Roberts et al.

New perspectives of endothelial cell function and

reinterpretation of previously available information

clearly indicate that preeclampsia is more than

pregnancy-induced hypertension. Unifying hypotheses

that take into account the multiplicity of physiologic

abnormalities associated with the preeclamptic syn­

drome are likely to lead to clarification and improved

treatment of this complex disease process.

REFERENCES

I. Chesley LC. Hypertensive disorders in pregnancy. New York: Appleton-Century-Crofts, 1978.

2. Roberts JM. Pregnancy related hypertension. In: Creasy RK, Resnik R, eds. Maternal fetal medicine: principles and practice. Philadelphia: WB Saunders, 1989.

3. Redman CWG. Beilin LJ, Bonnar J. Wilkinson RH. Plasma-urate measurements in predicting fetal death in hypertensive pregnancy. Lancet 1976; I : 1370-3.

4. Zuspan FP. Problems encountered in the treatment of pregnancy-induced hypertension . AM J OBSTET GVNECOL 1978;131 :591-7.

5. Jaffe EA. Cell biology of endothelial cells. Hum Pathol 1987;18:234-9.

6. Vanhoutte PM, Rubanyi GM, Miller VM. Houston DS. Modulation of vascular smooth muscle contraction by the endothelium. Ann Rev Physiol 1986;48:307-20.

7. Yanagisawa M, Kurihara H, Kimura S, et al. A novel po­lent vasoconstrictor peptide produced by vascular endo­thelial cells. Nature 1988;332:411-5.

November 1989 Am J Obstet Gynecol

8. Rodgers GM. Hemostatic properties of normal and per­tubed vascular cells. FASEB J 1988;2: 116-23.

9. Campbell DM, Campbell AJ. Evans blue disappearance rate in normal and preeclamptic pregnancy. Clin Exp Hy­pertens 1983;2:163-9.

10. Musci JM, Roberts JM, Rodgers GM, Taylor RN. Mito­genic activity is increased in the sera of preeclamptic women prior to delivery. AM J OBSTET GYNECOL 1988; 159: 1446-51.

II. Tulenko T, Schneider J, Floro C, Sicilla M. The in vitro effect on arterial wall function of serum from patients with pregnancy-induced hypertension. AM J OBSTET Gv­NECOL 1987;156:817-23.

12. Rodgers GM, Taylor RN, Roberts JM. The pregnancy disorder, preeclampsia, is associated with a serum factor cytotoxic to human endothelial cells. AM J OBSTET Gy­NECOL 1988;159:908-14.

13. Robertson WB, Khong TY, Brosens I, Wolf FD, Sheppard BL, Bonnar J. The placental bed biopsy: review from three European centers. AM J OBSTET GYNECOL 1986; 155:401-12.

14. Brownlee M, Cerami A, Vlassara H. Advanced glycosy­lation end products in tissue and the biochemical basis of diabetic complications. N EnglJ Med 1988;318:1315-21.

15. Rappaport V, Hirata G, Yap HK, Jordan SC. Anti­vascular endothelial cell antibodies in severe preeclamp­sia. AM J OBSTET GYNECOL 1990; 162 [In press].

16. Hubel CA, Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Me Laughlin MK. Lipid peroxidation in pregnancy: new perspectives on preeclampsia. AM J OBSTET GYNECOL 1989; 161: 1025-34.

A complete lzst of references zs available from the authors on request.

Antagonism of antihypertensive drug therapy in pregnancy by indomethacin?

A. Schoenfeld, MD, S. Freedman, MD, M. Hod, MD, and Y. Ovadia, MD

Petak Tikva, Israel

Two women with preeclampsia treated with pindolol and propranolol became profoundly hypertensive when indomethacin was added because of premature contractions. The interaction of nonsteroidal antiinflammatory agents and j3-blockers and their role in the control of blood pressure in obstetrics are discussed. Indomethacin should not be given to pregnant patients with hypertension treated with

j3-blockers. (AM J OesTET GVNECOL 1989;161 :1204-5.)

Key words: Preeclampsia, antihypertensive drugs, indomethacin, drug interaction

The [3-adrenergic receptor-blocking agents (pro­

pranolol, pindolol, and others) are those most used,'

and experience has shown that the fetal and neonatal

effects have been minimal and that benefits outweigh

risks .

From the Pennatal Diviswn. Department of Obstetncs and Gynecol­ogy, Beillnson Medical Center, TelAviv Universi(vMedlcal School.

