Slow-Release Theophylline in Pregnant Asthmatics*

Transcription

1 Slow-Release in Pregnant Asthmatics* Brita Stenius-Aarniala, MD, FCCP; Seija Riikonen, MD; and Kari Teramo, MD Study objective: Oral theophylline treatment may be helpful in controlling severe asthma during pregnancy. This treatment, however, has been suspected of causing both complications and malformations. The objective of this investigation was to study the influence of theophylline treatment on the course of pregnancy and delivery and on maternal and infant health. Setting: Respiratory unit, antenatal outpatient departments, and labor and delivery rooms. Design: Case-control study. Patients: The data of pregnant asthmatics with theophylline treatment (AT) were compared with findings in pregnant asthmatics without theophylline (A) and nonasthmatic pregnant control subjects (C). Results: There were no significant differences among groups as to age, height, age of onset of asthma, lung function, parity, or smoking. In the AT group, 19% were treated for acute exacerbations of the asthma as compared with 6% in the A group (p<0.001). The incidence of preeclampsia was higher in the AT (15.6%) than in the C (6.4% ) group (p<0.03). treatment at term was not associated with premature contractions or premature rupture of membranes, hemorrhage, placenta previa, abruption of the placenta, abnormal fetus position, frequent induction or augmentation of labor, prolonged third phase of delivery, or increased hemorrhage post partum. No differences among groups were seen with regard to gestational age, birth weight, Apgar scores, or perinatal deaths. Jaundice in the newborn, necessitating treatment with blue light, was more common in the AT (15.0%) than in the C group (7.8%) (p<0.05). Three infants of 121 patients treated with theophylline during the first trimester were born with malformations; in the 91 patients treated with theophylline only during the second and third trimester, and the asthmatic control group, the corresponding figures were 4 and 3. Conclusions: During the second and third trimesters until term, theophylline treatment using moderate doses can be considered safe. The safety of theophylline treatment during the first trimester with regard to teratogenicity remains to be determined. (Chest 1995; 107:642-47) Key words: asthma; jaundice; malformations; pregnancy; slow-release theophylline Earlier studies have suggested that theophylline treatment during pregnancy may be associated with prolongation of the third phase of delivery and increased blood loss. 1 2 medication in the course of pregnancy is also reported to be associated with prematurity and low birth weight3 and with a decreased incidence of preeclampsia.4 In animal experiments, theophylline has been shown to cause cardiovascular and bone defects in the fetus5 6 but available human data suggest that there is little risk of teratogenic effects from theophylline therapy during pregnancy.7 Recently, however, three cases were described8 in which theophylline treatment during pregnancy could be suspected as a cause of cardiovascular anomalies. The aims of the present study were to investigate whether theophylline treatment of pregnant asthmatics influences the course of pregnancy or delivery or maternal or infant health. *From the D e p a r of ~ Pulmonary m e n t Medicine, Departments 1 2 of O b ~ t eand t ngynaecology, c s University Central Hospital, a ~ City d Maternity Hospital, Helsinki, Finland. received May 12, 1994; revision accepted July 11. a ~ d M a n ~ s c n p t Repnnt requests: Dr. ~ t e ~ i u s - ~ a r n i a l a, Department of Pulmonary MediCine, Helsmk1 Umversity Center Hospital Helsinki, Finland ' METHODS The patient series comprised 504 consecutive women with asthma who were referred to the pulmonary medicine and maternity outpatient clinics for regular checkups during pregnancy from the beginning of 1982 to September Of these, were treated with oral theophylline to control the asthma. The patients not treated with theophylline comprised the asthmatic control group. This group included 12 women who were not treated with a maintenance dose of oral theophylline, but who were given theophylline parenterally over 1 to 2 days for an exacerbation of asthma during pregnancy. The pregnancies resulted in 509 children (5 twin births). The characteristics of patients and controls are presented in Tables 1 and 2. The patients who received theophylline and the healthy controls were comparable with regard to age and parity, while the asthmatic