decrease in the ges­tational blood pressure circadian rhythm to be statis­tically significant, even though the parameter tends to increase during the second and third trimester of preg­nancy.

Cosmt analysis. The analysis of baric impact and its reference limits is summarized in Table VII. The es­timates indicate that the baric impact of both the systolic and diastolic blood pressure circadian rhythms is re­duced in pregnant women as compared with nonpreg­nant women. A t test found the gestational decrease of baric impact to be statistically significant.

Comment

An unanswered question relates to the reason(s) why blood pressure changes so deeply during pregnancy. To answer this question it is mandatory to explore blood pressure in its naturally occurring changes, taking into consideration that the physiologic arrangement is char­acterized by a within-day variability.5-7

We are aware that an approach to the 24-hour blood pressure patterns may be informative if the time series are analyzed by appropriate descriptive statistics. Thus, the statistical approach to the gestational 24-hour blood pressure patterns was made in this study in the most extensive way possible.

The first approach was the macroscopic cumulative biometry, which was performed with the scope of es-

Volume 166 Number I, Part I

Blood pressure patterns in physiologic pregnancy 59

Table VI. Reference limits for circadian rhythm of systolic and diastolic blood pressure in nonpregnant and pregnant women

Group

Nonpregnant women

Pregnant women First trimester

Second trimester

Third trimester

Blood pressure p

Systolic <0.001

Diastolic <0.001

Systolic <0.001

Diastolic <0.001

Systolic <0.001

Diastolic <0.001

Systolic <0.001

Diastolic <0.001

Mesor (mm Hg)

117 (107; 126)

70 (60: 79)

103* (75; 130)

64t (45; 82)

107* (88; 125)

67t (39; 94)

106t (60; 143)

66t (47; 84)

Mean (90% TL)

I Amplitude

I Acrophase

(mm Hg) (hr:mm)

5 14:28 (4; 6) (13:44; 15: 12)

2 13:36 (1; 3) (12:04; 15:08)

9t 20:12t (5; 13) (18:40; 21:40)

8t 21:12t (2; 13) (19:12; 23:08)

9t 15:44t (7; 12) (14:04; 17:20)

7t 15: 12* (I; 12) (11 :32; 18:48)

8t 13:32§ (2; 13) (10:00; 17:00)

6t 14:08§ (3; 8) (12:00; 16:12)

TL, Tolerance limits; p, significant level for the statistical validation of circadian rhythm. *p = 0.02 by parameter test in contrast with nonpregnant women. tp = < .001. tp = <0.01. § N ot significant.

Table VII. Reference limits for baric impact caused by circadian rhythm of systolic and diastolic blood pressure in nonpregnant and pregnant women

SBP (mm Hgl24 hr) DBP (mm Hgl24 hr)

Group Mean I 90% TL Mean I 90% TL

Nonpregnant women 27,807 (22,794; 32,819) 17,092 (13,200; 20,975) Pregnant women

First trimester 25,806* (21,771; 29,840) 16,763* (12,901; 20,624) Second trimester 24,331 t (19,946; 29,215) 16,099t (11,757; 20,440) Third trimester 25,499:1: (20,279; 30,618) 15,913:1: (13,230; 18,595)

TL, Tolerance limits; SBP, systolic blood pressure; DBP, diastolic blood pressure. *Not significant by t test in contrast with nonpregnant women. tp < 0.001. tp < 0.05

timating the overall distribution of both the 24-hour systolic and diastolic blood pressure patterns. The anal­ysis invariably documented a less pronounced mean level in gestational blood pressure. The frequency anal­ysis, in turn, revealed that blood pressure values in pregnancy are consistently shifted toward the left side of the distribution. The discriminant analysis clarified that such a shift is statistically significant. The shift not­withstanding, the gestational blood pressure values ap­pear to be normally distributed, authorizing the ap­proach to their reference limits via the parametric sta­tistics. Accordingly the reference limits computed in our study by the statistical correction of t distribution appear to be appropriate for deciphering the normality in the gestational 24-hour blood pressure pattern.

The second approach was the macroscopic temporal biometry performed to quantify the distribution of the gestational 24-hour blood pressure pattern around the clock. The time-qualified measures of central distri­bution documented that gestational blood pressure val­ues show a homogeneous decrease in mean levels caus­ing the temporal profile to reach a less pronounced height. The lower level of the within-day curve suggests

that pregnancy acts to modify the physiologic prop­erties of blood pressure in their global structure. This is the reason why the time-qualified standard limits re­ported in our study may be regarded as appropriate ref­erences for the gestational blood pressure monitoring.

The third approach was the microscopic temporal biometry that provided an unambiguous interpretation

60 Cugini et al.

of the bioperiodicity of the gestational 24-hour blood pressure pattern. Basically, the cosinor method docu­mented that the blood pressure circadian rhythm shows peculiar properties in pregnant women. The rhyth­mometric changes manifested themselves during the first trimester; the blood pressure fluctuation took place late in the evening with a delay of about 6 hours. How­ever, the acrophase tends to advance timing, the or­thodox phase being adjusted since the second trimester of pregnancy. It is important that the blood pressure circadian rhythm in pregnancy was invariably seen to show a consistent reduction in mesor, unequivocable expression of a structural interaction with the entire pattern. The reference limits of this adjustment are clearly computed in our study.

The last approach in the microscopic temporal biometry was the cosint analysis, which documented the gestational 24-hour blood pressure pattern to change in one of the most important physiologic attributes. Because the baric impact is frankly reduced, it can be concluded that pregnancy globally reduces the blood pressure load during the 24-hour span. The standard limits of this reduction are clearly visible in our study.

It must be stressed that the physiologic properties of biologic rhythms have a meaning from a functional point of view. With respect to this, it is important to remember that the mesor is the measurable expression of the tonic level for a given periodic function. The amplitude and acrophase, in turn, are the quantitative and temporal estimates of the phasic activity for a given rhythm. When the mesor varies in magnitude, its change may be seen as a quantitative modulation of the tonic property. When the amplitude changes in extent, its variation can be regarded as a quantitative modu­lation of the phasic activity. Last, when the acrophase rotates in timing its shift may be considered a temporal readjustment of the phasic periodicity. Translating this into the present findings means that the gestational 24-hour blood pressure pattern changes prominently in its tonic regulation. The readjustment of the blood pressure circadian tone is the mechanism for which pregnancy is able to reduce the baric impact, providing concrete protection to arterial vasculature.

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