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Atenolol and short umbilical cords
Atenolol and short umbilical cords Vern Katz, M.D., George Blanchard, B.A., Cathy Dingman, M.D., Watson A. Bowes, Jr., M.D., and Robert C. Cefalo, M.D., Ph.D. Chapel Hill, North Carolina Umbilical cord length may be a function of fetal movement. Agents that cause decreased fetal movement may cause short umbilical cords. This investigation examined the effect of the l3-blocker atenolol on umbilical cord length in rabbits. Fetuses of rabbits treated with atenolol had significantly shorter cords than control animals (p ,,;; 0.0005). Since short cords are associated with problems in labor, low Apgar scores, and abruption, we recommend careful surveillance of mothers and fetuses who are given l3-blocking agents in the first 30 weeks of pregnancy. (AM J OasTET GVNECOL 1987;156:1271-2.)
Key words:
~-blockers,
umbilical cord length
Short umbilical cords may be associated with problems in labor, low Apgar scotes, neonatal problems, and psychomotor and neurologic abnormalities. I. 2 Whether these perinatal complications are caused by short cords or merely an association of other obstetric problems resulting from a common cause is unclear. One cause of short cords, however, is believed to be related to decreased movement in utero. s Experiments in animals and case reports in humans suggest that the tensile forces exerted by fetal movement induce cord growth.2-5 Recently, a 31-year-old multigravida patient who had been treated with atenolol for maternal superventricular tachycardia for 20 weeks was delivered of an infant with a cord less than 25 cm at 38 weeks. In retrospect, she informed us that the infant moved very little during the pregnancy. One of the side effects of the use of ~-blockers is a feeling of lethargy, sluggishness, and fatigue. 6 Because of the possible correlation of ~-blockers and decreased fetal movement, the relationship between ~-blockers and short umbilical cords was investigated.
Material and methods Ten healthy adult New Zealand white rabbit does were mated at day O. Normal gestational period is 28 to 30 days. The animals were given unrestricted amounts of rabbit food and water. All procedures and care followed the guidelines of the University Animal Care and Use Committee in compliance with National Institute of Health guidelines for animal research. Six rabbits were given an intraperitoneal injection of 1 mg
From the Department of Obstetrics and Gynecology, University of North Carolina School of Medicine. Received for publication May 28, 1986; revised September 4, 1986; accepted December 24, 1986. Reprint requests: Vern Katz, M.D., Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC 27514.
of atenolol suspended in 2 ml of sterile saline solutiori from day 7 through day 25. This dose was chosen to correspond approximately to the usual human adult dose of 0.7 mg/kg. The six rabbits were then giveh 2 mg of atenolol in 2 ml of sterile saline solution from day 16 through day 24. The increased dose was used to compensate for the increasing weights of the pregnant rabbits. On day 26 the rabbits were killed with intravenous injections of sodium pentothal. The uteri and their contents were then examined immediately after maternal death. The litter sizes were counted, and the placentas and fetuses were weighed separately. Umbilical cord lengths were measured from abdominal insertion to placental insertion. Four rabbits served as control animals. The same procedures were followed with control rabbits except that sterile saline solution without atenolol was injected intraperitoneally. Statistical analysis was performed with the unpaired Student t test.
Results Two rabbits, one from each group, were not pregnant. Another rabbit from the atenolol-treated group died of a respiratory infection on day 9. Thus the total number of pregnant rabbits successfully completing the study was four atenolol-treated animals and three control animals. Twenty-eight fetuses were from the control group and 27 fetuses were from the atenololtreated group. The behavior and the eating habits of the rabbits were the same from both groups. The results are shown in Table I. The mean litter sizes were 9.3 for the control group and 6.7 for the atenolol-treated rabbits. The significance of this difference was not assessed because of the small sample size (three and four rabbits). Assessment of mean fetal body weight showed that the atenolol-treated fetuses were not significantly different (16.3 versus 15.4 gm). The placentas of the atenolol-treated fetuses were heavier (4.73 versus 3.97 gm, p,,;; 0.02). The mean length 1271
1272 Katz et al.
May 1987 Am J Obstet Gynecol
Table I. Results in control and atenolol-treated rabbits Rabbits
Control Atenolol
Fetuses
Mean litter size
Mean fetal body weight (gm)
Mean placental weight (gm)
Mean cord length (em)
28 27
9.3 6.7
16.3 ± 3.4 15.4 ± 6.4 NS
3.97 ± 1.1 4.73 ± 1.4 P"" 0.02
3.08 ± 0.38 2.37 ± 0.76 P "" 0.0005
Significance
of the umbilical cords of the atenolol-treated fetuses were 77% of the control animals (3.08 versus 2.37 cm, p ~ 0.0005). The fetuses of one of the atenolol-treated rabbits were extremely growth retarded with a mean weight of 6.0 gm. Although the placentas of these fetuses had normal weights, the cord lengths were very short with a mean length of 1.3 cm. After the data from this rabbit were excluded from that of the three other atenololtreated rabbits, the mean length of the umbilical cords was 2.76 cm ± 0.38, which is still significantly less that that of the control animals (3.08 cm, p ~ 0.005). However, the mean weights of the atenolol-treated fetuses, excluding the growth-retarded litter, was 18.6 ± 2.6 gm (p ~ 0.01), which was significantly larger than the control fetuses.
