- Email: [email protected]
Treatment of preeclampsia with prostaglandin A1
Carleton, Forsythe, and Flores
5. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hypertension in pregnancy: Clinical-pathological correlations and remote prognosis. Medicine 1981;60:;267-76. 6. Surian M, lmbasciat E, Barbiano di Belgiososa G, Brancaccio D, Minelli L, Ponticelli C. Glomerular disease and pregnancy. Nephron 1984;36; 101-5.
July 1988 Am J Obstet Gynecol
7. Kida H, Takeda S, Yokoyama HL, Tomosugi N, Abe T, Hattori N. Focal glomerular sclerosis in pre-eclampsia. Clin Nephrol l 985;24:221-7.
Treatment of preeclampsia with prostaglandin A1 Mokhtar K. Toppozada, MD, Ahmed A. A. Ismail, MD, Hassan M. Hegab, MS, and Mostafa A. Kamel, MD Alexandria, Egypt The vasodepressor prostaglandin A, appeared to offer a major clinical potential solution in cases of severe pregnancy-induced hypertension. Thirty pregnant women with severe pregnancy-induced hypertension and a low Bishop score were studied in three equal groups. Group 1 received prostaglandin A, infusions alone (0.5 µ.g/kg/min for a maximum of 24 hours). Group 2 had received initial priming by prostaglandin E2 vaginal gel 6 hours before the onset of the prostaglandin A, infusion, and group 3 was treated by conventional therapy and oxytocin induction. In the first two groups blood pressure was reduced to normotensive values, and labor was induced satisfactorily in 15 of the 20 cases, but four patients in group 1 were delivered within 24 hours after infusion. Group 2 offered the most favorable results because 80% were delivered during the infusion; thus the postinfusion rebound rise in blood pressure was avoided. Group 3 presented the least acceptable results, with the highest failure rate and an increased number of operative deliveries. (AM J 0BSTET GYNECOL 1988;159:160-5.)
Key words: Severe preeclampsia, prostaglandin A 1, induction of labor
Severe preeclampsia represents a serious health hazard and creates a situation of high risk to both mother and fetus. As long as the exact causes remain unknown, therapy continues to be directed toward the main triad of manifestations, edema, hypertension, and albuminuria, as well as toward the prevention of complications. Bed rest, hypotensive agents, sedatives, and magnesium sulfate are the principal agents used to control pregnancy-induced hypertension. u However, most patients with severe pregnancy-induced hypertension should be delivered electively because it is usually too dangerous to await spontaneous labor. Successful medical induction of labor would avoid the possible dangers of cesarean section in these serious cases. The pathogenesis of pregnancy-induced hypertension appears to involve a true or a relative deficiency state of vasodepressor, anti-platelet-aggregator prostaglandins (PCs)." Therefore replacement therapy to compensate for the deficiency can serve as a direct ap-
From the Department of Obstetrics and Gynecology, University of Alexandria. Received for publication April 23, 1987; revised November 13, 1987; accepted December 15, 1987. Reprint requests: Professor M. K. Toppouula, MD, Shatby University Hospital, Shatby, Alexandria, Egypt.
160
proach to rectifying the impaired balance in prostanoid release. The E series of PCs seemed to be unsuitable for this role because of the high ratio of uterine stimulation to vasodepressor properties; i.e., vasodepressor doses will induce severe uterine hyperstimulation. On the other hand, the A series showed a favorable ratio in this respect, i.e., weak uterine stimulation and a strong hypotensive effect. Moreover, initial studies demonstrated that treatment' with PCA 1 could also markedly improve renal function.'· 5 PCA1 was infused in cases of severe preeclampsia at different dose levels for various time periods, and the renal, circulatory, oxytocic, and obstetric effects were evaluated. The results indicated that the optimal dose was 0.5 µg/kg/min and that a continuous infusion for up to 24 hours appeared to offer the most acceptable results. 6 However, as most of the treated subjects were in early labor or in prelabor, the actual labor-inducing capability of this agent was not fully evaluated. Accordingly, the present study was planned with the primary objective being to evaluate the use of PCA, infusion alone or combined with the initial ripening of the cervix in the treatment of women with severe preeclampsia and unripe cervices. A comparison with conventional therapy plus oxytocin induction was also an integral part of the planned investigation.
Treatment of preeclampsia with PGA,
Volume 159 Number I
161
Blood pressure
mm Hg 200
PGA 1 infusion
175
150 125
Systolic
100 75
Dlastolic
01,---~---"T~~"-"T"""~~--.-~~..,.-~~..--~---. 0
6
12
18 Hours
24
30
36
Fig. I. Mean of systolic and diastolic blood pressures before, during, and after prostaglandin infusion in group I. The data of group 2 were almost identical to those of group I.
