Sympatholytic (Antihypertensive)
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 2nd and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Atenolol may cause growth restriction and reduced placental weight. The drug does not possess ISA (i.e., partial agonist). The reduced fetal growth appears to be related to increased vascular resistance in both the mother and the fetus and is a function of the length of drug exposure. Treatment starting early in the 2nd trimester is associated with the greatest decrease in fetal and placental weights, whereas treatment restricted to the 3rd trimester primarily affects only placental weight. Although growth restriction is a serious concern, the benefits of maternal therapy with β-blockers, in some cases, might outweigh the risks to the fetus and must be judged on a case-by-case basis. Because only one case has been reported, an association between atenolol and fetal retroperitoneal fibromatosis requires confirmation. Newborns exposed to atenolol near delivery should be closely observed during the first 24–48 hours for signs and symptoms of β-blockade. The long-term effects of prolonged in utero exposure to this class of drugs have not been studied but warrant evaluation.
FETAL RISK SUMMARY
Atenolol is a cardioselective β1-adrenergic blocking agent used for the treatment of hypertension. The drug did not cause structural anomalies in pregnant rats and rabbits, but a dose-related increase in embryo and fetal resorptions in rats was observed at doses ≥25 times the maximum recommended human antihypertensive dose based on 100 mg/day in a 50-kg patient (MRHD). This effect was not seen in rabbits at doses up to 12.5 times the MRHD (1).
In contrast with propranolol and sotalol, atenolol exposure during gestation did not increase the motor activity or cause poor performance in rat offspring (2). The adverse effects observed with propranolol and sotalol, but not atenolol, were attributed to the β2-blocking activity of propranolol and sotalol.
A 2002 abstract, reviewing both published and nonpublished sources to assess atenolol developmental toxicity, found that fetal growth restriction occurred in both animals and humans (3). The animal–human concordance was thought to result from the reduced placental and fetal circulation induced by atenolol.
Atenolol readily crosses the placenta to the fetus producing steady-state fetal levels approximately equal to those in the maternal serum (4–11). When 11 pregnant patients were treated with 100 mg/day, the serum half-life (8.1 hours) and the 24-hour urinary excretion (52 mg) were similar to those values in nonpregnant women (8). In nine women treated with atenolol for cardiac disease, the average maternal and cord drug concentrations at delivery were 133 and 126 ng/mL, respectively (11). No evidence of altered atenolol pharmacokinetics during pregnancy was found. Atenolol transfer was one-third to one-fourth the transfer of the more lipid-soluble β-blockers propranolol, timolol, and labetalol in an in vitro experiment using perfused human placentas (12).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 105 newborns had been exposed to atenolol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 12 (11.4%) major birth defects were observed (4 expected). Specific data were available for six defect categories, including (observed/expected) 3/1 cardiovascular defects, 1/0 oral clefts, 0/0 spina bifida, 0/0 polydactyly, 1/0 limb reduction defects, and 4/0 hypospadias. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother’s disease, concurrent drug use, and chance, may be involved.
A 1997 abstract (13) and later full report (14) described a case of retroperitoneal fibromatosis in a fetus exposed in utero to atenolol from the second month of gestation through delivery at 37 weeks. The obese (134 kg at term), 25-year-old mother, in her third pregnancy, was treated for hypertension with 100-mg atenolol daily until giving birth to the 3790-g male infant. Other drug therapy included magnesium supplements and occasional metoclopramide. The mother had no familial history of cancer and both of her other children were normal. Treatment of the tumor with chemotherapy during the first 3 months of life was successful, but a severe scoliosis was present in the child at 4 years of age. The authors attributed the rare tumor to the drug because, among other reasons, the location of the mass was similar to that of fibroses reported in adults exposed to atenolol (13,14).
The use of atenolol for the treatment of hypertension in pregnant women has been described frequently (7,10,15–28). No fetal malformations attributable to atenolol have been reported in these trials, but in most cases, the treatment with atenolol did not occur during the 1st trimester.
In a 1981 study, 13 women—11 in the 3rd trimester and 2 in the 2nd trimester—were treated for gestational hypertension with atenolol 100 mg/day until delivery (15). The birth weights of 12 of the 13 newborns were less than the 50th percentile (3 were less than the 10th percentile), but the authors thought they were consistent with severe preeclampsia. The pharmacokinetic profiles of atenolol in the pregnant subjects were similar to those measured in nonpregnant women (15).