Received for pubhcation June 21 , 1989; accepted August 1, 1989. R epnnt requests: Dr. Alex Schoenfeld, Department of Obstetncs and

Gynecology, BezlinsonMedical Center, 49100 Petah Tzkva, Israel. 6/1 /15875

1204

[3-Blockers lower systemic blood pressure but their

mechanism of action has not been established. Negative

cardiac chronotropic and inotropic effects, anti renin

effects. and central nervous system effects may all con­

tribute to their hypotensive action in man. Durao et aJ.2

proposed that [3-receptor blockade may stimulate for­

mation of prostaglandins, since indomethacin, a potent

inhibitor of prostaglandin synthesis, can attenuate the

hypotensive effects of long-term propranolol and pin­

dolol treatment in man. 3

We report two cases of women with preeclampsia

Volume 161 Number 5

treated with propranolol and pindolol who showed an exaggerated hypertensive response when treated with indomethacin because of premature contractions.

Case reports Case 1. A 26-year-old woman, gravida 2, para 1, had

a history of labile hypertension of 6 years' duration. She had developed preeclampsia in her first preg­nancy, which ended with delivery of a severely growth­retarded infant at 37 weeks. In this pregnancy hyper­tension developed at week 28. She was admitted at week 30 with headache, hyperreflexia, and generalized edema. Blood pressure was 1401110 mm Hg with a regular pulse of 75 beats/min. Results of ophthalmo­scopic examination were normal. Laboratory findings showed the following: hematocrit level 45%, uremia 37 mg/dl, serum creatinine level 0.83 mg/dl, uric acid level 8.5 mg/dl, serum potassium level 4.3 mEq/L, platelet count 270 X 103 /mm" and urinary protein level 16 gm/24 hr. She was treated with propranolol 80 mg/dl with good response (blood pressure 135/85 mm Hg) for 2 weeks. At 32 weeks, because of pre­mature contractions, indomethacin, initial dose of two 100 mg suppositories and then 25 mg capsules daily, was added for a period of 3 days. On day 4 a marked elevation of blood pressure (240/140 mm Hg) occurred with cardiotocographic changes in fetal vitality. A ce­sarean section was performed, and the severely re­tarded newborn died 72 hours later. Postpartum blood pressure was 135/90 mm Hg.

Case 2. A 20-year-old primigravid patient had an uncomplicated pregnancy until 31 weeks' gestation, when she developed frontal headaches, blurred vision, and generalized edema. On admission, she had a blood pressure of 1501100 mm Hg, heart rate 80 beats/min, proteinuria (3 +), and urine specific gravity l.026. Ophthalmoscopic examination revealed a grade 1 hy­pertensive retinopathy. Laboratory findings showed the following: hematocrit level 45%, uremia 38 mg/dl, se­rum creatinine level 0.85 mg/dl, serum uric acid level 8.6 mg/dl, serum potassium level 4.0 mEq/L, plate­let count 230 X lO'l/mm'. She was treated with pin­dolol 15 mg/day with good response (blood pressure 130/70 mm Hg) for 2 weeks. At 33 weeks, because of premature contractions, indomethacin, loading dose of 100 mg x 2 and then 25 mg daily, was given for a

[3-Blockers, indomethacin, and pregnancy 1205

period of 5 days. On day 5 a sudden rise in blood pressure (230/130 mm Hg) occurred with cardia to­co graphic changes in fetal vitality, A cesarean sec­tion was performed, and the low-weight neonate sur­vived. Postpartum blood pressure returned to normal (125/85 mm Hg).

Comment

This remarkable hypertensive response to indo­methacin in two patients (receiving two different 13-blockers) pushed these patients to the brink of disaster. It illustrates that indomethacin (and other) nonsteroi­dal antiinflammatory drugs vitiate the action of anti­hypertensive drugs and that in some patients the hy­pertensive response may be severe. The mechanism of this phenomenon is not known. That such an elevation in blood pressure occurs despite the reduction in renin release known to result from indomethacin emphasizes the pathophysiologic complexity that results in this ef­fect. Possible explanations include, but are not limited to, retention of sodium, removal of tonic vasodilation produced by prostaglandin, and alteration of adre­nergic neurotransmission. Hypertensive responses to

indomethacin have been reported after 10 days of treat­ment," but we believe that ours are the first reported in obstetrics after a short course of treatment of only 3 to 5 days. It is possible that the pathophysiologic characteristics of pregnancy-induced hypertension are responsible for this time difference in onset.

Because the use of indomethacin and f3-blockers is still frequent, we suggest that obstetricians be aware of the possibility of a sudden exaggerated hypertensive response to this combination of drugs.

REFERENCES

1. Lubbe WF. Hypertension in pregnancy: whom and how to treat. Br J Clin Pharmacol 1987;24:155.

2. Durao V, Martins PM, Goncalves LMP. Modification of an­tihypertensive effect of [3-adrenoceptor-blocking agents by inhibition of endogenous prostaglandin synthesis. Lancet 1977;2:1005-7.

3. Oates JA. Antagonism of antihypertensive drug therapy by nonsteroidal anti-inflammatory drugs. Hypertension 1988; II(II):4-6.