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Increased blood pressure in neonates and infants whose mothers smoked during pregnancy
Increased blood pressure in neonates and infants whose mothers smoked during pregnancy Nicholas G, Beratis, MD, Dimitrios Panagoulias, MD, a n d Anastasia Varvarigou, MD From the Department of Pediatrics, Universityof PatrasSchool of Medicine, General University Hospital, Patras, Greece
Objectives: To determine whether maternal smoking during pregnancy is associated with increased blood pressure (BP) in neonates. Study design: We measured BP in the following groups: (I) 73 neonates of mothers who smoked during pregnancy, (2) 43 neonates of mothers who quit smoking early during pregnancy, (3) 83 neonates of passive smoking mothers, and (4) 170 neonates of nonsmoking parents. Three BP measurements were made at I, 24, 48, and 72 hours of life. Some of the neonates were followed for 2 years. Results: We observed a significant positive correlation between the number of cigarettes smoked by the mothers during pregnancy and the BP of the neonates. From the first to the seventy-second hour of life the BP in the infants of the mothers who smoked 15 or more cigarettes per day was significantly higher than in the infants of the nonsmoking mothers, whereas the increase in BP was intermediate when the mothers smoked 7 to 15 cigarettes per day. The BP was similar to that of the control subjects when the mothers smoked 3 to 5 cigarettes per day, were passive smokers, or quit smoking during pregnancy. On reexamination between 4 and 9 months and at 12 months, in infants of mothers who smoked 15 or more cigarettes per day both the systolic and the diastolic BP were significantly higher than in the control subjects; at 12 months 5 of the infants of mothers who smoked cigarettes had BP greater than the 95th percentile for age and gender. At 24 months of life there was no significant difference in systolic or diastolic BP between infants of smoking and nonsmoking mothers. Conclusions: Neonates and infants of mothers who smoked during pregnancy have an elevation of BPthat is related to the number of cigarettes smoked per day. Smoking 15 or more cigarettes per day may cause BPelevation in infancy, but the BP returns to normal during the second year of life. (J Pediatr 1996;128:806-12) Smoking during pregnancy has been implicated in several adverse effects on the fetus, including fetal stress I and increased concentrations of erythropoietin and hemoglobin in cord blood that have been attributed to chronic tissue hypoxia. 2 Recently it was reported that the systolic blood pres-
sure in children 7fi to 8 years of age was significantly lower in those born to smoking compared with nonsmoking mothers before 33 weeks of gestation, whereas it was significantly higher in those born between 33 and 39 weeks. 3 I
Submitted for publication May 17, 1995; accepted Feb. 8, 1996. Reprint requests: Nicholas G. Beratis, MD, Department of Pediatrics, University of Patras School of Medicine, PO Box 1045, 261 10 Patras, Greece. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9•20•72654
806
ANOVA BP
Analysis of variance Blood pressure
A sudden decrease of the intervillous blood flow associated with cigarette smoking, which lasts for 5 to 15 minutes, has been demonstrated by use of xenon 133. 4 A significant transient increase in the umbilical and the aortic blood flow
The Journal of Pediatrics Volume 128, Number 6
has been observed, as shown by an increase in the fetal heart rate, the blood velocity, and the fetal aortic diameter. 5' 6 A parallel decrease of the pulsatility index of the fetal aortic maximum blood velocity waveform also has been found immediately after maternal smoking. 6 Cigarette smoking also causes a chronic reduction of the placental intervillous blood flow. 7 Nicotine in cigarette smoke presumably causes these abnormalities; nicotine leads to a release of catecholamines, which cause vasoconstriction, and an increase in heart rate and cardiac output, s' 9 These circulatory changes also could cause increased BP in the fetus and the neonate. Therefore we measured the BP in children of mothers who smoked during pregnancy and compared the findings with those of newborn infants of mothers who did not smoke.
METHODS Subjects. We studied 333 successive term neonates, appropriate in size for gestational age and born during a 6-month period in the Maternity Hospital of Patras, Greece. All study infants were born after an uneventful pregnancy, without medications and with normal labor and clear amniotic fluid, and the infants had a healthy appearance, no signs of fetal distress, no intrauterine growth retardation, and Apgar scores of 7 or more at 1 and 5 minutes. In addition, we studied 18 term, appropriate for gestational age neonates of mothers who smoked during pregnancy and 18 matched control neonates of nonsmoking parents born in the Department of Obstetrics and Gynecology of the General University Hospital of Patras. These control neonates were born soon after the study neonates and were included in the study provided they fulfilled the criteria of the protocol. All neonates were healthy during the first 3 days of life and had no signs of irritability, lethargy, poor feeding, or acidosis. Of the 369 study infants, 170 were delivered by mothers who claimed that both they and their husbands were nonsmokers, 43 by mothers who quit smoking soon after the onset of pregnancy, 83 by passive smoking mothers (their husbands smoked 20 to 60 cigarettes per day), and 73 by mothers who smoked during pregnancy. Of the 73 smoking mothers, 24 smoked 15 or more cigarettes per day (mean 29 +- 7, range 15 to 55); 25 smoked 7 to 14 cigarettes per day (mean 10 _+ 2); and 24 smoked 3 to 5 cigarettes per day (mean 4 _+ 1). No pregnant women reported smoking only 1 to 2 or 6 cigarettes per day. The mothers did not have preeclampsia, diabetes, or hypertension and denied the use of any illicit substances during pregnancy. The study was approved by the ethics committee of the General University Hospital. Blood pressure measurement. Blood pressure was measured with the Dinamap model 1846 SX/P oscillometric recorder (Critikon, Tampa, Fla.), as recommended) ° In brief,
Beratis, Panagoulias, and Varvarigou
807