Material and methods
The study included 30 pregnant women who were not in labor, who had an unripe cervix (Bishop score <5), and who had severe preeclampsia (blood pressure ;;,,, 160/ 110 mm Hg, albuminuria, and edema). All patients were ;;,,,34 weeks' gestation, with a parity range of 0 to 5 and no contraindications to the induction of labor or the use of prostaglandins. An informed consent was obtained from all patients. Group 1: PGA, alone. Ten patients received a continuous intravenous infusion of PGA, (0.5 µg/kg/min until delivery or to a maximum duration of 24 hours). (The PGA, was kindly supplied as a sterile solution containing 30 mg of PGA, in 3 ml per ampule by Professor S. Bergstrom, Karolinska Institute, Stockholm, Sweden.) Group 2: Vaginal PGE, gel and PGA,. Ten patients received 3 mg of PGE 2 (The C pjohn Co., Ltd., Crawley, England) suspended in a viscous gel of 5 ml tylose introduced intravaginally as far as the fornices by a polyethylene catheter; then 6 hours later they received PGA, infusion in the same dose and duration as in group I. Group 3: Conventional therapy and oxytocin induction. Ten patients received treatment for severe preeclampsia in the form of bed rest, sedation (diazepam, 5 mg tablets three times a day), magnesium sulfate (modified Pritchard regimen, 4 gm in 20% solution given slowly intravenously, then 5 gm of 50% solution intramuscularly every 4 hours"), hypotensives (methyldopa, 250 mg tablets three times a day), and hypertonic glucose given by intravenous infusion (250 ml of
Table I. Clinical data (mean ± SD) of subjects in the different groups at admission
Age (yr) Parity Duration of pregnancy (wk) Weight (kg)
Group I
Group 2
Group 3
(n = 10)
(n = JO)
(n = 10)
29.2 ± 2.9 0.8 ± 0.9 38.4 ± 2.45
28.8 ± 4.9 I. I ± 1.4 38.l ± 2.9
28.7±5.18 0.9 ± 1.4 38.l ± 2.0
84.6 ± 7.4
83.3 ± 7.7
85.4 ± 8.9
25% solution every 12 hours). Two days later, simultaneous amniotomy and continuous oxytocin (Syntocinon, Sandoz Pharmaceutical Co., Switzerland) infusion was started until the patient was delivered of her infant or to a maximum of 24 hours by the oxytocin titration method. Fetal heart rate and uterine activity were monitored in all patients by the Fetasonde SA machine (Roche Electronics, Everett, Me.) with external methods. Blood pressure and pulse rate were monitored continuously by a Dinamap vital signs monitor (Critikon Inc., Tampa, Fla.) up to 12 hours after the induction trial. The PGA, infusion (0.5 µg/kg/min) or dose of oxytocin was controlled by an I vac 231 infusion controller (I vac House, Harrow, Middlesex, United Kingdom). The progress of labor was monitored closely, and assessment of the newborn infants with Apgar scores was performed. Side effects during treatment were carefully recorded. Potentially serious side effects caused by PGA, are rare"; if they do develop, temporary
162 Toppozada et al.
July 1988 Am J Obstet Gynecol
Blood pressure mm Hg 200
I.
~r~~~~-
Oxytocin infusion
··.......... 175 Systolic
150
125
·········...
···------~---------Diastolic
100
J~~--,-~-,--~~r----.-----. -48
0
6
12
18
24
30
36
Hours
Fig. 2. Mean of systolic and diastolic blood pressures during the 48 hours of conventional therapy (dotted lines) during the 24 hours of oxytocin induction and in the postinfusion follow-up phase of
12 hours in group 3.
short-term cessation or dose reduction of the infusion is advisable.