A 1982 study described the pregnancy outcomes of 10 women with chronic hypertension who were treated with atenolol 100–200 mg/day beginning at 11–32 weeks (16). One woman delivered a stillborn infant at 41+ weeks’ gestation, but the remaining nine women delivered at a median of 39 weeks. The median birth weight was 82% of the gestational mean with placental weights ranging from 235 to 795 g.
A 1983 retrospective study examined the effects of atenolol (N = 87) and metoprolol (N = 2), either alone or in combination with other antihypertensives, for the treatment of hypertension (chronic or preeclampsia) in pregnancy (17). Birth weights were not given. There were three stillbirths, but the maternal therapy in these cases was not specified.
A randomized, double-blind study published in 1983 compared atenolol (N = 46) with placebo (N = 39) for the treatment of mild-to-moderate gestational hypertension (18). Treatment was started at a mean 34 weeks’ gestation in both groups. The mean gestational ages at delivery were 38 weeks (placebo) and 39 weeks (atenolol) (p < 0.05). No differences in the incidence of hypoglycemia, respiratory distress syndrome, or hyperbilirubinemia were observed between the groups. Although not statistically significant, both the mean birth weights (2961 vs. 3017 g) and placental weights (549 vs. 608 g) were lower in those treated with atenolol. However, significantly more atenolol-exposed newborns had bradycardia, 39% (18 of 46) vs. 10% (4 of 39) (p< 0.01). None of the infants required treatment for the lowered heart rate. Three intrauterine deaths occurred, two in the placebo group and one in the atenolol group (18). In the same year, the authors of this study and a previous report (16) commented briefly on the benefits of β-blockers in the management of hypertension during pregnancy (19).
A 1992 study evaluated the effectiveness of atenolol in three groups of pregnant women having chronic hypertension (N = 12), gestational hypertension without proteinuria (N = 52), or preeclampsia (N = 6) (20). The mean doses in the three groups were 62.5, 70.0, and 100.0 mg, respectively. The drug was started at a mean gestational age of 24.5, 29.8, and 31.0 weeks, respectively. The mean birth weights observed were approximately 2902, 3059, and 2431 g, respectively.
The effect of β-blockers in pregnancy was reviewed in a 1988 article. Citing only three reports, the authors concluded that atenolol was safe and effective therapy during pregnancy (21).
Antihypertensive therapy with atenolol has been associated with fetal growth restriction in a number of studies (7,10,22–27). A nonrandomized 1983 study compared atenolol (N = 28; enrolled before May 1981) with labetalol (N = 28; enrolled after May 1981) in the treatment of chronic (N = 6) or gestational hypertension (N = 50) (7). The average daily doses were 144.6 mg (atenolol) and 614 mg (labetalol). Newborn weights were significantly higher in those exposed to labetalol, 3280 vs. 2750 g, respectively (p < 0.001). Two newborns were premature (<37 weeks) in the atenolol group compared with one in the labetalol group. In addition, two mothers treated with atenolol delivered stillborn infants at 29 and 38 weeks, respectively (7).
A 1984 case report described the pregnancy outcome of a woman treated with atenolol (50 mg/day increased to 100 mg/day at 33 weeks’) throughout a 36-week gestation (10). Intrauterine growth restriction (IUGR) was diagnosed by ultrasound and a small (weight not given) but otherwise-normal baby girl was delivered with Apgar scores of 5, 7, and 9 at 1, 5, and 10 minutes, respectively. The maternal plasma and cord blood atenolol concentrations were 510 and 380 ng/mL, respectively. Other than a transient decrease in heart rate to 100 beats/minute at 16 hours of age, the infant had no complications (10).
A 1980 report described 60 pregnancy outcomes from 59 women treated with β-blockers for hypertension (22). The agents used were atenolol (N = 10; daily dose 100–200 mg), acebutolol (N = 28; daily dose 200–600 mg), pindolol (N = 21; daily dose 10–20 mg), and propranolol (N = 1; daily dose 40 mg). Although the birth weights were not differentiated by drug, 9 newborns weighed <2500 g, 11 were 2500–2800 g, and 40 were >2800 g (21). Two years later, this research group compared atenolol (N = 31), acebutolol (N = 56), and pindolol (N = 38) in a nonrandomized study for the treatment of hypertension during pregnancy (23). One year later, the researchers increased the number of atenolol cases to 37 (24). The mean birth weights of the three groups were 2.82, 3.16, and 3.38 kg, respectively (23,24).