infants were quiet, awake, and lying supine in a quiet area. Three BP measurements were made by one of the investigators (D.P.) unaware of the hypothesis, 5 minutes apart, in the infant's right arm. Measurements were performed at 1, 24, 48, and 72 hours of life. The greatest deviation from the time scheduled for BP measurements was 10 minutes for the 1-hour and 1 hour for the subsequent determinations. The cuff size for a given child was sufficiently long to encircle the circumference of the arm and sufficiently wide to cover approximately 75% of the upper arm. The third reading, which was the lowest or equal to one or to both other measurements in approximately 90% of the cases, was used in the study. The procedure was repeated if the measurements differed by more than 4 mm Hg. All measurements were performed with the same i n s ~ m e n t , which was tested for accuracy against intraarterial pressure in the neonatal age group. The curves describing the age-specific distributions of systolic and diastolic BP for boys and girls from the Second Task Force on Blood Pressure Control in Children 1° were used. Follow-up. Twenty o f t h e 23 infants (12 boys) whose mothers smoked 15 or more cigarettes per day during pregnancy were reexamined between 4 and 9 months of life. In addition, 12 and 13 of the infants were restudied at the ages of 1 and 2 years, respectively. At the age of 1 year, three infants were lost to follow-up (two children without a permanent address, one child changed address without any notification), and in one case the mother refused to have her child reexamined. At the age of 2 years the same children, as well as the child of the mother who had previously refused reexamination, participated in the study. The remaining seven children had not yet reached the age of 1 and 2 years. Of the 20 infants who were reevaluated between 4 and 9 months, 14 were exclusively formula fed, whereas of the 6 breast-fed infants, 4 were weaned before the age of 1 month and 2 between 1 and 2fi months of life. Twenty infants (12 boys) whose parents were both nonsmokers were used as control subjects in the follow-up study. These 20 infants were originally included in the 170 control neonates evaluated during the first 3 days of life. Their selection was random, provided that their birthdays were close to those of the study infants, they could be located, and the parents agreed to participate in the follow-up study. Of the 20 infants, 2 could not be located and the parents of 2 refused to Cooperate. In addition, 12 infants whose mothers were nonsmokers, but whose fathers smoked 20 or more cigarettes per day (passive smoking infants) were included in the follow-up. In addition, at the age of 1 year, 12 of the 26 children (7 boys) included in the group of the neonates whose mothers had smoked 7 to 14 cigarettes per day were reevaluated. Of the remaining 14 infants, 5 were lost to follow-up and 9 had not reached the age of 1 year. For the 12 infants who were
808
Beratis,Panagoulias, and Varvarigou
The Journal of Pediatrics June 1996
Table I. Mean (_+SD) gestational age, birth weight, birth length, head circumference, and Apgar score of newborn infants of mothers who smoked and of mothers who did not smoke during pregnancy Cigarette smoking Parameter Gestational age (wk) Birth weight (gin) Birth length (cm) Head circumference (cm) Apgar score (1 rain)
Nonsmoking 39.6 ± 3339 ± 51.2 ± 34.6 ± 8.6 ±
3-5 cigarettes/day
1.7 381" 2.3 2.9 1.0
39.8 ± 3484 ± 50.8 ± 35.1 ± 8.8 ±
1.6 737 2.3 1.8 0.7
7-14 cigarettes/day
->15 ,cigarettes/day
39.6 ± 1.5 3231.9 ± 242.8 51.8 _+3.4 34.1 ± 2.1 8.0 ± 1.3
39.1 _+ 1.5 3084 _+353* 50.3 ± 1.8 34.8 ± 2.3 8.7 ± 1.1
*t = 2.982, p = 0.003; statisticalsignificanceat 0.017 (0.05 + 3).
reevaluated, the mean number of cigarettes smoked per day by the mothers was 9.4 +_ 1.1, with a range from 7 to 10. The BP measurements were performed between 8 AM and 11 AM in all infants included in the follow-up. Statistical analysis. Data on the BP measurements of the children of the mothers who smoked and of the mothers who did not smoke were analyzed with the F A S T A T program for the Macintosh computer, version 2 (Systat, Inc., Evanston, Ill.). The infants included in the study were stratified in groups according to the number of cigarettes smoked by their mothers during pregnancy. Values are expressed as means -+ SD. Simple linear regression analysis was used to test the correlation between the BP and the number of cigarettes smoked per day by the mothers during pregnancy, as well as between the BP and the birth weight. Scattergrams with the lines of best fit were chosen to express graphically the linear regression of the BP with the number of cigarettes smoked per day. Analysis of variance was applied to the regression to test the significance of the correlation. The ANOVA for repeated measures, with grouping factor, was applied to analyze the differences of the mean BP across time (1 to 72 hours) between the neonates of the mothers who were nonsmokers and of those who smoked 3 to 5, 7 to 14, and 15 or more cigarettes per day during pregnancy. The same ANOVA was applied to test the differences of the mean BP as related to maternal smoking. An unpaired t test was used to test the difference of the BP between the neonates of the smoking and the nonsmoking mothers on the same day of life, for the follow-up measurements, and for the comparison of the characteristics of each group. The Bonferroni correction was applied as appropriate. A l l p values are two-sided. A p value -<0.05 was considered to indicate statistical significance.
RESULTS The mean systolic BP in the mothers who smoked 15 or more cigarettes per day during pregnancy was 114.7 _+ 10.9 m m Hg, whereas in the nonsmoking mothers it was
115.1 _+ 10.9 m m Hg (t= 0.160, p = 0.873). The diastolic BP was 67.7 + 9.6 and 66.9 _+ 8.1 m m Hg, respectively (t = 0.361, p = 0.718). Similar mean systolic and diastolic BPs were found in the groups of mothers who smoked 7 to 14 or 3 to 5 cigarettes per day, were passive smokers, or quit smoking during pregnancy, as in mothers who were not smokers. First 3 days of life. The gestational age, somatic measurements, and the Apgar scores of the neonates of the mothers who smoked and of those who did not smoke during pregnancy are listed in Table I. The lowest birth weight of the neonates of the smoking or nonsmoking mothers included in the study was 2590 gm. The BP readings at 1, 24, 48, and 72 hours of the 243 neonates of the smoking mothers and the nonsmoking parents varied significantly in relation to the number of cigarettes smoked per day by their mothers; both systolic and diastolic BP increased with the increasing number of cigarettes (F = 10.81, p -<0.000; and F = 31.77, p ~-0.000, respectively). Linear regression analysis between BP and the number of cigarettes smoked per day showed the regression slope " and the correlation coefficient to be highly significant (Figure). The A N O V A applied to regression showed a significant correlation between BP and the number of cigarettes smoked per day at 1 (F = 4.17 and 6.76,p = 0.042 and 0.010), 24 (F = 19.05 and 10.85,p <0.000 and 0.001), 48 (F -- 45.88 and 18.11,p <0.000) and 72 (F = 51.62 and 10.30, p <0.000 and 0.002) hours of life for the systolic and diastolic BP, respectively. On the contrary, there was no correlation between the BP and the birth weight in both the neonates of either the smoking or the nonsmoking mothers (data not shown). Both the systolic and diastolic BP of the neonates of the mothers who smoked 15 or more cigarettes per day during pregnancy was significantly greater than the systolic and diastolic BP of the control neonates from the first hour of life (Tables II and III). The mean systolic BP was significantly higher in the neonates of the mothers who smoked 7 to 14 cigarettes per day
The Journal of Pediatrics Volume 128, Number 6
Beratis, Panagoulias, and Varvarigou
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Figure. Scattergram plots and lines of best fit between the number of cigarettes smoked by the mothers and the blood pressure (BP), both systolic and diastolic, of 73 neonates of smoking mothers and 170 neonates of nonsmoking parents at 1, 24, 48, and 72 hours of life. The vertical bars show the mean BP _+ SD of the nonsmoking mothers' neonates. The estimate models of the BP of the neonates and the correlation coefficients (R) are shown on the graphs.