Results The clinical data of the subjects in the different groups at admission to the study are shown in Table I. The numbers of primigravid women in the different groups were four, five, and five, respectively. Effect of treatment on blood pressure. In groups l and 2 in which PGA, was infused, both systolic and diastolic blood pressure dropped gradually in all patients, except for the systolic pressure in one patient in group I who proved to have essential hypertension. A much lower reduction in blood pressure was noted in group 3 during the 48-hour phase of medical treatment than during PGA, infusion in the first two groups (Table II). During the PGA, infusion period in groups l and 2, the systolic and diastolic blood pressure reached the lowest level between 8 and 23 hours from the onset of infusion. The means of the lowest blood pressure readings (reached at various time intervals in different subjects) were 122.7/70.3 and 119.5/69.4 mm Hg, respectively (Fig. 1). When compared with the admission values, the decrease was highly significant (p < 0.001) (Table II). After the infusion was stopped, there was a slight, gradual rise in systolic and diastolic blood pressure that reached a mean maximum of 134.6/79.8 and 137.5/81.9 mm Hg for groups l and 2, respectively (Fig. 1). This rise was not statistically significant (p > 0.05), except for the systolic blood pressure in group 2 (p < 0.05). However, the rebound rise in blood pressure in undelivered patients was much more than
in the successful cases, but the rise did not exceed preinfusion levels. In patients with PGE 2 gel applied vaginally 6 hours before the infusion (group 2), no changes in blood pressure were observed during the cervical ripening phase (p > 0.05). In group 3 (treated with conventional therapy for 2 days, then with oxytocin induction), the lowest mean reading of systolic blood pressure was 166.4 ± 12.9 mm Hg, which was not significantly different from the pretreatment value (p > 0.05) (Fig. 2). However, the mean diastolic blood pressure reached a minimum of 108.6 ± 7.1 mm Hg, which was significantly lower than the pretreatment value (p < 0.01) (Fig. 2). The mean arterial blood pressure decreased significantly during infusion in patients of the first two groups from admission values of 139.7 and 143.3 mm Hg to minimum levels during PGA, infusion of 88.3 and 85.7 mm Hg, respectively (p < 0.001) (Fig. 3). The initial mean arterial blood pressure in group 3 was 142.0 mm Hg; it dropped during the 48-hour phase of medical treatment and reached a minimum of 127.3 mm Hg (p < 0.0 l ). During the phase of treatment in all groups the pulse rates increased significantly by mean values of 10.6, 8.1, and 3.0 beats/min, respectively (p < 0.05). Obstetric course and outcome. In group 2, in which vaginal PGE, was used to ripen the cervix, the Bishop score increased 6 hours after the gel application from an initial figure of 2.6 to 6.0 (p < 0.01 ). The trial was successful if vaginal delivery occurred within the infusion phase of 24 hours. In this respect the trial was successful in three, eight, and three patients in the three groups studied (30%, 80%, and 30%, respectively). However, in four patients in group 1 and one patient
Volume 159 Number I
Treatment of preeclampsia with PGA,
Table II. Maximum reductions (mean ± SD) in systolic and diastolic blood pressures in the three groups during treatment
Group I (n = 10) Group 2 (n = 10) Group 3 (n = 10)
Svsto/ic bl
DirL1tolic blood pressure
(mm Hg)
(mm Hg)
62.4 ± 25.24* 70.2 ± 19.27* 18.2 ± 04.10
47.4 ± 12.93* 56.3 ± 15.93* 12.4 ± 06.58t
Before treatment During treatment (minimum)
163
c==J 11'$
*Significant (p < 0.00 I). tSignificant (/J < 0.0 I).
in group 3, spontaneous vaginal delivery occurred within the postinfusion phase of 24 hours. Regardless of success or failure, spontaneous vaginal delivery occurred in all patients in group 1, in nine patients of group 2, and in five patients of group 3. Cesarean section was done in one patient in group 2 because of fetal distress caused by three turns of the umbilical cord around the fetal neck and in three patients of group 3 (two because of failed induction and one because of fetal distress). In two patients in the latter group delivery was assisted by forceps extraction. The mean induction-delivery interval (including the phase of cervical ripening by PGE" in group 2, with failures not included) was 20.9 hours in group 1, 17.4 hours in groups 2, and 22.0 hours in group 3. Abnormal fetal heart rate patterns were observed in two patients in group 1 (one with late decelerations and one with baseline tachycardia), in two patients of group 2 (one with bradycardia and one with tachycardia), and in four patients of group 3 (two with late decelerations, one with bradycardia, and one with variable decelerations). These patterns disappeared spontaneously when the dose was temporarily reduced or the infusion was interrupted. In group 1 (PGA, infusion alone) no abnormal uterine activity was observed, but in group 2 (preinfusion cervical ripening) one patient had hyperstimulation in two instances. In group 3 two patients had uterine hyperactivity; the first had persistent late decelerations that required cesarean section, and the second patient had a temporary phase of variable decelerations in the fetal heart rate. The mean birth weights of all newborn infants were 2.68, 2.65, and 2.62 kg, respectively, for the three groups. The means of the 1- and 5-minute Apgar scores were 8.1 and 9, 7.8 and 10.0, and 6.3 and 9.0, respectively. Only one fetal death occurred in a patient in group I with preeclampsia superimposed on essential hypertension and with severe intrauterine fetal growth retardation. Persistent late declerations were observed and cesarean section was immediately decided on. However, when the infusion was stopped, a marked rebound rise in blood pressure and an eclamptic seizure developed, and fetal heartbeats stopped. The mother was then treated med-
group I
Group II
Group ill
Fig. 3. Changes in the mean arterial blood pressure as a result of treatment in the three groups.