In a prospective, randomized, double-blind study, women with mild essential hypertension were given either atenolol (50–200 mg/day) or placebo starting at a mean gestational age of 15.9 weeks (25). The 15 newborns in the treated group had a significantly lower birth weight than the 14 untreated controls (2620 vs. 3530 g; p < 0.001). In the treated group, 5 of the newborns had weights below the 5th percentile and 10 were below the 10th percentile, compared with 1 newborn below the 25th percentile in controls. In addition, the atenolol group had significantly smaller placentas (442 vs. 635 g; p < 0.002) (25).
A 1992 report described the outcomes of 29 women with pregnancy-induced hypertension in the 3rd trimester (26). The women were randomized to receive either atenolol (N = 13) or pindolol (N = 16). The decrease in mean maternal arterial blood pressure in the two groups was similar. In comparing the women’s status before and after therapy, several significant changes were measured in fetal hemodynamics with atenolol but, except for fetal heart rate, no significant changes were measured with pindolol. The atenolol-induced changes included a decrease in fetal heart rate; increases in the pulsatility indices (and thus the peripheral vascular resistance) of the fetal thoracic descending aorta, the abdominal aorta, and the umbilical artery; and a decrease in the umbilical venous blood flow (26). Although no difference in birth weights was observed in the two groups, the placental weight in atenolol-treated pregnancies was significantly less, 529 vs. 653 g (p = 0.03).
A 1997 report described an open, retrospective survey on the use of antihypertensives in 398 consecutive pregnant women who attended an antenatal hypertension clinic from 1980 to 1995 (27). The 76 women who used atenolol were compared with those using calcium channel blockers (N = 22), diuretics (N = 26), methyldopa (N = 17), other β-blockers (N = 12), or no drug therapy (N = 235). The mean birth weights/placental weights in the groups were atenolol 2.19 kg/390 g (p < 0.001); other β-blockers 2.36 kg/450 g; calcium channel blockers 2.50 kg/385 g (p = 0.001); diuretics 2.53 kg/500 g; methyldopa 2.70 kg/500 g; and no drug treatment 2.78 kg/535 g. The ponderal index (kg/m3 × 104), an indirect measure of impaired placental function in some forms of IUGR, also was calculated for each group: 2.21 (p < 0.001), 2.44, 2.22, 2.33, 2.67, and 2.39, respectively. The authors concluded that atenolol was associated with IUGR and reduced placental weights and should be avoided in women who are trying to conceive or are in the early stages of gestation (27).
A 1999 retrospective cohort study reported the outcomes of 312 pregnancies in 223 women treated for gestational hypertension (N = 80), preeclampsia (N = 19), chronic hypertension (N = 179), or superimposed preeclampsia on chronic hypertension (N = 34) (28). The women were treated with atenolol monotherapy (N = 78), other monotherapy (N = 53), combination therapy (N = 90; atenolol in 57), or no treatment (N = 91). The atenolol outcomes were statistically significant when compared with other monotherapy or with no treatment. (Combination therapy implied more severe disease and consistently had the worst outcomes.) Birth weights were as follows: atenolol 2372 g vs. other monotherapy 2756 g or no treatment 3068 g (p < 0.05), and combination therapy 2220 g; birth lengths were as follows: atenolol 47.9 cm vs. other monotherapy 48.3 cm, no treatment 50.4 cm, (p < 0.05), and combination therapy 46.3 cm. There were two nonsignificant trends: higher prevalence of preterm delivery (<37 weeks) atenolol 33% vs. other monotherapy 26%, no treatment 15%, and combination therapy 46%; and higher prevalence of small-for-gestational-age (<10th percentile) atenolol 49% vs. other monotherapy 34%, no treatment 21%, and combination therapy 52%. The adverse fetal effects of atenolol were more pronounced when the therapy was started early in pregnancy and were duration-dependent (28).