T a b l e II. Systolic blood pressure (in millimeters o f mercury) of neonates of smoking and nonsmoking mothers during the first 72 hours o f life*
Age
3-5 Cigarettes/day
7-14 Cigarettes/day
_>15 Cigareffes/day
(hr)
Nonsmoking: Mean _+ SD
Mean _+ SD
p'l"
Mean 4- SD
P'I"
Mean 4- SD
PI"
1 24 48 72
61.4 4- 8.1 65.2 4- 7.9 67.8 4- 7.8 69.5 4- 7.5
60.7 -+ 8.1 68.3 -+ 8.6 69.8 4- 7.8 71.8 4- 4.7
0.731 0.113 0.288 0.233
64.6 4- 6.9 68.2 _+6.9 72.6 4- 7.5 75.9 4- 7.3
0.056 0.074 0.005 -<0.000
66.3 4- 8.7 72.9 4- 11.5 79.9 4- 1i.2 82.0 4- 10.6
0.008 -<0.000 -<0.000 <-0.000
*Analysis of variance between the systolicblood pressure of the neonates of the smoking and the nonsmokingmothers from 1 to 72 hours: ->15 cigarettesper day versus nonsmoking,F = 32.56, p <-0.000; 7 to 14 cigarettesper day versus nonsmoking,F = 10.22, p = 0.002; 3 to 5 cigarettesper day versus nonsmoking, F = 0.46, p = 0.496. tCompared with the blood pressure of the neonates of the nonsmokingmothers; statistical significanceat p <0.017 (0.05 + 3).
at 48 and at 72 hours o f life (Table II). On the other hand, the mean diastolic B P was higher in the neonates of the mothers who smoked 7 to 14 cigarettes per day only at the first hour o f life (Table III). Both the systolic and diastolic
BP o f the neonates of the mothers who smoked 3 to 5 cigarettes per day during pregnancy did not differ significantly from the B P of the neonates o f the nonsmoking parents from the first to the seventy-second hour o f life (Tables II and III).
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Beratis,Panagoulias, and Varvarigou
The Journal of Pediatrics June 1996
Table Ill. Diastolic blood pressure (in millimeters of mercury) of neonates of smoking and nonsmoking mothers during the first 72 hours of life* 3-5 Cigarettes/day
7-14 Cigarettes/day
_>15 Cigarettes/day
Age (hr)
Nonsmoking: Mean ± SD
Mean _+SD
Pt
Mean ± SD
Pt
Mean ± SD
pJ"
1 24 48 72
38.5 -+ 6.7 42.7 ± 7.5 45.6 ± 7.t 47.6 ± 8.1
41.3 -+ 7.4 46.7 ± 7.4 47.5 + 8.3 50.6 ± 6.4
0.112 0.051 0.258 0.136
43.3 +_ 6.6 46.4 ± 7.9 48.2 -+ 7.5 50.2 -+ 8.4
0.002 0.023 0.084 0.158
42.5 --- 7.5 49.3 ± 12.6 54.3 + 11.8 56.3 --- 11.0
0.015 --<0.000 --<0.000 --<0.000
*Analysis of variancebetween the diastolicblood pressure of the neonates of the smoking and the nonsmoking mothers from 1 to 72 hours: ->15 cigarettes per day versus nonsmoking, F = 23.51, p <0.000; 7 to 14 cigarettes per day versus nonsmoking, F = 9.11, p = 0.003; 3 to 5 cigarettes per day versus nonsmoking, F = 3.68, p = 0.056. tCompared with the blood pressure of the neonates of the nonsmoking mothers; statistical significanceat p <0.017 (0.05 + 3).
Table IV. Blood pressure of children of smoking and nonsmoking mothers at the age of 12 and 24 months Systolic (mm Hg)
Significance
Diastolic (mm Hg)
Significance
Age (mo)
No.
Smoking
No.
Nonsmoking
t
p
No.
Smoking
No.
Nonsmoking
t
p
12 24
12 13
102.8± 4.5 99.3 -+ 2.8
12 13
97.1 ± 4.1 97.4 + 4.0
3.20 1.29
0.004 0.21
12 13
66.9 ± 5.9 62.2 -+ 3.1
12 13
61.5 ± 4.1 60.3 -+ 3.1
2.61 1.47
0.016 0.157
Both the systolic and diastolic BP of the neonates of the mothers who used to smoke but discontinued smoking in early pregnancy did not differ significantly from those of the neonates of the mothers who never smoked. There was also no significant difference in either the systofic or the diastolic BP between the neonates of the passive smoking mothers and the control neonates (data not shown; available from authors on request). Follow-up, 4 to 9 months. The 20 infants of mothers who smoked 15 or more cigarettes per day during pregnancy and the 20 infants of nonsmoking parents, who were included in the follow-up study, had an age of 6.8 _+ 1.5 and 6.5 --- 1.5 months, a weight of 10.2 _+ 0.7 and 10.3 + 0.6 kg, a length of 76.7 ± 2.0 and 76.3 _+ 2.1 cm, and aheart rate of 124 + 6 and 125 _+ 8 beats/rain, respectively. The systolic BP in the infants of the mothers who smoked during pregnancy and in those whose parents did not smoke was 101.3 _+ 6.0 m m Hg and 91.2 _+ 8.1 m m Hg, respectively (t = 4.44, p -<0.000). The diastolic BPs were 68.7 -+ 9.6 m m Hg and 61.9 _+ 6.5 m m Hg, respectively (t = 2.58, p = 0.014). Three boys and two girls, whose mothers smoked during pregnancy, had a diastolic BP above the 95th percentile, and another two boys and one girl had a systolic BP between the 90th and the 95th percentiles. None of the control infants had the systolic or diastolic BP above the 90th percentile. The systolic and the diastolic BP of the 12 infants included in the follow-up study whose mothers as well as themselves were passive smokers was 94.0 -+ 5.8 m m Hg and 58.3 + 8.4 m m Hg, respectively. The difference from the control infants
whose parents did not smoke was not significant (t = 1.490 and 1.262, p = 0.150 and 0.220, respectively). Follow-up at 12 and 24 mouths. At the age of 12 months both the systolic and the diastolic BP of the infants of the mothers who smoked 15 or more cigarettes per day was significantly greater than in the control infants, whereas at the age of 24 months there was no significant difference between the two groups (Table IV). The children of the smoking and the nonsmoking mothers had similar weight, length, and heart rate at both 12 and 24 months of age.