ically, and 8 hours later a stillborn fetus weighing 1.2 kg was spontaneously delivered vaginally. The mean duration of the third stage was within normal limits in all patients. Only one patient in group 3 had atonic postpartum hemorrhage. Follow-up evaluation of the su~jects for I week after delivery showed no fetal or maternal death. Only one patient, the previously mentioned patient with essential hypertension, had persistence of high blood pressure. Nausea, vomiting, diarrhea, and headache constituted the main side effects of PGA, but the symptoms were mild and not serious (three patients in group I and two patients in group 2). Comment
Several hypotheses have emerged in recent years that attempt to explain the pathogenesis of pregnancyinduced hypertension. The available evidence indicates that pregnancy-induced hypertension may be a deficiency disease of vasodepressor anti-plateletaggregating prostanoids, such as PCC or PGD,, or may be caused by the excessive release of vasoactive proaggregating prostanoids (such as thromboxanes) or a combination of both." '·" Correction of the disturbed biochemical parameters may be achieved through the administration of vasodepressor PCs, such as PGA, or prostacyclin, as a direct approach to maintaining a normal vascular homeostasis."· ' 0 · " PCs of the A type were previously believed to serve as possible renal antihypertensive hormones, but later evidence indicated that the measured PGA compounds
164 Toppozada et al.
may represent analytic artifacts.'' Initially, PGA was administered by intravenous infusion to male volunteers for the control of different types of hypertension which confirmed its hypotensive properties and beneficial renal effects.'" The vasodepressor effects are probably achieved through peripheral arteriolar dilatation that is induced by a direct action and does not involve cholinergic, histaminergic, or adrenergic nerve endings.'' The fact that pregnancy-induced hypertension is a temporary form of hypertension made a limited infusion period of PGA, a potentially useful therapeutic measure in this disease. Clinical application confirmed the anticipated hypotensive response and showed further advantages in terms of improved renal function and mild oxytocic properties.,_., Furthermore, the weak anti-platelet aggregation effect of this agent represented another favorable aspect of the compound in patients with severe pregnancy-induced hypertension.1.·. The present study was aimed at answering two specific questions: (I) Does PGA, represent a better therapeutic modality than what is presently used as a nonsurgical line of treatment? (2) Do we need additional cervical ripening by vaginal PGE 2 gel to supplement the weak oxytocic property of PGA,, particularly in patients with unripe cervices? The induction of labor in patients with preeclampsia is clinically indicated when intrauterine fetal existence is attended with certain risks that outweigh those of prematurity or if the toxemic process imposes immediate maternal dangers and does not respond to proper treatmenl. PGA, alone (group I) induced labor in only 30% of patients during the infusion phase of 24 hours, and 40% more were delivered the next day because of the progress of an already initiated labor. In a previous study, the same dose schedule was successful in terminating pregnancy in all cases because the patients were either in early labor or had a farnrable Bishop score compared with scores of unripe cervices in the present study." Accordingly, preinduction cervical ripening by PGE 2 gel appears to be a valuable supplement to the weakly oxytocic PGA, therapy whenever the inducibility score is low. During PGA, infusions the observed fetal heart rate changes were generally of a temporary nature and were within the expected range of occurrence in patients with severe pregnancy-induced hypertension and placental insufficiency.'" Moreover, the fact that the condition of all newborn infants was rather good provides further reassurance concerning the fetal safety of this form of therapy. Concerning the maternal safety, the maintenance of a normotensive blood pressure and the lack of serious side effects during infusion preclude an increased risk during the induction phase. The infrequent and mild side effects observed appear to be ac-