A prospective randomized study compared 24 atenolol-treated women with 27 pindolol-treated women (29). No differences between the groups were found in gestational length, birth weight, Apgar scores, rates of cesarean section, or umbilical cord blood glucose levels. Treatment in both groups started at about 33 weeks’ gestation. Placentas in the atenolol group weighed less than those from pindolol-treated women, 440 vs. 533 g, p < 0.02.
A 1987 study used Doppler ultrasound to evaluate maternal and fetal circulation during atenolol therapy in 14 women (9 nulliparous) with pregnancy-induced hypertension at a mean gestational age of 35 weeks (range 33–38 weeks) (30). The studies were conducted before and during the first and third days of treatment. During treatment, the volume of blood flow remained unchanged in the fetal descending aorta and the umbilical vein. In contrast, the pulsatility index increased in the fetal descending aorta and the maternal arcuate artery, suggesting that peripheral vascular resistance had increased on both the maternal and fetal sides of the placenta. No effect on placental or fetal weight occurred because of the short treatment period (delivery occurred a mean 18 days after the start of the study) (30). The study design and techniques were criticized based on concerns for reproducibility, including day-to-day variability in Doppler measurements, the lack of controls, and the uncertainty of the clinical significance of velocity waveform measurements (31).
A 1995 randomized study examined the short-term effects of IV 15- to 20-minute infusions of atenolol or pindolol in 24 women with gestational hypertension (32). Comparisons were made for uterine and umbilicoplacental vascular impedance, fetal hemodynamics, and cardiac function. Both drugs significantly decreased maternal blood pressure and maternal heart rate immediately after infusion, but the effect of atenolol still was evident 30 minutes after the end of the infusion. Pindolol produced no changes in uteroplacental or umbilicoplacental vascular impedance, whereas atenolol increased vascular impedance in the nonplacental uterine artery. The umbilical artery pulsatility indices, an indication of increased vascular resistance, were higher after atenolol than after pindolol. Pindolol had no effects on fetal hemodynamics whereas atenolol decreased pulsatility indices in the fetal renal artery. In addition, atenolol significantly decreased peak systolic velocity in the fetal pulmonary trunk. The investigators concluded that both drugs were equally effective in lowering maternal blood pressure, that atenolol increased uteroplacental vascular impedance, and that atenolol had direct effects on fetal hemodynamics. Based on these findings, pindolol was the preferred agent (32).
A 1995 review of vasoactive drugs in pregnancy stated that pregnancy-induced hypertension (now known as gestational hypertension) was associated with increased vascular resistance that could reduce uteroplacental blood flow by 40%–70% (33). In addition, atenolol treatment was associated with increased resistance in uterine arteries and decreased peak velocity in the fetal pulmonary trunk, but that pindolol lacked these effects (32). They concluded that the use of vasoconstricting β-blockers during pregnancy should be reconsidered (33).
Normotensive women at risk for preeclampsia (cardiac output > 7.4 L/minute before 24 weeks’ gestation) were enrolled in a 1999 double-blind, randomized, controlled trial to determine if atenolol could reduce this risk (34). The treatment groups were nulliparous: atenolol (N = 21) or placebo (N = 19); diabetics: atenolol (N = 7) or placebo (N = 9); and controls: no treatment (N= 18). A significant decrease (p = 0.04) in the incidence of preeclampsia was noted in the atenolol-treated women, but their offspring had a birth weight of 440 g less than that of placebo infants (p = 0.02). However, no increase in the rate of small-for-gestational-age fetuses was observed. Previous research by these investigators had suggested that in women with hypertension, fetal growth restriction occurred primarily when increased vascular resistance was present but not when hypertension was mediated by increased cardiac output (34). They concluded that a change in therapy was indicated if the maternal cardiac output was less than the mean for gestational age or if peripheral resistance was greater than 1150 dyne second/cm5. If these guidelines had been followed, atenolol therapy would have been changed in seven subjects, including four cases involving the smallest infants (34).