DISCUSSION The findings of this prospective study have demonstrated an association between maternal smoking during pregnancy and increased BP in the newborn infant that is maintained through the first year of life. It appears that BP levels in these children return to levels similar to those of nonsmoking mothers during the second year. The significant progressive increase in the BP found in the control neonates over the first 3 days of life has been reported earlier.11 However, the steeper elevation of the BP observed in the neonates of the smoking mothers during the first 72 hours of life resulted in the higher BP measured in the neonates of the mothers who smoked during pregnancy. It has been reported that the BP in newborn infants correlates positively with the birth weight. 11 The absence of a correlation between BP and birth weight in this study most probably is related to the fact that we included only healthy, term, appropriate for gestational age neonates, and thus their
The Journal of Pediatrics Volume 128, Number 6
birth weights varied within a rather narrow range around the normal mean. The observation that the neonates of the mothers who quit smoking at the beginning of pregnancy had a similar BP to that of neonates of nonsmoking mothers indicates that the increased BP results from the direct effect of the tobacco smoke on the placental and the fetal circulatory systems. Likewise, cessation of smoking during pregnancy improves fetal growth and reduces infant morbidity in the neonatal period, Z2 It is unlikely that passive smoking caused the increased BP in the infants of the smoking mothers because infants born to nonsmoking mothers, but whose fathers smoked 20 or more cigarettes per day, had similar BP levels compared with those of the infants of nonsmoking parents. However, the finding that maternal passive smoking did not cause an increase in the BP of the neonates cannot be considered as conclusive evidence that passive smoking does not affect the BP of the neonate because the amount of tobacco smoke inhaled by the pregnant women remains uncertain. The question of whether infants of smoking mothers are at risk of continued elevated BP warrants further investigation because the sample size of the infants followed to a later age was rather small. Nonetheless, only infants of smoking mothers had elevated BP after 4 months of age. The natural history of the elevated BP observed in the children of mothers who smoked during pregnancy is not completely known because the follow-up period was only up to 2 years. The elevated BP observed in the children of mothers who smoked during pregnancy seemed to return to normal levels during the second year of life, suggesting that the increased BP reflects physiologic rather than anatomic changes caused by the tobacco smoke during intrauterine life. Although the BP measurements obtained from the neonates of the smoking mothers were compared with those from matched control neonates, the interpretation of these results according to the standard curves obtained from American childrenl° should be done with caution. The elevation of both the systolic and diastolic BP suggests that the increased BP may be associated with an increased total peripheral vascular resistance, similar to that found in cases of long-standing established hypertension. The circulatory abnormalities identified in fetuses after maternal smoking,4-7 as well as the observation that fetuses of smoking mothers are in a state of chronic tissue hypoxia,2 may be related to the increased BP found in the infants of such mothers. It appears that the effect of maternal cigarette smoking on the BP of the neonate and the infant is different from that on the smoker. Although smoking has been reported to cause a sudden rise in BP, 13-15 several epidemiologic studies have
Beratis, Panagoulias, and Varvarigou
811
shown that chronic smokers have the same or even lower BP than nonsmokers. 16-21 However, more recently an elevated daytime ambulatory systolic BP has been found among untreated hypertensive smokers older than age 50 years. 22 The elevated BP observed in neonates and infants of mothers who smoked during pregnancy may be of concern because the possibility of an association between this early increase of BP and the development of essential hypertension later in life cannot be eliminated. Additional studies are needed to determine the natural history of the elevated BP found in infants of mothers who smoked during pregnancy. REFERENCES
1. Beratis NG, Varvarigou A, Makri M, Vagenakis AG. Prolactin, growth hormone and insulin-like growth factor-I in newborn children of smoking mothers. Clin Endocrinol 1994; 40:179-85. 2. VarvarigouA, Beratis NG, Malai M, VagenakisAG. Increased levels and positive correlation between erythropoietin and hemoglobin concentrationsin newborn children of mothers who are smokers. J Pediatr 1994;124:480-2. 3. Morley R, Payne CL, Lucas A. Maternal smoking and blood pressure in 7.5 to 8 year old offspring. Arch Dis Child 1995; 72:120-4. 4. Lehtovirta P, Forss M. The acute effect of smoking on intervillous blood flow of the placenta. Br J Obstet Gynaecol 1978;85:729-31. 5. Andersen KV, HermannN. Placenta flow reductionin pregnant smokers. Acta Obstet Gynecol Scand 1984;63:707-9. 6. Sindberg EP, Marsal K. Acute effects of maternal smoking on fetal blood flow. Acta Obstet Gynecol Scand 1984;63:391-7. 7. Lindblad A, Marsal K, Andersson K-E. Effect of nicotine on l~umanfetal blood flow. Obstet Gynecol 1988;72:371-82. 8. Pirani BBK. Smoking during pregnancy. Obstet Gynecol Surv 1978;33:1-13. 9. Quigley ME, Sheehan KL, Wilkes MM, YEN SSC. Effects of maternal smoking on circulating catecholamine levels and fetal heart rates. Am J Obstet Gynecol 1979;133:685-90. 10. Task Force on Blood Pressure Control in Children. Report of the Second Task Force on Blood Pressure Control in Children-1987. Pediatrics 1987;79:1-25. 11. Hulman S, Edwards R, Chen YQ, Polansky M, Falkner B. Blood pressure patterns in the first three days of life. J Perinatol 1991;11:231-34. 12. Ahlsten G, Cnattingius S, Lindmark G. Cessation of smoMng during pregnancy improves foetal growth and reduces infant morbidity in the neonatal period: a population-basedprospective study. Acta Paediatr 1993;82:177-81. 13. Celina GU, Honour AJ, Littler WA. Direct arterial pressure, heart rate, and electrocardiogramduring cigarette smoking in unrestricted patients. Am Heart J 1975;89:18-25. 14. Freestone S, Ramsay LE. Effect of coffee and cigarette smoking on the blood pressure of untreated and diuretic-treatedhypertensive patients. Am J Med 1982;73:348-53. 15. Berlin I, Coumot A, Renout P, Duchier J, Safar M. Peripheral haemodynamic effects of smoking in habitual smokers: a methodological study. Eur J Clin Pharmacol 1990;38:57-60. 16. Higgins MW, Kjelsberg M. Characteristics of smokers and
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Beratis, Panagoulias, and Varvarigou
nonsmokers in Tecumseh, Michigan. II. The distribution of selected physical measurements and physiologic variables and the prevalence of certain diseases in smokers and nonsmokers. Am J Epidemiol 1967;86:60-77. 17. Jenkins CD, Rosenman RH, Zyzanski SJ. Cigarette smoking: its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Circulation 1968;38:1140-55. 18. Berglund G, Wilhelmsen L. Factors related to blood pressure in a general population sample of Swedish men. Acta Med Scand 1975;198:291-8. 19. Goldbourt U, Medalie JH. Characteristics of smokers, non-
The Journal of Pediatrics June 1996
smokers, and ex-smokers among 10,000 adult males in Israel. II. Physiologic, biochemical and genetic characteristics. Am J Epidemiol 1977;105:75-86. 20. Greene SB, Aavedal MJ, Tyroler HA, Davis CE, Haines CG. Smoking habits and blood pressure change: a seven year follow-up. Journal of Chronic Diseases 1977;30:401-13. 21. Green MS, Jucha E, Luz Y. Blood pressure in smokers and nonsmokers: epidemiologic findings. Am Heart J 1986;111: 932-40. 22. Mann SJ, James GD, Wang RS, Picketing TG. Elevation of ambulatory systolic blood pressure in hypertensive smokers: a case-control study. JAMA 1991;265:2226-8.