control group included a somewhat larger proportion of primiparae than the other two groups. The prepregnancy weight of the patients receiving theophylline was significantly higher (p<0.001) than that of the other groups (Table 1). There were no significant differences between groups as to age of onset of the asthma, atopy, or aspirin sensitivity (Table 2). The controls were chosen from the University Hospital labor records and defined as the next consecutive healthy parturient that matched the asthmatic for age ( ± 2 years) and parity (primiparous or multiparous). All theophylline-treated patients had a matched control. In addition, 25 non matched controls were included in the calculations, because it was not possible to separate them from the matched controls in the computer file. Asthma follow -up and treatment was conducted by the authors 642 Slow-Release in Pregnant Asthmatics (Stenius-Aarniala, Riikonen, Teramo)

2 Table!-Patients and Controls: Demographics Asthmatics Age, yr, mean (range) Primiparae, % >35 yr,% Prepregnancy weight, mean, kg ( ±SD) Smoking during pregnancy, % Cigarettes per day, mean (range) 29.2 (17-43) (15.1) (2-20) No Healthy Controls 28.6 (16-44) (11.5) (2-20) 28.9 (17-39) (9.9) (2-25) in all cases. Eighty-six percent of the asthmatic patients gave birth in the university maternity department, the others in five different regional hospitals. All patients and all controls were part of the social security system and were subjected to 10 to 14 routine checkups in maternity centers during pregnancy. These checkups were carried out independently of the visits to specialist clinics. A prepregnancy value of theophylline plasma concentration was accepted if the dose had remained unchanged, but if the dose had changed during pregnancy, only recent values were accepted. Thus, a concentration value was available in 183 cases. The mean plasma concentration ( ± SD) was 45.5 JLmol/L (19.2). Premedication and postmedication morning and evening peak flows were measured during 2 weeks prior to each visit to the respiratory outpatient department. Peak flow variation is expressed as the mean difference between premedication and postmedication peak flows during two consecutive pregnancy weeks of stable and optimally treated asthma. All patients satisfied the criteria of asthma set by the American Thoracic Society and American College of Chest Physicians in An exacerbation of asthma was defined as any worsening of the disease causing the patient to seek emergency medical help outside the routine control scheme. Patients with two or more positive skin tests on testing with a routine panel of inhalant allergens were called atopic. Preeclampsia was defined as a blood pressure of 140/ 90 mm Hg or more measured at least twice during pregnancy, in combination with a proteinuria of 0.3 g/ L or more. Gestational diabetes was defined using the World Health Organization criteria for impaired glucose tolerance. Neonatal hyperglycemia was defined as a blood glucose level of 1.8 g/ L or less during the first 24 h of life. Jaundice was regarded as being present if treatment with blue light was considered necessary. Statistics The data were analyzed (Stat View 512+TM [Brainpower Inc] for Apple Macintosh). The significance of differences between groups was tested using Student's t test for continuous variables and the x2 test with continuity correction for group frequencies. Table 2-Characteristics of the Patients With Asthma Patients Patients Receiving Not Receiving Age of onset of asthma, yr, mean (range) (0-42) (0-43) Positive skin tests, % Aspirin sensitivity, % RESULTS There was no difference between the asthma groups with regard to lung function in stable state during pregnancy. An exacerbation of the asthma during pregnancy occurred significantly more often in the theophylline-treated patients than in the asthmatic controls (Table 3). The patients receiving theophylline were seen significantly more often than the asthmatic controls at the respiratory and antenatal outpatient departments (Table 4). The mean (±SD, range) diurnal dose of theophylline, taking the highest maintenance dose into account, in those 121 patients taking theophylline during the first trimester was mg ( ± 180, 125 to 1,200). The corresponding figure for the 97 patients receiving theophylline at term was 476 (179.5, 125 to 1,200). The patients receiving theophylline had more intensive overall antiasthmatic treatment than the asthmatic controls (Table 5). Preeclampsia was significantly more frequent in Table 3-Lung Function Values and Exacerbations During Pregnancy Patients Patients Receiving Not Receiving Best FEV1.% 92 (14.7) 95 (15.3) predicted mean (±SD) PEF variation, 171 (57.0) 174 (58.0) L/ s,* mean (±SD) Best PEF,% (12.6) (11.1 ) predicted, mean (±SD) % of patients lt with one or more exacerbations *During 2 weeks of stable asthma in pregnancy. PEF=peak expiratory flow. tp<o.ool. CHEST I 1 07 I 3 I MARCH,