A 2001 retrospective review of pregnancies (N = 235) at risk for preeclampsia that were treated with atenolol (25–100 mg/day) early in gestation was reported by the same authors as those of the above study (35). The goals of therapy were to reduce cardiac output to 1 standard deviation above the mean for gestational age and to lower mean arterial pressure to <90 mmHg. To maintain fetal growth, this was modified to maintaining cardiac output above the mean for gestational age and maintaining peripheral vascular resistance at <1150 dyne second/cm5. Low birth weight was associated with (a) prior pregnancy with IUGR (p = 0.001); (b) failure to adjust the dose properly for cardiac output and peripheral vascular resistance (p < 0.001); and (c) a pregnancy in an earlier year of the investigator’s experience (p < 0.001). In the study population, the birth weight increased from the 20th percentile at the beginning of the study period (1991) to the 40th percentile by the end (1999) (p = 0.002) (35).
In a group of pregnant women with symptomatic mitral valve stenosis, 11 were treated with atenolol and 14 with propranolol (36). The mean birth weight of the 25 infants was 2.8 kg (range 2.1–3.5 kg). Atenolol, 25 mg twice daily, was administered from 18 weeks’ gestation to term in a normotensive woman who had suffered a myocardial infarction (37). She delivered a 2720-g infant with normal Apgar scores and blood gases.
Intrauterine fetal deaths have been observed in women with severe hypertension treated with atenolol, but this also has occurred with other β-blockers and in hypertensive women not treated with drugs (7,16–18,38). Four cases of fetal death (at 18, 29, and 33 weeks) or neonatal death (at 6.5 days) have been reported when the mothers were treated with atenolol combined with either angiotensin-converting enzyme inhibitors (39–41) or a selective angiotensin II receptor antagonist (42).
In eight women treated with atenolol or pindolol, a decrease in the basal fetal heart rate was noted only in atenolol-exposed fetuses (43). Before and during treatment, fetal heart rates in the atenolol patients were 136 and 120 beats/minute, respectively, whereas the rates for the pindolol group were 128 and 132 beats/minute, respectively. In 60 patients treated with atenolol for pregnancy-induced hypertension, no effect on fetal heart rate pattern in response to uterine contractions was observed (44). Accelerations, variables, and late decelerations all were easily distinguishable.
Persistent β-blockade was observed in a newborn whose mother was treated with atenolol, 100 mg/day, for hypertension (5). At 15 hours of age, the otherwise normal infant developed bradycardia at rest and when crying, and hypotension. The serum atenolol concentration was 0.24 mcg/mL. Urinary excretion of the drug during the first 7 days ranged from 0.085 to 0.196 mcg/mL.
A 1992 case report described a pregnant woman who was diagnosed with a pheochromocytoma at 28 weeks’ gestation (45). She was treated with atenolol (100 mg/day) and phenoxybenzamine (30 mg/day) to control her blood pressure. An elective cesarean section was performed at 37 weeks to deliver a normal female infant (birth weight not given).
A woman with a renal transplant was treated with cyclosporine, prednisolone, and atenolol (50 mg/day) throughout a normotensive pregnancy without proteinuria (46). An 820-g (below the 3rd percentile) male infant was delivered at 30 weeks’ gestation because of severe IUGR. The authors attributed the growth restriction to cyclosporine, but atenolol and prednisolone probably contributed to the condition.
A review published in 2002 examined the pharmacokinetic and pharmacodynamic issues relevant to the toxic effects of atenolol exposure during pregnancy (47). The authors concluded that (a) maternal hypertension can potentiate the adverse effects of atenolol on placental and fetal circulation, resulting in decreased placental and birth weight; (b) decreased placental weight has been significantly associated with IUGR and lower birth weight independent of gestational age; (c) the effects of atenolol are duration-dependent; and (d) several other agents have a more favorable effect on birth weight, including labetalol, pindolol, acebutolol, and calcium channel blockers (47).
The duration of treatment, rather than the dose used, appears to be a critical factor in causing atenolol-induced fetal growth restriction (48). At one center, adjustment of the dose for maternal cardiac output and peripheral vascular resistance reduced these toxic effects. Infant behavior is apparently not affected by atenolol exposure, as no differences were noted in the development at 1 year of age of offspring from mothers treated during the 3rd trimester for mild-to-moderate pregnancy-induced hypertension with either bed rest alone or rest combined with atenolol (49). The mean duration of therapy in the atenolol-treated patients was 5 weeks.