be much less affected by administration of l3-blockers during the third trimester than if the drugs are administered earlier in pregnancy. Short umbilical cords are associated with conditions of decreased fetal movement in utero, such as oligohydramnios, uterine malformations, and limb dysfunctions. I .' Whether the short umbilical cord is a cause or an effect of decreased fetal movement is presently unknown. One of the side effects of the use of l3-blocking agents is lethargy, malaise, and a sense of depression. 6 Short cords also may cause labor complications such as abruptio placenta, fetal heart rate abnormalities, and inadequate descent.1. 2 Since this experiment suggests a relationship between decreased cord length and the l3-blocker atenolol, We recommend careful surveillance of mothers and fetuses when such drugs are used in early pregnancy.
Comment This investigation suggests that the l3-blocker aten0101 is associated with decreased umbilical cord length in our animal species. This experiment does not delineate the mechanism of this effect. However, the basis for the shorter cord lengths does not seem to be through growth retardation, since both fetal weight and placental weight were the same or larger in treated rabbits. Little is written on the use of l3-blockers throughout pregnancy, although large numbers of patients have been treated for hypertension in the late third trimester with these agents. Naeye" suggests that the length of the umbilical cord is established by 28 weeks. After 28 weeks, umbilical cord growth slows. From 34 weeks on, the cord grows less than 10%. Thus cord length may
REFERENCES 1. Rayburn WF, Beynen A, Brinkman DC. Umbilical cord length and intrapartum complications. Obstet Gynecol 1981;57:450. 2. Naeye RL. Umbilical cord length: clinical significance. J Pediatr 1985;107:278. 3. Miller ME, Higginbottom M, Smith DW. Short umbilical cord: its origin and relevance. Pediatrics 1981;67:618. 4. Moessinger AC, Blanc WA, Marone PA, Polsen DC. Umbilical cord length as an index of fetal activity: experimental study and clinical implications. Pediatr Res 1982;16:109. 5. Shenker L, Reed K, Anderson C, et al. Syndrome of camptodactyly, ankyloses, facial anomalies, and pulmonary hypoplasia (Pena-Shokeir syndrome): obstetric and ultrasound aspects. AM J OSSTET GYNECOL 1985;152:303. 6. Goodman LS, Gillman A, eds. The pharmacological basis of therapeutics. 5th Ed. New York: MacMillan Publishing Co, Inc, 1975:552.
Key words:
~-blockers,
umbilical cord length
Short umbilical cords may be associated with problems in labor, low Apgar scotes, neonatal problems, and psychomotor and neurologic abnormalities. I. 2 Whether these perinatal complications are caused by short cords or merely an association of other obstetric problems resulting from a common cause is unclear. One cause of short cords, however, is believed to be related to decreased movement in utero. s Experiments in animals and case reports in humans suggest that the tensile forces exerted by fetal movement induce cord growth.2-5 Recently, a 31-year-old multigravida patient who had been treated with atenolol for maternal superventricular tachycardia for 20 weeks was delivered of an infant with a cord less than 25 cm at 38 weeks. In retrospect, she informed us that the infant moved very little during the pregnancy. One of the side effects of the use of ~-blockers is a feeling of lethargy, sluggishness, and fatigue. 6 Because of the possible correlation of ~-blockers and decreased fetal movement, the relationship between ~-blockers and short umbilical cords was investigated.
Material and methods Ten healthy adult New Zealand white rabbit does were mated at day O. Normal gestational period is 28 to 30 days. The animals were given unrestricted amounts of rabbit food and water. All procedures and care followed the guidelines of the University Animal Care and Use Committee in compliance with National Institute of Health guidelines for animal research. Six rabbits were given an intraperitoneal injection of 1 mg
From the Department of Obstetrics and Gynecology, University of North Carolina School of Medicine. Received for publication May 28, 1986; revised September 4, 1986; accepted December 24, 1986. Reprint requests: Vern Katz, M.D., Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC 27514.
of atenolol suspended in 2 ml of sterile saline solutiori from day 7 through day 25. This dose was chosen to correspond approximately to the usual human adult dose of 0.7 mg/kg. The six rabbits were then giveh 2 mg of atenolol in 2 ml of sterile saline solution from day 16 through day 24. The increased dose was used to compensate for the increasing weights of the pregnant rabbits. On day 26 the rabbits were killed with intravenous injections of sodium pentothal. The uteri and their contents were then examined immediately after maternal death. The litter sizes were counted, and the placentas and fetuses were weighed separately. Umbilical cord lengths were measured from abdominal insertion to placental insertion. Four rabbits served as control animals. The same procedures were followed with control rabbits except that sterile saline solution without atenolol was injected intraperitoneally. Statistical analysis was performed with the unpaired Student t test.