3 Table 4-Frequency of Outpatient Visits, of Visits, Mean, ± SD Patients Receiving Patients Not Receiving Healthy Controls Significance In respiratory unit In antenatal unit p p1< p1<0.03 p2< p3< p2 p3 Table 5-Concomitant Antiasthmatic Treatment During Pregnancy Patients Receiving Patients Not Receiving Significance Treatment, % of patients Inhaled /32-agonist 99.0 Inhaled budesonide or beclomethasone 83.0 Courses of oral corticosteroid therapy 36.0 Continuous oral corticosteroid therapy p< p< p< p<0.01 the theophylline-treated asthmatics than in the control groups, and intrahepatic cholestasis of pregnancy occurred more often in the asthmatics than the healthy controls. The occurrence of gestational diabetes did not differ between groups. There were no significant differences with regard to the number of preterm births. Bleeding during the second and third trimester was significantly less common in the asthmatics than in the controls (Table 6). An elective cesarean section was done in 15% in the theophylline-treated group compared with 9.6% in the asthmatic control group and to 2.2% in the healthy control group, the differences between the asthmatic groups and the controls being significant (p<o.oool and p<o.ool, respectively). The corresponding figures for emergency cesarean sections were 7.6%, 6.9%, and 8.6%, with no significant differences among groups. Table 6-Pregnancy Complications Asthmatics Disorder No Healthy Controls Statistical Significance Preeclampsia, % Intrahepatic cholestasis of pregnancy, % Gestational diabetes, % Bleeding during second or third trimester, % Preterm births, % ( <37 wk) p1= p2<0.003 p3= p1= p2= p3<0.04 p1= p2<0.05 p3<0.0l p1 p2 p3 =nol significant. 644 Slow-Release in Pregnant Asthmatics (Stenius-Aamiala, Riikonen, Teramo)

4 Table 1-0utcome of the Newborn Infant Asthmatics Fate No Healthy Controls Significance Perinatal deaths, % Malformations, % Treatment in the NICU, % Apgar 1 min, median (range) Relative birth weight, mean ( ±SO) Blood glucose <1.8 mmol/l,% Jaundice,% (2-10) (1.06) (4-10) (0.9) (0-10) (1.0) p1<0.03 p2<0.05 p3=. p1 p2 p3 NICU=neonatal intensive care unit; =not significant. treatment was not associated with a higher incidence of premature rupture of membranes, premature contractions, placenta previa, or premature separation of the placenta. In the patients treated with theophylline at term there was no prolongation of the third phase of delivery or excessive blood loss compared with the healthy controls. No correlation was observed between the dose of theophylline and the length of gestation, the amount of hemorrhage during delivery, or duration of the third phase of deli very. In general, the health condition of the newborn was good. Neonatal jaundice that required light treatment was more frequent in the newborns of theophylline-treated mothers than in the neonates of the asthmatic controls or the healthy controls (Table 7). No toxic signs attributable to theophylline treatment were recorded in the newborns. There were four cases of perinatal death, the details being as follows. In the theophylline-treated group, one newborn infant died after 3 days because of left heart hypoplasia. In the asthmatic control group, one infant born to a mother with systemic lupus erythematosus in addition to asthma died of multiple malformations. In the control group, one infant died of Potter's syndrome and another, born macerated in the 35th week of gestation, had died in utero for unknown reason at an approximated gestational age of 27 weeks. Among the infants born to the 121 asthmatics treated with theophylline during the first trimester there were 3 (2.5%) with malformations: one with left heart hypoplasia (mentioned above), one with synostosis humeroradialis, and one with finger defects. In the other asthmatics, including not receiving theophylline and the 91 patients treated with theophylline during the second and third trimester only, the corresponding figure was 7 (1.8%) : one infant with multiple malformations (the case of systemic lupus erythematosus mentioned above), one with left heart hypoplasia, four