BREASTFEEDING SUMMARY
Atenolol is excreted into breast milk (6,8,10,47,50–54). The drug is a weak base, and when used during lactation, accumulation in the milk will occur with concentrations significantly greater than corresponding plasma levels (6,8,47,50–53). Peak milk concentrations after single-dose (50 mg) and continuous-dosing (25–100 mg/day) regimens were 3.6 and 2.9 times greater, respectively, than simultaneous plasma levels (52). Atenolol has been found in the serum and urine of breastfed infants in some studies (6,8,10,50). Other studies have been unable to detect the drug in the infant serum (test limit 10 ng/mL) (51,52).
Symptoms consistent with β-adrenergic blockade were observed in a breastfed, 5-day-old, full-term female infant, including cyanosis, hypothermia (35.5°C rectal), and bradycardia (80 beats/minute) (54). Blood pressure was 80/40 mmHg. Except for these findings, physical examination was normal and bacterial cultures from various sites were negative. The mother had been treated orally with atenolol, 50 mg every 12 hours, for postpartum hypertension. Breastfeeding was stopped 3 days after onset of the symptoms and 6 hours later, the infant’s symptoms had resolved. A milk sample, collected 10 days postpartum and 1.5 hours after a 50-mg dose, contained 469 ng/mL of atenolol. Concentrations in the infant’s serum, 48 and 72 hours after breastfeeding, were 2010 and 140 ng/mL, respectively. The calculated serum half-life in the infant was 6.4 hours. By extrapolation, the minimum daily dose absorbed by the infant was estimated to be 8.97 mg, approximately 9% of the mother’s daily dose (54). (These calculations have been questioned and defended [55,56].)
Except for the single case cited above, adverse reactions in infants have not been reported. However, because milk accumulation occurs with atenolol, nursing infants must be closely monitored for bradycardia and other signs and symptoms of β-blockade. Moreover, one author has recommended that water-soluble, low-protein-bound, renally excreted β-blockers, such as atenolol, should not be used during lactation (57). Because of the availability of safer alternatives, this seems to be good advice. Long-term effects on infants exposed to β-blockers from breast milk have not been studied but warrant evaluation.
The American Academy of Pediatrics classifies atenolol as a drug that has been associated with significant effects in nursing infants (cyanosis and bradycardia) and should be used by nursing mothers with caution (58).
References
1.Product information. Tenormin. Zeneca Pharmaceuticals, 2003.
2.Speiser Z, Gordon I, Rehavi M, Gitter S. Behavioral and biochemical studies in rats following prenatal treatment with β-adrenoceptor antagonists. Eur J Pharmacol 1991;195:75–83.
3.Tabacova SA, Kimmel CA, Wall K, McCloskey CA. Animal-human concordance in the developmental toxicity of two antihypertensive agents (abstract). Teratology 2002;65:304.
4.Melander A, Niklasson B, Ingemarsson I, Liedholm H, Schersten B, Sjoberg NO. Transplacental passage of atenolol in man. Eur J Clin Pharmacol 1978;14:93–4.
5.Woods DL, Morrell DF. Atenolol: side effects in a newborn infant. Br Med J 1982;285:691–2.
6.Liedholm H. Transplacental passage and breast milk accumulation of atenolol in humans. Drugs 1983;25(Suppl 2):217–8.
7.Lardoux H, Gerard J, Blazquez G, Chouty F, Flouvat B. Hypertension in pregnancy: evaluation of two beta blockers atenolol and labetalol. Eur Heart J 1983;4(Suppl G):35–40.
8.Thorley KJ. Pharmacokinetics of atenolol in pregnancy and lactation. Drugs 1983;25(Suppl 2):216–7.
9.Boutroy MJ. Fetal and neonatal effects of the beta-adrenoceptor blocking agents. Dev Pharmacol Ther 1987;10:224–31.
10.Fowler MB, Brudenell M, Jackson G, Holt DW. Essential hypertension and pregnancy: successful outcome with atenolol. Br J Clin Pract 1984;38:73–4.
11.Hurst AK, Shotan A, Hoffman K, Johnson J, Goodwin TM, Koda R, Elkayam U. Pharmacokinetic and pharmacodynamic evaluation of atenolol during and after pregnancy. Pharmacotherapy 1998;18:840–6.