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Objectives: To determine whether maternal smoking during pregnancy is associated with increased blood pressure (BP) in neonates. Study design: We measured BP in the following groups: (I) 73 neonates of mothers who smoked during pregnancy, (2) 43 neonates of mothers who quit smoking early during pregnancy, (3) 83 neonates of passive smoking mothers, and (4) 170 neonates of nonsmoking parents. Three BP measurements were made at I, 24, 48, and 72 hours of life. Some of the neonates were followed for 2 years. Results: We observed a significant positive correlation between the number of cigarettes smoked by the mothers during pregnancy and the BP of the neonates. From the first to the seventy-second hour of life the BP in the infants of the mothers who smoked 15 or more cigarettes per day was significantly higher than in the infants of the nonsmoking mothers, whereas the increase in BP was intermediate when the mothers smoked 7 to 15 cigarettes per day. The BP was similar to that of the control subjects when the mothers smoked 3 to 5 cigarettes per day, were passive smokers, or quit smoking during pregnancy. On reexamination between 4 and 9 months and at 12 months, in infants of mothers who smoked 15 or more cigarettes per day both the systolic and the diastolic BP were significantly higher than in the control subjects; at 12 months 5 of the infants of mothers who smoked cigarettes had BP greater than the 95th percentile for age and gender. At 24 months of life there was no significant difference in systolic or diastolic BP between infants of smoking and nonsmoking mothers. Conclusions: Neonates and infants of mothers who smoked during pregnancy have an elevation of BPthat is related to the number of cigarettes smoked per day. Smoking 15 or more cigarettes per day may cause BPelevation in infancy, but the BP returns to normal during the second year of life. (J Pediatr 1996;128:806-12) Smoking during pregnancy has been implicated in several adverse effects on the fetus, including fetal stress I and increased concentrations of erythropoietin and hemoglobin in cord blood that have been attributed to chronic tissue hypoxia. 2 Recently it was reported that the systolic blood pres-
sure in children 7fi to 8 years of age was significantly lower in those born to smoking compared with nonsmoking mothers before 33 weeks of gestation, whereas it was significantly higher in those born between 33 and 39 weeks. 3 I
Submitted for publication May 17, 1995; accepted Feb. 8, 1996. Reprint requests: Nicholas G. Beratis, MD, Department of Pediatrics, University of Patras School of Medicine, PO Box 1045, 261 10 Patras, Greece. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9•20•72654
806
ANOVA BP
Analysis of variance Blood pressure
A sudden decrease of the intervillous blood flow associated with cigarette smoking, which lasts for 5 to 15 minutes, has been demonstrated by use of xenon 133. 4 A significant transient increase in the umbilical and the aortic blood flow
The Journal of Pediatrics Volume 128, Number 6
has been observed, as shown by an increase in the fetal heart rate, the blood velocity, and the fetal aortic diameter. 5' 6 A parallel decrease of the pulsatility index of the fetal aortic maximum blood velocity waveform also has been found immediately after maternal smoking. 6 Cigarette smoking also causes a chronic reduction of the placental intervillous blood flow. 7 Nicotine in cigarette smoke presumably causes these abnormalities; nicotine leads to a release of catecholamines, which cause vasoconstriction, and an increase in heart rate and cardiac output, s' 9 These circulatory changes also could cause increased BP in the fetus and the neonate. Therefore we measured the BP in children of mothers who smoked during pregnancy and compared the findings with those of newborn infants of mothers who did not smoke.
METHODS Subjects. We studied 333 successive term neonates, appropriate in size for gestational age and born during a 6-month period in the Maternity Hospital of Patras, Greece. All study infants were born after an uneventful pregnancy, without medications and with normal labor and clear amniotic fluid, and the infants had a healthy appearance, no signs of fetal distress, no intrauterine growth retardation, and Apgar scores of 7 or more at 1 and 5 minutes. In addition, we studied 18 term, appropriate for gestational age neonates of mothers who smoked during pregnancy and 18 matched control neonates of nonsmoking parents born in the Department of Obstetrics and Gynecology of the General University Hospital of Patras. These control neonates were born soon after the study neonates and were included in the study provided they fulfilled the criteria of the protocol. All neonates were healthy during the first 3 days of life and had no signs of irritability, lethargy, poor feeding, or acidosis. Of the 369 study infants, 170 were delivered by mothers who claimed that both they and their husbands were nonsmokers, 43 by mothers who quit smoking soon after the onset of pregnancy, 83 by passive smoking mothers (their husbands smoked 20 to 60 cigarettes per day), and 73 by mothers who smoked during pregnancy. Of the 73 smoking mothers, 24 smoked 15 or more cigarettes per day (mean 29 +- 7, range 15 to 55); 25 smoked 7 to 14 cigarettes per day (mean 10 _+ 2); and 24 smoked 3 to 5 cigarettes per day (mean 4 _+ 1). No pregnant women reported smoking only 1 to 2 or 6 cigarettes per day. The mothers did not have preeclampsia, diabetes, or hypertension and denied the use of any illicit substances during pregnancy. The study was approved by the ethics committee of the General University Hospital. Blood pressure measurement. Blood pressure was measured with the Dinamap model 1846 SX/P oscillometric recorder (Critikon, Tampa, Fla.), as recommended) ° In brief,
Beratis, Panagoulias, and Varvarigou
807
infants were quiet, awake, and lying supine in a quiet area. Three BP measurements were made by one of the investigators (D.P.) unaware of the hypothesis, 5 minutes apart, in the infant's right arm. Measurements were performed at 1, 24, 48, and 72 hours of life. The greatest deviation from the time scheduled for BP measurements was 10 minutes for the 1-hour and 1 hour for the subsequent determinations. The cuff size for a given child was sufficiently long to encircle the circumference of the arm and sufficiently wide to cover approximately 75% of the upper arm. The third reading, which was the lowest or equal to one or to both other measurements in approximately 90% of the cases, was used in the study. The procedure was repeated if the measurements differed by more than 4 mm Hg. All measurements were performed with the same i n s ~ m e n t , which was tested for accuracy against intraarterial pressure in the neonatal age group. The curves describing the age-specific distributions of systolic and diastolic BP for boys and girls from the Second Task Force on Blood Pressure Control in Children 1° were used. Follow-up. Twenty o f t h e 23 infants (12 boys) whose mothers smoked 15 or more cigarettes per day during pregnancy were reexamined between 4 and 9 months of life. In addition, 12 and 13 of the infants were restudied at the ages of 1 and 2 years, respectively. At the age of 1 year, three infants were lost to follow-up (two children without a permanent address, one child changed address without any notification), and in one case the mother refused to have her child reexamined. At the age of 2 years the same children, as well as the child of the mother who had previously refused reexamination, participated in the study. The remaining seven children had not yet reached the age of 1 and 2 years. Of the 20 infants who were reevaluated between 4 and 9 months, 14 were exclusively formula fed, whereas of the 6 breast-fed infants, 4 were weaned before the age of 1 month and 2 between 1 and 2fi months of life. Twenty infants (12 boys) whose parents were both nonsmokers were used as control subjects in the follow-up study. These 20 infants were originally included in the 170 control neonates evaluated during the first 3 days of life. Their selection was random, provided that their birthdays were close to those of the study infants, they could be located, and the parents agreed to participate in the follow-up study. Of the 20 infants, 2 could not be located and the parents of 2 refused to Cooperate. In addition, 12 infants whose mothers were nonsmokers, but whose fathers smoked 20 or more cigarettes per day (passive smoking infants) were included in the follow-up. In addition, at the age of 1 year, 12 of the 26 children (7 boys) included in the group of the neonates whose mothers had smoked 7 to 14 cigarettes per day were reevaluated. Of the remaining 14 infants, 5 were lost to follow-up and 9 had not reached the age of 1 year. For the 12 infants who were
808
Beratis,Panagoulias, and Varvarigou
The Journal of Pediatrics June 1996
Table I. Mean (_+SD) gestational age, birth weight, birth length, head circumference, and Apgar score of newborn infants of mothers who smoked and of mothers who did not smoke during pregnancy Cigarette smoking Parameter Gestational age (wk) Birth weight (gin) Birth length (cm) Head circumference (cm) Apgar score (1 rain)
Nonsmoking 39.6 ± 3339 ± 51.2 ± 34.6 ± 8.6 ±
3-5 cigarettes/day
1.7 381" 2.3 2.9 1.0
39.8 ± 3484 ± 50.8 ± 35.1 ± 8.8 ±
1.6 737 2.3 1.8 0.7
7-14 cigarettes/day
->15 ,cigarettes/day
39.6 ± 1.5 3231.9 ± 242.8 51.8 _+3.4 34.1 ± 2.1 8.0 ± 1.3
39.1 _+ 1.5 3084 _+353* 50.3 ± 1.8 34.8 ± 2.3 8.7 ± 1.1
*t = 2.982, p = 0.003; statisticalsignificanceat 0.017 (0.05 + 3).