Results Two rabbits, one from each group, were not pregnant. Another rabbit from the atenolol-treated group died of a respiratory infection on day 9. Thus the total number of pregnant rabbits successfully completing the study was four atenolol-treated animals and three control animals. Twenty-eight fetuses were from the control group and 27 fetuses were from the atenololtreated group. The behavior and the eating habits of the rabbits were the same from both groups. The results are shown in Table I. The mean litter sizes were 9.3 for the control group and 6.7 for the atenolol-treated rabbits. The significance of this difference was not assessed because of the small sample size (three and four rabbits). Assessment of mean fetal body weight showed that the atenolol-treated fetuses were not significantly different (16.3 versus 15.4 gm). The placentas of the atenolol-treated fetuses were heavier (4.73 versus 3.97 gm, p,,;; 0.02). The mean length 1271
1272 Katz et al.
May 1987 Am J Obstet Gynecol
Table I. Results in control and atenolol-treated rabbits Rabbits
Control Atenolol
Fetuses
Mean litter size
Mean fetal body weight (gm)
Mean placental weight (gm)
Mean cord length (em)
28 27
9.3 6.7
16.3 ± 3.4 15.4 ± 6.4 NS
3.97 ± 1.1 4.73 ± 1.4 P"" 0.02
3.08 ± 0.38 2.37 ± 0.76 P "" 0.0005
Significance
of the umbilical cords of the atenolol-treated fetuses were 77% of the control animals (3.08 versus 2.37 cm, p ~ 0.0005). The fetuses of one of the atenolol-treated rabbits were extremely growth retarded with a mean weight of 6.0 gm. Although the placentas of these fetuses had normal weights, the cord lengths were very short with a mean length of 1.3 cm. After the data from this rabbit were excluded from that of the three other atenololtreated rabbits, the mean length of the umbilical cords was 2.76 cm ± 0.38, which is still significantly less that that of the control animals (3.08 cm, p ~ 0.005). However, the mean weights of the atenolol-treated fetuses, excluding the growth-retarded litter, was 18.6 ± 2.6 gm (p ~ 0.01), which was significantly larger than the control fetuses.
be much less affected by administration of l3-blockers during the third trimester than if the drugs are administered earlier in pregnancy. Short umbilical cords are associated with conditions of decreased fetal movement in utero, such as oligohydramnios, uterine malformations, and limb dysfunctions. I .' Whether the short umbilical cord is a cause or an effect of decreased fetal movement is presently unknown. One of the side effects of the use of l3-blocking agents is lethargy, malaise, and a sense of depression. 6 Short cords also may cause labor complications such as abruptio placenta, fetal heart rate abnormalities, and inadequate descent.1. 2 Since this experiment suggests a relationship between decreased cord length and the l3-blocker atenolol, We recommend careful surveillance of mothers and fetuses when such drugs are used in early pregnancy.
Comment This investigation suggests that the l3-blocker aten0101 is associated with decreased umbilical cord length in our animal species. This experiment does not delineate the mechanism of this effect. However, the basis for the shorter cord lengths does not seem to be through growth retardation, since both fetal weight and placental weight were the same or larger in treated rabbits. Little is written on the use of l3-blockers throughout pregnancy, although large numbers of patients have been treated for hypertension in the late third trimester with these agents. Naeye" suggests that the length of the umbilical cord is established by 28 weeks. After 28 weeks, umbilical cord growth slows. From 34 weeks on, the cord grows less than 10%. Thus cord length may
REFERENCES 1. Rayburn WF, Beynen A, Brinkman DC. Umbilical cord length and intrapartum complications. Obstet Gynecol 1981;57:450. 2. Naeye RL. Umbilical cord length: clinical significance. J Pediatr 1985;107:278. 3. Miller ME, Higginbottom M, Smith DW. Short umbilical cord: its origin and relevance. Pediatrics 1981;67:618. 4. Moessinger AC, Blanc WA, Marone PA, Polsen DC. Umbilical cord length as an index of fetal activity: experimental study and clinical implications. Pediatr Res 1982;16:109. 5. Shenker L, Reed K, Anderson C, et al. Syndrome of camptodactyly, ankyloses, facial anomalies, and pulmonary hypoplasia (Pena-Shokeir syndrome): obstetric and ultrasound aspects. AM J OSSTET GYNECOL 1985;152:303. 6. Goodman LS, Gillman A, eds. The pharmacological basis of therapeutics. 5th Ed. New York: MacMillan Publishing Co, Inc, 1975:552.