12.Schneider H, Proegler M. Placental transfer of B-adrenergic antagonists studied in an in vitro perfusion system of human placental tissue. Am J Obstet Gynecol 1988;159:42–7.
13.Satge D, Sasco AJ, Col JY, Lemonnier PG, Hemet J, Robert E. Antenatal exposure to atenolol and retroperitoneal fibromatosis (abstract). Teratology 1997;55:103.
14.Satge D, Sasco AJ, Col J-Y, Lemonnier PG, Hemet J, Robert E. Antenatal exposure to atenolol and retroperitoneal fibromatosis. Reprod Toxicol 1997;11:539–41.
15.Thorley KJ, McAinsh J, Cruickshank JM. Atenolol in the treatment of pregnancy-induced hypertension. Br J Clin Pharmacol 1981;12:725–30.
16.Rubin PC, Butters L, Low RA, Reid JL. Atenolol in the treatment of essential hypertension during pregnancy. Br J Clin Pharmacol 1982;14:279–81.
17.Liedholm H. Atenolol in the treatment of hypertension of pregnancy. Drugs 1983;25(Suppl 2):206–11.
18.Rubin PC, Butters L, Clark DM, Reynolds B, Sumner DJ, Steedman D, Low RA, Reid JL. Placebo-controlled trial of atenolol in treatment of pregnancy-associated hypertension. Lancet 1983;1:431–4.
19.Rubin PC, Butters L, Low RA, Clark DC, Reid JL. Atenolol in the management of hypertension during pregnancy. Drugs 1983;25(Suppl 2):212–4.
20.Fabregues G, Alvarez L, Varas Juri P, Drisaldi S, Cerrato C, Moschettoni C, Pituelo D, Baglivo HP, Esper RJ. Effectiveness of atenolol in the treatment of hypertension during pregnancy. Hypertension 1992;19(Suppl II):II129–31.
21.Frishman WH, Chesner M. Beta-adrenergic blockers in pregnancy. Am Heart J 1988;115:147–52.
22.Dubois D, Petitcolas J, Temperville B, Klepper A. Beta blockers and high-risk pregnancies. Int J Biol Res Pregnancy 1980;1:141–5.
23.Dubois D, Petitcolas J, Temperville B, Klepper A, Catherine P. Treatment of hypertension in pregnancy with β-adrenoceptor antagonists. Br J Clin Pharmacol 1982;13(Suppl):375S–8S.
24.Dubois D, Peticolas J, Temperville B, Klepper A. Treatment with atenolol of hypertension in pregnancy. Drugs 1983;25(Suppl 2):215–8.
25.Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during pregnancy. BMJ 1990;301:587–9.
26.Montan S, Ingemarsson I, Marsal K, Sjoberg N-O. Randomized controlled trial of atenolol and pindolol in human pregnancy: effects on fetal haemodynamics. BMJ 1992;304:946–9.
27.Lip GYH, Beevers M, Churchill D, Shaffer LM, Beevers DG. Effect of atenolol on birth weight. Am J Cardiol 1997;79:1436–8.
28.Lydakis C, Lip GYH, Beevers M, Beevers DG. Atenolol and fetal growth in pregnancies complicated by hypertension. Am J Hypertens 1999;12:541–7.
29.Tuimala R, Hartikainen-Sorri A-L. Randomized comparison of atenolol and pindolol for treatment of hypertension in pregnancy. Curr Ther Res 1988;44:579–84.
30.Montan S, Liedholm H, Lingman G, Marsal K, Sjoberg N-O, Solum T. Fetal and uteroplacental haemodynamics during short-term atenolol treatment of hypertension in pregnancy. Br J Obstet Gynaecol 1987;94:312–7.
31.Rubin PC. Beta blockers in pregnancy. Br J Obstet Gynaecol 1987;94:292–3.
32.Rasanen J, Jouppila P. Uterine and fetal hemodynamics and fetal cardiac function after atenolol and pindolol infusion. A randomized study. Eur J Obstet Gynecol Reprod Biol 1995;62:195–201.
33.Jouppila P, Rasanen J, Alahuhta S, Jouppila R. Vasoactive drugs in obstetrics: a review of data obtained by Doppler and color Doppler methods. Hypertens Pregnancy 1995;14:261–75.