July 1988 Am .J Obstet Gynecol
ceptable in return for the achieved clinical response. Delivery in itself represents an end point of danger in most cases, but postpartum continuation of the infusions for several hours may prove to be beneficial in the event of the rare development of postpartum eclampsia. Group 3, with oxytocin induction, presented the least favorable results and the highest rate of failure, the longest induction-delivery interval, and an increased incidence of operative delivery despite the higher initial Bishop score. Also, oxytocin did not offer an effective hypotensive response and was associated with more serious fetal heart rate patterns. Moreover, the potential hazards of oxytocin infusion for prolonged periods in pregnancy-induced hypertension represent an additional drawback. From the data obtained from the present study and from previous experience with PGA, infusion in patients with pregnancy induced hypertension, it can be concluded that this prostaglandin offers a new and useful modality in the management of pregnancy induced hypertension. Blood pressure is reduced and maintained at normotensive levels, renal function is improved, and labor is induced with a relatively safe approach for both mother and fetus. Whenever the cervix is unripe, additional priming with PGE 2 gel is indicated. We wish to acknowledge the continuous encouragement and support we received from Professor Sune Bergstrom, the Karolinska Institute, Stockholm, Sweden. REFERENCES I. Wood SM. Drugs in the treatment of hypertension in pregnancy. In: Studd .J, ed. Progress in obstetrics and gynaecology. Edinburgh: Churchill Livingstone, 1982 vol 2:94-107. 2. Kelly JV. Drugs in the treatment of toxemia of pregnancy. Clin Obstet c;ynecol 1977;20:'.~95-409. '.{. Ylikorkala 0, Makita U'.\I. Prostacvclin and thromboxane in gynecology and obstetrics. A~ .J 0BSTET GY:\ECOL 1985; 152:'.H8-29. 4. Toppozada MK, El-Damarawy H, Kamel M. Renal prostaglandins for induction of labor-a dual clinical advanProstaglandins tage in toxemia of pregnancy. 1976;12:581-97. 5. Toppozada '.\1K, Ghoncim A, Habib Y, El-Ziadi L, ElDamarawy 11. Effect of prostaglandin A, on renal hemodynaniics in pregnancy toxemia. A:-.i .J OBSTET GY:\ECOL 1979; J 35:581-5. 6. Toppozada '.\1K, Shaala S, Moussa H. Therapeutic use of p(;A, infusions in severe preeclampsia. A major clinical potential. Clin Exp Hypertens [B] 1983; 82:217-32. 7. Pritchard .JA, Stone SR. Clinical and laboratory observat_i'._>ns on eclampsia. A~1.J 011STET GY:\ECOL I 967;99:7546;).
8. Downing I, Shepherd GL, Lewis P.J. Reduced prostacyclin production in prceclampsia. Lancet 1980;2: 1374-5. 9. Lewis PJ. Does prostacyclin deficiency play a role in preedampsia? In: Lewis ~J. Moncada S, O'Grady.J, eds. Prostacyclin in pregnancy. !\:cw York: Raven Press, 1983:21520. IO. Pipkin FB, Symonds EM. Pregnancy induced hypcrten-
Volume 159 Number I
sion. In: Bygdeman M, Berger GS, Keith G, eds. Prostaglandins and their inhibitors in clinical obstetrics and gynecology. Lancaster, England: MTP Press, 1986:33766. 11. Toppozada M, Khowessah M, Shaala S, Shalaby T. Effect of prostacyclin infusion in se\'ere pre-eclampsia. Clin Exp Hypertens [BJ 1987;B5(3):331-47. 12. Middleditch BS. PGA: fact or artefact. Prostaglandins 1975;9:409. 13. Carr AA. Hemodynamic and renal effect of prostaglandin A, in subjects with essential hypertension. Am J Med Sci 1970;259:2 I.
Treatment of preeclampsia with PGA,
14. Smith ER, Mc:\forrow JV, Co\'ino B, Lee JB. In: Rammwell PW, Shaw JF. eds. Prostaglandin symposium of Worcester. New York: Wilev Interscience, 1968:259-66. 15. Nishizawa EE. Prostaglandin analogs in the treatment of thrombosis. In: Prostaglandins in hematology. Proceedings of the international symposium. Philadelphia: Spectrum. 1977:321-9. 16. Liu DT. Blackwell RJ, Tukel S. The relevance of antenatal and intrapartum foetal heart rate patterns to foetal outcome. Br J Obstet c;ynaecol 1978:85:270-7.
Abdominal ultrasound examination of the first-trimester fetus J. J.