reevaluated, the mean number of cigarettes smoked per day by the mothers was 9.4 +_ 1.1, with a range from 7 to 10. The BP measurements were performed between 8 AM and 11 AM in all infants included in the follow-up. Statistical analysis. Data on the BP measurements of the children of the mothers who smoked and of the mothers who did not smoke were analyzed with the F A S T A T program for the Macintosh computer, version 2 (Systat, Inc., Evanston, Ill.). The infants included in the study were stratified in groups according to the number of cigarettes smoked by their mothers during pregnancy. Values are expressed as means -+ SD. Simple linear regression analysis was used to test the correlation between the BP and the number of cigarettes smoked per day by the mothers during pregnancy, as well as between the BP and the birth weight. Scattergrams with the lines of best fit were chosen to express graphically the linear regression of the BP with the number of cigarettes smoked per day. Analysis of variance was applied to the regression to test the significance of the correlation. The ANOVA for repeated measures, with grouping factor, was applied to analyze the differences of the mean BP across time (1 to 72 hours) between the neonates of the mothers who were nonsmokers and of those who smoked 3 to 5, 7 to 14, and 15 or more cigarettes per day during pregnancy. The same ANOVA was applied to test the differences of the mean BP as related to maternal smoking. An unpaired t test was used to test the difference of the BP between the neonates of the smoking and the nonsmoking mothers on the same day of life, for the follow-up measurements, and for the comparison of the characteristics of each group. The Bonferroni correction was applied as appropriate. A l l p values are two-sided. A p value -<0.05 was considered to indicate statistical significance.
RESULTS The mean systolic BP in the mothers who smoked 15 or more cigarettes per day during pregnancy was 114.7 _+ 10.9 m m Hg, whereas in the nonsmoking mothers it was
115.1 _+ 10.9 m m Hg (t= 0.160, p = 0.873). The diastolic BP was 67.7 + 9.6 and 66.9 _+ 8.1 m m Hg, respectively (t = 0.361, p = 0.718). Similar mean systolic and diastolic BPs were found in the groups of mothers who smoked 7 to 14 or 3 to 5 cigarettes per day, were passive smokers, or quit smoking during pregnancy, as in mothers who were not smokers. First 3 days of life. The gestational age, somatic measurements, and the Apgar scores of the neonates of the mothers who smoked and of those who did not smoke during pregnancy are listed in Table I. The lowest birth weight of the neonates of the smoking or nonsmoking mothers included in the study was 2590 gm. The BP readings at 1, 24, 48, and 72 hours of the 243 neonates of the smoking mothers and the nonsmoking parents varied significantly in relation to the number of cigarettes smoked per day by their mothers; both systolic and diastolic BP increased with the increasing number of cigarettes (F = 10.81, p -<0.000; and F = 31.77, p ~-0.000, respectively). Linear regression analysis between BP and the number of cigarettes smoked per day showed the regression slope " and the correlation coefficient to be highly significant (Figure). The A N O V A applied to regression showed a significant correlation between BP and the number of cigarettes smoked per day at 1 (F = 4.17 and 6.76,p = 0.042 and 0.010), 24 (F = 19.05 and 10.85,p <0.000 and 0.001), 48 (F -- 45.88 and 18.11,p <0.000) and 72 (F = 51.62 and 10.30, p <0.000 and 0.002) hours of life for the systolic and diastolic BP, respectively. On the contrary, there was no correlation between the BP and the birth weight in both the neonates of either the smoking or the nonsmoking mothers (data not shown). Both the systolic and diastolic BP of the neonates of the mothers who smoked 15 or more cigarettes per day during pregnancy was significantly greater than the systolic and diastolic BP of the control neonates from the first hour of life (Tables II and III). The mean systolic BP was significantly higher in the neonates of the mothers who smoked 7 to 14 cigarettes per day
The Journal of Pediatrics Volume 128, Number 6
Beratis, Panagoulias, and Varvarigou
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Figure. Scattergram plots and lines of best fit between the number of cigarettes smoked by the mothers and the blood pressure (BP), both systolic and diastolic, of 73 neonates of smoking mothers and 170 neonates of nonsmoking parents at 1, 24, 48, and 72 hours of life. The vertical bars show the mean BP _+ SD of the nonsmoking mothers' neonates. The estimate models of the BP of the neonates and the correlation coefficients (R) are shown on the graphs.