34.Easterling TR, Brateng D, Schmucker B, Brown Z, Millard SP. Prevention of preeclampsia: a randomized trial of atenolol in hyperdynamic patients before onset of hypertension. Obstet Gynecol 1999;93:725–33.
35.Easterling TR, Carr DB, Brateng D, Diederichs C, Schmucker B. Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth. Obstet Gynecol 2001;98:427–33.
36.Al Kasab SM, Sabag T, Al Zaibag M, Awaad M, Al Bitar I, Halim MA, Abdullah MA, Shahed M, Rajendran V, Sawyer W. β-Adrenergic receptor blockade in the management of pregnant women with mitral stenosis. Am J Obstet Gynecol 1990;163:37–40.
37.Soderlin MK, Purhonen S, Haring P, Hietakorpi S, Koski E, Nuutinen LS. Myocardial infarction in a parturient. Anaesthesia 1994;49:870–2.
38.Lubbe WF. More on beta-blockers in pregnancy. N Engl J Med 1982; 307:753.
39.Knott PD, Thorpe SS, Lamont CA. Congenital renal dysgenesis possibly due to Captopril. Lancet 1989;1:451.
40.Mehta N, Modi N. ACE inhibitors in pregnancy. Lancet 1989;2:96.
41.Smith AM. Are ACE inhibitors safe in pregnancy? Lancet 1989;2:750–1.
42.Briggs GG, Nageotte MP. Fatal fetal outcome with the combined use of valsartan and atenolol. Ann Pharmacother 2001;35:859–61.
43.Ingemarsson I, Liedholm H, Montan S, Westgren M, Melander A. Fetal heart rate during treatment of maternal hypertension with beta-adrenergic antagonists. Acta Obstet Gynecol Scand 1984;118(Suppl):95–7.
44.Rubin PC, Butters L, Clark D, Sumner D, Belfield A, Pledger D, Low RAL, Reid JL. Obstetric aspects of the use in pregnancy-associated hypertension of the B-adrenoceptor antagonist atenolol. Am J Obstet Gynecol 1984;150:389–92.
45.Bakri YN, Ingemansson SE, Ali A, Parikh S. Pheochromocytoma and pregnancy: report of three cases. Acta Obstet Gynecol Scand 1992;71:301–4.
46.Pickrell MD, Sawers R, Michael J. Pregnancy after renal transplantation: severe intrauterine growth retardation during treatment with cyclosporin A. BMJ 1988;296:825.
47.Tabacova SA, Kimmel CA. Atenolol: pharmacokinetic/dynamic aspects of comparative developmental toxicity. Reprod Toxicol 2002;16:1–7.
48.Sibai BM. Chronic hypertension in pregnancy. In reply. Obstet Gynecol 2002;100:1358–9.
49.Reynolds B, Butters L, Evans J, Adams T, Rubin PC. First year of life after the use of atenolol in pregnancy associated hypertension. Arch Dis Child 1984;59:1061–3.
50.Liedholm H, Melander A, Bitzen PO, Helm G, Lonnerholm G, Mattiasson I, Nilsson B, Wahlin-Boll E. Accumulation of atenolol and metoprolol in human breast milk. Eur J Clin Pharmacol 1981;20:229–31.
51.Kulas J, Lunell NO, Rosing U, Steen B, Rane A. Atenolol and metoprolol. A comparison of their excretion into human breast milk. Acta Obstet Gynecol Scand 1984;118(Suppl):65–9.
52.White WB, Andreoli JW, Wong SH, Cohn RD. Atenolol in human plasma and breast milk. Obstet Gynecol 1984;63:42S–4S.
53.White WB. Management of hypertension during lactation. Hypertension 1984;6:297–300.
54.Schmimmel MS, Eidelman AJ, Wilschanski MA, Shaw D Jr, Ogilvie RJ, Koren G. Toxic effects of atenolol consumed during breast feeding. J Pediatr 1989;114:476–8.
55.Diamond JM. Toxic effects of atenolol consumed during breast feeding. J Pediatr 1989;115:336.
56.Koren G. Toxic effects of atenolol consumed during breast feeding. J Pediatr 1989;115:336–7.
57.Anderson PO. Drugs and breast milk. Pediatrics 1995;95:957.
58.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.