Green, MS, RDMS, and J. C. Hobbins, MD
New Haven, Connecticut The first-trimester fetus can now be comprehensively studied with ultrasound. Various biometric measurements correlate well with gestational age, such as crown-rump length (r2 = 0.938) and cranial apex to ear diameter (r2 = 0.983). On the other hand, yolk sac diameter (r2 = 0.129) and abdominal perimeter (r2 = 0.58) correlate poorly with gestational age. By 10 weeks' gestation, kidneys can be visualized in 60% of cases; 98% will be seen at 11 weeks; and 100% of cases will be visible by 12 weeks. The bladder appears later, and by 12 weeks' gestation this organ can be identified in 50% of cases. It is likely that renal agenesis can be diagnosed (or excluded) reliably in the first trimester. With improving technology, prenatal diagnosis of some fetal anomalies is now possible in the first trimester. (AM J OssTET GYNECOL 1988;159:165-75.)
Key words: L:ltrasound, first trimester, fetus In the past 5 years there has been a virtual explosion in prenatal diagnosis that has enabled the detection of fetal defects whose diagnosis seemed unattainable. The two major reasons for this progress have been the improved resolution of diagnostic ultrasound and triumphs in molecular genetics. Until the advent of chorion villus sampling, the main diagnostic thrust had been in the second trimester. Very recently, however, further improvement in ultrasound technology has allowed detailed study of the first-trimester embryo. Moving prenatal diagnosis back to the first trimester has obvious benefits that, along with logistic, economic, and humane advantages, open up the possibility of fetal treatment at a time in immunologic development when the fetus has less chance of "graft" rejection. In this attempt to apprise the reader of the vast scope of first trimester diagnosis, original data of the authors will be melded with the published experience of other invesFrom the Department of Obstetrics and Gynecology, Yale University School of Medicine. Received for publication ,\,larch 19, 1987; rei•ised November 23, 1987; accepted March 5, 1988. Reprint requests: Jacqueline Creen, MS, RDMS, Department of Obstetrics and G)'l1ecolog;·, Yale L'niversity School of Medicine, 333 Cedar St., New Haven, CT 06510.
tigators. All of the authors' studies were performed in clinicallv well-dated, uncomplicated pregnancies. Dating was validated by ultrasound measurement of crown-rump length. All studies were performed with an Aloka 5 MHz Sector scanner (280 SL) applied abdominallv. First trimester biometry
Crown-rump length. One of the first biometric indices used to date pregnancv was the crown-rump length of the embryo. In 1975 Robinson and Fleming' published data correlating crown-rump length with gestational age. Despite the fact that their imestigation of the active first-trimester fetus was conducted with a static scanner, that work represents one of the most reproducible studies undertaken before the advent of real-time imagery. Others'·" have since studied crownrump length with real-time ultrasound and found a very reasonable correlation between this measurement and gestational age until 13 weeks, after which considerable variability was encountered. Fig. 1 was constructed at Yale from data from 500 clinically well-dated pregnancies. The r' of 0.943 represents a high degree of correlation between crown-rump length and dates in the first trimester. 165
5. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hypertension in pregnancy: Clinical-pathological correlations and remote prognosis. Medicine 1981;60:;267-76. 6. Surian M, lmbasciat E, Barbiano di Belgiososa G, Brancaccio D, Minelli L, Ponticelli C. Glomerular disease and pregnancy. Nephron 1984;36; 101-5.
July 1988 Am J Obstet Gynecol
7. Kida H, Takeda S, Yokoyama HL, Tomosugi N, Abe T, Hattori N. Focal glomerular sclerosis in pre-eclampsia. Clin Nephrol l 985;24:221-7.
Treatment of preeclampsia with prostaglandin A1 Mokhtar K. Toppozada, MD, Ahmed A. A. Ismail, MD, Hassan M. Hegab, MS, and Mostafa A. Kamel, MD Alexandria, Egypt The vasodepressor prostaglandin A, appeared to offer a major clinical potential solution in cases of severe pregnancy-induced hypertension. Thirty pregnant women with severe pregnancy-induced hypertension and a low Bishop score were studied in three equal groups. Group 1 received prostaglandin A, infusions alone (0.5 µ.g/kg/min for a maximum of 24 hours). Group 2 had received initial priming by prostaglandin E2 vaginal gel 6 hours before the onset of the prostaglandin A, infusion, and group 3 was treated by conventional therapy and oxytocin induction. In the first two groups blood pressure was reduced to normotensive values, and labor was induced satisfactorily in 15 of the 20 cases, but four patients in group 1 were delivered within 24 hours after infusion. Group 2 offered the most favorable results because 80% were delivered during the infusion; thus the postinfusion rebound rise in blood pressure was avoided. Group 3 presented the least acceptable results, with the highest failure rate and an increased number of operative deliveries. (AM J 0BSTET GYNECOL 1988;159:160-5.)