T a b l e II. Systolic blood pressure (in millimeters o f mercury) of neonates of smoking and nonsmoking mothers during the first 72 hours o f life*
Age
3-5 Cigarettes/day
7-14 Cigarettes/day
_>15 Cigareffes/day
(hr)
Nonsmoking: Mean _+ SD
Mean _+ SD
p'l"
Mean 4- SD
P'I"
Mean 4- SD
PI"
1 24 48 72
61.4 4- 8.1 65.2 4- 7.9 67.8 4- 7.8 69.5 4- 7.5
60.7 -+ 8.1 68.3 -+ 8.6 69.8 4- 7.8 71.8 4- 4.7
0.731 0.113 0.288 0.233
64.6 4- 6.9 68.2 _+6.9 72.6 4- 7.5 75.9 4- 7.3
0.056 0.074 0.005 -<0.000
66.3 4- 8.7 72.9 4- 11.5 79.9 4- 1i.2 82.0 4- 10.6
0.008 -<0.000 -<0.000 <-0.000
*Analysis of variance between the systolicblood pressure of the neonates of the smoking and the nonsmokingmothers from 1 to 72 hours: ->15 cigarettesper day versus nonsmoking,F = 32.56, p <-0.000; 7 to 14 cigarettesper day versus nonsmoking,F = 10.22, p = 0.002; 3 to 5 cigarettesper day versus nonsmoking, F = 0.46, p = 0.496. tCompared with the blood pressure of the neonates of the nonsmokingmothers; statistical significanceat p <0.017 (0.05 + 3).
at 48 and at 72 hours o f life (Table II). On the other hand, the mean diastolic B P was higher in the neonates of the mothers who smoked 7 to 14 cigarettes per day only at the first hour o f life (Table III). Both the systolic and diastolic
BP o f the neonates of the mothers who smoked 3 to 5 cigarettes per day during pregnancy did not differ significantly from the B P of the neonates o f the nonsmoking parents from the first to the seventy-second hour o f life (Tables II and III).
8 10
Beratis,Panagoulias, and Varvarigou
The Journal of Pediatrics June 1996
Table Ill. Diastolic blood pressure (in millimeters of mercury) of neonates of smoking and nonsmoking mothers during the first 72 hours of life* 3-5 Cigarettes/day
7-14 Cigarettes/day
_>15 Cigarettes/day
Age (hr)
Nonsmoking: Mean ± SD
Mean _+SD
Pt
Mean ± SD
Pt
Mean ± SD
pJ"
1 24 48 72
38.5 -+ 6.7 42.7 ± 7.5 45.6 ± 7.t 47.6 ± 8.1
41.3 -+ 7.4 46.7 ± 7.4 47.5 + 8.3 50.6 ± 6.4
0.112 0.051 0.258 0.136
43.3 +_ 6.6 46.4 ± 7.9 48.2 -+ 7.5 50.2 -+ 8.4
0.002 0.023 0.084 0.158
42.5 --- 7.5 49.3 ± 12.6 54.3 + 11.8 56.3 --- 11.0
0.015 --<0.000 --<0.000 --<0.000
*Analysis of variancebetween the diastolicblood pressure of the neonates of the smoking and the nonsmoking mothers from 1 to 72 hours: ->15 cigarettes per day versus nonsmoking, F = 23.51, p <0.000; 7 to 14 cigarettes per day versus nonsmoking, F = 9.11, p = 0.003; 3 to 5 cigarettes per day versus nonsmoking, F = 3.68, p = 0.056. tCompared with the blood pressure of the neonates of the nonsmoking mothers; statistical significanceat p <0.017 (0.05 + 3).
Table IV. Blood pressure of children of smoking and nonsmoking mothers at the age of 12 and 24 months Systolic (mm Hg)
Significance
Diastolic (mm Hg)
Significance
Age (mo)
No.
Smoking
No.
Nonsmoking
t
p
No.
Smoking
No.
Nonsmoking
t
p
12 24
12 13
102.8± 4.5 99.3 -+ 2.8
12 13
97.1 ± 4.1 97.4 + 4.0
3.20 1.29
0.004 0.21
12 13
66.9 ± 5.9 62.2 -+ 3.1
12 13
61.5 ± 4.1 60.3 -+ 3.1
2.61 1.47
0.016 0.157
Both the systolic and diastolic BP of the neonates of the mothers who used to smoke but discontinued smoking in early pregnancy did not differ significantly from those of the neonates of the mothers who never smoked. There was also no significant difference in either the systofic or the diastolic BP between the neonates of the passive smoking mothers and the control neonates (data not shown; available from authors on request). Follow-up, 4 to 9 months. The 20 infants of mothers who smoked 15 or more cigarettes per day during pregnancy and the 20 infants of nonsmoking parents, who were included in the follow-up study, had an age of 6.8 _+ 1.5 and 6.5 --- 1.5 months, a weight of 10.2 _+ 0.7 and 10.3 + 0.6 kg, a length of 76.7 ± 2.0 and 76.3 _+ 2.1 cm, and aheart rate of 124 + 6 and 125 _+ 8 beats/rain, respectively. The systolic BP in the infants of the mothers who smoked during pregnancy and in those whose parents did not smoke was 101.3 _+ 6.0 m m Hg and 91.2 _+ 8.1 m m Hg, respectively (t = 4.44, p -<0.000). The diastolic BPs were 68.7 -+ 9.6 m m Hg and 61.9 _+ 6.5 m m Hg, respectively (t = 2.58, p = 0.014). Three boys and two girls, whose mothers smoked during pregnancy, had a diastolic BP above the 95th percentile, and another two boys and one girl had a systolic BP between the 90th and the 95th percentiles. None of the control infants had the systolic or diastolic BP above the 90th percentile. The systolic and the diastolic BP of the 12 infants included in the follow-up study whose mothers as well as themselves were passive smokers was 94.0 -+ 5.8 m m Hg and 58.3 + 8.4 m m Hg, respectively. The difference from the control infants
whose parents did not smoke was not significant (t = 1.490 and 1.262, p = 0.150 and 0.220, respectively). Follow-up at 12 and 24 mouths. At the age of 12 months both the systolic and the diastolic BP of the infants of the mothers who smoked 15 or more cigarettes per day was significantly greater than in the control infants, whereas at the age of 24 months there was no significant difference between the two groups (Table IV). The children of the smoking and the nonsmoking mothers had similar weight, length, and heart rate at both 12 and 24 months of age.