cases of bone defects, including a missing left arm, a double thumb, hypoplasia of the toes, and hypoplasia of the thumb; and one case of hypospadia. In the healthy control group there were 2 (0.8%) malformations: one case of Potter's syndrome and one case of a large defect of the abdominal wall. The average frequency of malformations in Finland is 2%. The sample size is not sufficient to draw definite statistical conclusions. DISCUSSION In our patients, most asthmatics (93%) and all the controls gave birth in the same hospital, which excludes the possibility that some parturients or infants would have been more closely observed than others. Comparison with our previous study 1 revealed some minor differences in patient characteristics. Smoking had become more common among the asthmatics and, in this respect, the asthmatics no longer differed significantly from healthy controls. The average prepregnancy body weight was greater in the theophylline group than in the two groups of asthmatic and healthy controls. One explanation for this may be greater exposure of the theophylline- CHEST / MARCH,

5 treated patients to the systemic effects of corticosteroid treatment. Also, the theophylline-treated patients may have taken less physical exercise because of their asthma. According to our results, theophylline treatment was associated with an increased incidence of preeclampsia. This relationship may not be a direct drug effect, but it is possibly explained by the theophylline-treated asthmatics having a more severe disease. Controversially, in a report from the United States,4 theophylline was found to reduce the risk of preeclampsia. At the time of that study, inhaled steroids were used less frequently and in smaller doses in the United States than in our country. Thus, the asthma was possibly better controlled and the risk of preeclampsia was smaller in those asthmatics treated with theophylline than in those who were not treated with theophylline. Our asthmatic patients were subjected to more frequent checkups during pregnancy than the controls, which may have increased the likelihood for recording elevated blood pressure. However, a diagnosis of preeclampsia also leads to more frequent controls. As our definition of preeclampsia included proteinuria, we believe the elevated frequency of this condition observed in our asthmatics to be real. The incidence of gestational bleeding was lower in the asthmatics than in the controls. The tocolytic effect of bronchodilators, such as theophylline and /3-agonists, may explain this result in patients receiving oral medication. Another possible explanation could be that the asthmatics did not expose themselves to physical stress as frequently as the controls. Our earlier investigation established that elective cesarean section was fairly common in patients with severe asthma, although the asthma was seldom the sole indication for the operation. In the present series, severe asthma and theophylline treatment were linked with one another and the frequent decisions in favor of cesarean section are probably attributable to the disease itself. relaxes smooth muscles and has been used as a tokolytic. 2 Therefore, theophylline could be expected to cause complications during labor because of a reduction in the tonus of the uterine muscle. Our previous study showed an almost significant adverse effect of theophylline on hemorrhage and length of the third phase of delivery. At that time, slow-release theophylline was not used in Finland, and the patients described were treated with short-acting theophylline. In the present study, no relationships were observed between the dose of theophylline and the length of gestation, duration of the third phase of delivery, or amount of hemorrhage during delivery. However, theophylline doses were kept low; no efforts were made to increase the plasma concentration of theophylline to a "therapeutic" level. The timing of the tests for theophylline plasma concentration in our material was inconsistent. It has been shown that theophylline metabolism may change during the course of pregnancy, 10 and thus no conclusions as to the relation between plasma theophylline concentrations and possible side effects can be made. Although no toxic signs attributable to theophylline were recorded in the newborns, these signs were not actively looked for, and this possibility should be taken in account in mothers with high concentrations of serum theophylline.u We could not confirm the finding3 that theophylline treatment