Key words: Severe preeclampsia, prostaglandin A 1, induction of labor
Severe preeclampsia represents a serious health hazard and creates a situation of high risk to both mother and fetus. As long as the exact causes remain unknown, therapy continues to be directed toward the main triad of manifestations, edema, hypertension, and albuminuria, as well as toward the prevention of complications. Bed rest, hypotensive agents, sedatives, and magnesium sulfate are the principal agents used to control pregnancy-induced hypertension. u However, most patients with severe pregnancy-induced hypertension should be delivered electively because it is usually too dangerous to await spontaneous labor. Successful medical induction of labor would avoid the possible dangers of cesarean section in these serious cases. The pathogenesis of pregnancy-induced hypertension appears to involve a true or a relative deficiency state of vasodepressor, anti-platelet-aggregator prostaglandins (PCs)." Therefore replacement therapy to compensate for the deficiency can serve as a direct ap-
From the Department of Obstetrics and Gynecology, University of Alexandria. Received for publication April 23, 1987; revised November 13, 1987; accepted December 15, 1987. Reprint requests: Professor M. K. Toppouula, MD, Shatby University Hospital, Shatby, Alexandria, Egypt.
160
proach to rectifying the impaired balance in prostanoid release. The E series of PCs seemed to be unsuitable for this role because of the high ratio of uterine stimulation to vasodepressor properties; i.e., vasodepressor doses will induce severe uterine hyperstimulation. On the other hand, the A series showed a favorable ratio in this respect, i.e., weak uterine stimulation and a strong hypotensive effect. Moreover, initial studies demonstrated that treatment' with PCA 1 could also markedly improve renal function.'· 5 PCA1 was infused in cases of severe preeclampsia at different dose levels for various time periods, and the renal, circulatory, oxytocic, and obstetric effects were evaluated. The results indicated that the optimal dose was 0.5 µg/kg/min and that a continuous infusion for up to 24 hours appeared to offer the most acceptable results. 6 However, as most of the treated subjects were in early labor or in prelabor, the actual labor-inducing capability of this agent was not fully evaluated. Accordingly, the present study was planned with the primary objective being to evaluate the use of PCA, infusion alone or combined with the initial ripening of the cervix in the treatment of women with severe preeclampsia and unripe cervices. A comparison with conventional therapy plus oxytocin induction was also an integral part of the planned investigation.
Treatment of preeclampsia with PGA,
Volume 159 Number I
161
Blood pressure
mm Hg 200
PGA 1 infusion
175
150 125
Systolic
100 75
Dlastolic
01,---~---"T~~"-"T"""~~--.-~~..,.-~~..--~---. 0
6
12
18 Hours
24
30
36
Fig. I. Mean of systolic and diastolic blood pressures before, during, and after prostaglandin infusion in group I. The data of group 2 were almost identical to those of group I.
Material and methods
The study included 30 pregnant women who were not in labor, who had an unripe cervix (Bishop score <5), and who had severe preeclampsia (blood pressure ;;,,, 160/ 110 mm Hg, albuminuria, and edema). All patients were ;;,,,34 weeks' gestation, with a parity range of 0 to 5 and no contraindications to the induction of labor or the use of prostaglandins. An informed consent was obtained from all patients. Group 1: PGA, alone. Ten patients received a continuous intravenous infusion of PGA, (0.5 µg/kg/min until delivery or to a maximum duration of 24 hours). (The PGA, was kindly supplied as a sterile solution containing 30 mg of PGA, in 3 ml per ampule by Professor S. Bergstrom, Karolinska Institute, Stockholm, Sweden.) Group 2: Vaginal PGE, gel and PGA,. Ten patients received 3 mg of PGE 2 (The C pjohn Co., Ltd., Crawley, England) suspended in a viscous gel of 5 ml tylose introduced intravaginally as far as the fornices by a polyethylene catheter; then 6 hours later they received PGA, infusion in the same dose and duration as in group I. Group 3: Conventional therapy and oxytocin induction. Ten patients received treatment for severe preeclampsia in the form of bed rest, sedation (diazepam, 5 mg tablets three times a day), magnesium sulfate (modified Pritchard regimen, 4 gm in 20% solution given slowly intravenously, then 5 gm of 50% solution intramuscularly every 4 hours"), hypotensives (methyldopa, 250 mg tablets three times a day), and hypertonic glucose given by intravenous infusion (250 ml of
Table I. Clinical data (mean ± SD) of subjects in the different groups at admission
Age (yr) Parity Duration of pregnancy (wk) Weight (kg)
Group I
Group 2
Group 3
(n = 10)
(n = JO)
(n = 10)
29.2 ± 2.9 0.8 ± 0.9 38.4 ± 2.45
28.8 ± 4.9 I. I ± 1.4 38.l ± 2.9
28.7±5.18 0.9 ± 1.4 38.l ± 2.0
84.6 ± 7.4
83.3 ± 7.7
85.4 ± 8.9
25% solution every 12 hours). Two days later, simultaneous amniotomy and continuous oxytocin (Syntocinon, Sandoz Pharmaceutical Co., Switzerland) infusion was started until the patient was delivered of her infant or to a maximum of 24 hours by the oxytocin titration method. Fetal heart rate and uterine activity were monitored in all patients by the Fetasonde SA machine (Roche Electronics, Everett, Me.) with external methods. Blood pressure and pulse rate were monitored continuously by a Dinamap vital signs monitor (Critikon Inc., Tampa, Fla.) up to 12 hours after the induction trial. The PGA, infusion (0.5 µg/kg/min) or dose of oxytocin was controlled by an I vac 231 infusion controller (I vac House, Harrow, Middlesex, United Kingdom). The progress of labor was monitored closely, and assessment of the newborn infants with Apgar scores was performed. Side effects during treatment were carefully recorded. Potentially serious side effects caused by PGA, are rare"; if they do develop, temporary