DISCUSSION The findings of this prospective study have demonstrated an association between maternal smoking during pregnancy and increased BP in the newborn infant that is maintained through the first year of life. It appears that BP levels in these children return to levels similar to those of nonsmoking mothers during the second year. The significant progressive increase in the BP found in the control neonates over the first 3 days of life has been reported earlier.11 However, the steeper elevation of the BP observed in the neonates of the smoking mothers during the first 72 hours of life resulted in the higher BP measured in the neonates of the mothers who smoked during pregnancy. It has been reported that the BP in newborn infants correlates positively with the birth weight. 11 The absence of a correlation between BP and birth weight in this study most probably is related to the fact that we included only healthy, term, appropriate for gestational age neonates, and thus their
The Journal of Pediatrics Volume 128, Number 6
birth weights varied within a rather narrow range around the normal mean. The observation that the neonates of the mothers who quit smoking at the beginning of pregnancy had a similar BP to that of neonates of nonsmoking mothers indicates that the increased BP results from the direct effect of the tobacco smoke on the placental and the fetal circulatory systems. Likewise, cessation of smoking during pregnancy improves fetal growth and reduces infant morbidity in the neonatal period, Z2 It is unlikely that passive smoking caused the increased BP in the infants of the smoking mothers because infants born to nonsmoking mothers, but whose fathers smoked 20 or more cigarettes per day, had similar BP levels compared with those of the infants of nonsmoking parents. However, the finding that maternal passive smoking did not cause an increase in the BP of the neonates cannot be considered as conclusive evidence that passive smoking does not affect the BP of the neonate because the amount of tobacco smoke inhaled by the pregnant women remains uncertain. The question of whether infants of smoking mothers are at risk of continued elevated BP warrants further investigation because the sample size of the infants followed to a later age was rather small. Nonetheless, only infants of smoking mothers had elevated BP after 4 months of age. The natural history of the elevated BP observed in the children of mothers who smoked during pregnancy is not completely known because the follow-up period was only up to 2 years. The elevated BP observed in the children of mothers who smoked during pregnancy seemed to return to normal levels during the second year of life, suggesting that the increased BP reflects physiologic rather than anatomic changes caused by the tobacco smoke during intrauterine life. Although the BP measurements obtained from the neonates of the smoking mothers were compared with those from matched control neonates, the interpretation of these results according to the standard curves obtained from American childrenl° should be done with caution. The elevation of both the systolic and diastolic BP suggests that the increased BP may be associated with an increased total peripheral vascular resistance, similar to that found in cases of long-standing established hypertension. The circulatory abnormalities identified in fetuses after maternal smoking,4-7 as well as the observation that fetuses of smoking mothers are in a state of chronic tissue hypoxia,2 may be related to the increased BP found in the infants of such mothers. It appears that the effect of maternal cigarette smoking on the BP of the neonate and the infant is different from that on the smoker. Although smoking has been reported to cause a sudden rise in BP, 13-15 several epidemiologic studies have
Beratis, Panagoulias, and Varvarigou
811
shown that chronic smokers have the same or even lower BP than nonsmokers. 16-21 However, more recently an elevated daytime ambulatory systolic BP has been found among untreated hypertensive smokers older than age 50 years. 22 The elevated BP observed in neonates and infants of mothers who smoked during pregnancy may be of concern because the possibility of an association between this early increase of BP and the development of essential hypertension later in life cannot be eliminated. Additional studies are needed to determine the natural history of the elevated BP found in infants of mothers who smoked during pregnancy. REFERENCES
1. Beratis NG, Varvarigou A, Makri M, Vagenakis AG. Prolactin, growth hormone and insulin-like growth factor-I in newborn children of smoking mothers. Clin Endocrinol 1994; 40:179-85. 2. VarvarigouA, Beratis NG, Malai M, VagenakisAG. Increased levels and positive correlation between erythropoietin and hemoglobin concentrationsin newborn children of mothers who are smokers. J Pediatr 1994;124:480-2. 3. Morley R, Payne CL, Lucas A. Maternal smoking and blood pressure in 7.5 to 8 year old offspring. Arch Dis Child 1995; 72:120-4. 4. Lehtovirta P, Forss M. The acute effect of smoking on intervillous blood flow of the placenta. Br J Obstet Gynaecol 1978;85:729-31. 5. Andersen KV, HermannN. Placenta flow reductionin pregnant smokers. Acta Obstet Gynecol Scand 1984;63:707-9. 6. Sindberg EP, Marsal K. Acute effects of maternal smoking on fetal blood flow. Acta Obstet Gynecol Scand 1984;63:391-7. 7. Lindblad A, Marsal K, Andersson K-E. Effect of nicotine on l~umanfetal blood flow. Obstet Gynecol 1988;72:371-82. 8. Pirani BBK. Smoking during pregnancy. Obstet Gynecol Surv 1978;33:1-13. 9. Quigley ME, Sheehan KL, Wilkes MM, YEN SSC. Effects of maternal smoking on circulating catecholamine levels and fetal heart rates. Am J Obstet Gynecol 1979;133:685-90. 10. Task Force on Blood Pressure Control in Children. Report of the Second Task Force on Blood Pressure Control in Children-1987. Pediatrics 1987;79:1-25. 11. Hulman S, Edwards R, Chen YQ, Polansky M, Falkner B. Blood pressure patterns in the first three days of life. J Perinatol 1991;11:231-34. 12. Ahlsten G, Cnattingius S, Lindmark G. Cessation of smoMng during pregnancy improves foetal growth and reduces infant morbidity in the neonatal period: a population-basedprospective study. Acta Paediatr 1993;82:177-81. 13. Celina GU, Honour AJ, Littler WA. Direct arterial pressure, heart rate, and electrocardiogramduring cigarette smoking in unrestricted patients. Am Heart J 1975;89:18-25. 14. Freestone S, Ramsay LE. Effect of coffee and cigarette smoking on the blood pressure of untreated and diuretic-treatedhypertensive patients. Am J Med 1982;73:348-53. 15. Berlin I, Coumot A, Renout P, Duchier J, Safar M. Peripheral haemodynamic effects of smoking in habitual smokers: a methodological study. Eur J Clin Pharmacol 1990;38:57-60. 16. Higgins MW, Kjelsberg M. Characteristics of smokers and
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Beratis, Panagoulias, and Varvarigou
nonsmokers in Tecumseh, Michigan. II. The distribution of selected physical measurements and physiologic variables and the prevalence of certain diseases in smokers and nonsmokers. Am J Epidemiol 1967;86:60-77. 17. Jenkins CD, Rosenman RH, Zyzanski SJ. Cigarette smoking: its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Circulation 1968;38:1140-55. 18. Berglund G, Wilhelmsen L. Factors related to blood pressure in a general population sample of Swedish men. Acta Med Scand 1975;198:291-8. 19. Goldbourt U, Medalie JH. Characteristics of smokers, non-
The Journal of Pediatrics June 1996
smokers, and ex-smokers among 10,000 adult males in Israel. II. Physiologic, biochemical and genetic characteristics. Am J Epidemiol 1977;105:75-86. 20. Greene SB, Aavedal MJ, Tyroler HA, Davis CE, Haines CG. Smoking habits and blood pressure change: a seven year follow-up. Journal of Chronic Diseases 1977;30:401-13. 21. Green MS, Jucha E, Luz Y. Blood pressure in smokers and nonsmokers: epidemiologic findings. Am Heart J 1986;111: 932-40. 22. Mann SJ, James GD, Wang RS, Picketing TG. Elevation of ambulatory systolic blood pressure in hypertensive smokers: a case-control study. JAMA 1991;265:2226-8.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of The Journal of Pediatrics for the preceding 5 years are maintained and are available for purchase from the publisher, Mosby-Year Book, Inc., at a cost of $11.00 per issue. The following quantity discounts are available: 25% o f f o n quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby-Year Book, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis MO 63146-3318, or call (800)453-4351 or (314)4534351 for information on availability of particular issues. If back issues are unavailable from the publisher, photocopies of complete issues are available from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.