or asthma as such in the mother are associated with prematurity or low birth weight of the newborn. Our previous finding that hypoglycemia was significantly more frequent in neonates of asthmatic mothers was not confirmed in this study. Jaundice occurred in 7 to 8% of the newborn infants in our earlier series of asthmatic mothers. In the present study, the frequency of jaundice was of the same magnitude in the newborn infants in the control group of asthmatics, whereas the frequency was twice as high in the neonates of theophylline-treated mothers. affects the metabolism of several vitamins and enzymes,12 13 but whether this can enhance hyperbilirubinemia in the newborn is unknown. In our study, mainly women with difficultto-control asthma were treated with theophylline, and thus the severe asthma as such may have influenced the incidence of jaundice in the newborns. There was no relationship between oral corticosteroid treatment on or within 4 weeks before parturition and the incidence of neonatal jaundice. The incidence of malformations in the different groups was of the same magnitude as in the general population. However, to achieve a power of 90%, one would need more than 2,000 probands in each group to calculate the risks of malformations in asthmatics compared with nonasthmatics. To investigate the corresponding risks connected to a certain treatment, for instance theophylline, the sample size would have to be around 10,000 individuals per group. All the same, the occurrence of two cases of fatal left heart hypoplasia and some bone defects in the infants born to asthmatic mothers is a matter of concern, and this aspect is subjected to further study at the moment. In our study, most of the theophylline-treated pregnant asthmatics were seen during the first years of the study period. In Finland, as in many other countries, the use of oral theophylline has decreased during the latter half of the 1980s, mainly because the increased use of inhaled corticosteroids. However, oral theophylline is still an important part of the pharmacologic treatment of a subgroup of asthmatics,14 and theophylline is widely used in countries 646 Slow-Release in Pregnant Asthmatics (Stenius-Aamia/a, Riikonen, Teramo)

6 where other therapy is not readily available. We conclude that, according to our results, pregnancy, delivery, and the health of mother and child are not adversely affected by moderate doses of theophylline. High doses should probably be avoided throughout pregnancy. ACKNOWLEDGMENTS: We thank specialist nurses Paivi Helin and Anja Lilja for invaluable help in collecting the data, Terttu Kovanen for skillful assistance at the computer, and the Astra Group for financial support. REFERENCES Stenius-Aarniala B, Piirila P, Teramo KA. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax 1988; 43: Pollowitz JA. during pregnancy. JAMA 1980; 243: Schatz M, Zeiger RS, Hoffman CP, et al. Preterm and low birthweight infants of asthmatic mothers. clinical correlations [abstract]. J Allergy Clin Immunol1988; 81 :275 4 Dombrowski MP, Bottoms SF, Boike GM, et al. Incidence of pre-eclampsia among asthmatic patients lower with theophylline. Am J Obstet Gynecol1986; 155: Gilbert EF, Bruyere HJ, Ishikawa S, et al. The effect of methylxanthines on catecholamine-stimulated and normal chick embryos. Teratology 1977; 16: Ishikawa S, Gilbert EF, Bruyere HJ, et a!. Aortic aneurysms associated with cardiac defects in theophylline-stimulated chick embryos. Teratology 1978; 18: Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy 1992; 68: Park JM, Schroer V, Myers TM. Cardiovascular anomalies associated with prenatal exposure to theophylline. South Med J 1990; 83: ACCP and ATS. Pulmonary terms and symbols: a report of the ACCP-ATS Joint Committee on Pulmonary Nomenclature. Chest 1975; 67: Gardner MJ, Schatz M, Cousins L, et al. Longitudinal effects of pregnancy on the pharmacokinetics of theophylline. Eur J Clin Pharmacol 1987; 31: Labovitz E, Spector S. Placental theophylline transfer in pregnant asthmatics. JAMA 1982; 247: Delport R, Ubbink JB, Bosman H, et al. Altered vitamin B6 homeostasis during aminophylline infusion in the beagle dog. Int J Vitam Nutr Res 1990; 60: Delport R, Ubbink JB, Serfontein WJ, et al. Vitamin B6 nutritional status in asthma: the effect of theophylline therapy on plasma pyridoxal-5' -phosphate and pyridoxal levels. Int J Vitam Nutr Res 1988; 58: Barnes PJ, Pauwels RA. in the management of asthma: time for reappraisal? Eur Respir J 1994; 7: CHEST /107/3/ MARCH,