162 Toppozada et al.
July 1988 Am J Obstet Gynecol
Blood pressure mm Hg 200
I.
~r~~~~-
Oxytocin infusion
··.......... 175 Systolic
150
125
·········...
···------~---------Diastolic
100
J~~--,-~-,--~~r----.-----. -48
0
6
12
18
24
30
36
Hours
Fig. 2. Mean of systolic and diastolic blood pressures during the 48 hours of conventional therapy (dotted lines) during the 24 hours of oxytocin induction and in the postinfusion follow-up phase of
12 hours in group 3.
short-term cessation or dose reduction of the infusion is advisable.
Results The clinical data of the subjects in the different groups at admission to the study are shown in Table I. The numbers of primigravid women in the different groups were four, five, and five, respectively. Effect of treatment on blood pressure. In groups l and 2 in which PGA, was infused, both systolic and diastolic blood pressure dropped gradually in all patients, except for the systolic pressure in one patient in group I who proved to have essential hypertension. A much lower reduction in blood pressure was noted in group 3 during the 48-hour phase of medical treatment than during PGA, infusion in the first two groups (Table II). During the PGA, infusion period in groups l and 2, the systolic and diastolic blood pressure reached the lowest level between 8 and 23 hours from the onset of infusion. The means of the lowest blood pressure readings (reached at various time intervals in different subjects) were 122.7/70.3 and 119.5/69.4 mm Hg, respectively (Fig. 1). When compared with the admission values, the decrease was highly significant (p < 0.001) (Table II). After the infusion was stopped, there was a slight, gradual rise in systolic and diastolic blood pressure that reached a mean maximum of 134.6/79.8 and 137.5/81.9 mm Hg for groups l and 2, respectively (Fig. 1). This rise was not statistically significant (p > 0.05), except for the systolic blood pressure in group 2 (p < 0.05). However, the rebound rise in blood pressure in undelivered patients was much more than
in the successful cases, but the rise did not exceed preinfusion levels. In patients with PGE 2 gel applied vaginally 6 hours before the infusion (group 2), no changes in blood pressure were observed during the cervical ripening phase (p > 0.05). In group 3 (treated with conventional therapy for 2 days, then with oxytocin induction), the lowest mean reading of systolic blood pressure was 166.4 ± 12.9 mm Hg, which was not significantly different from the pretreatment value (p > 0.05) (Fig. 2). However, the mean diastolic blood pressure reached a minimum of 108.6 ± 7.1 mm Hg, which was significantly lower than the pretreatment value (p < 0.01) (Fig. 2). The mean arterial blood pressure decreased significantly during infusion in patients of the first two groups from admission values of 139.7 and 143.3 mm Hg to minimum levels during PGA, infusion of 88.3 and 85.7 mm Hg, respectively (p < 0.001) (Fig. 3). The initial mean arterial blood pressure in group 3 was 142.0 mm Hg; it dropped during the 48-hour phase of medical treatment and reached a minimum of 127.3 mm Hg (p < 0.0 l ). During the phase of treatment in all groups the pulse rates increased significantly by mean values of 10.6, 8.1, and 3.0 beats/min, respectively (p < 0.05). Obstetric course and outcome. In group 2, in which vaginal PGE, was used to ripen the cervix, the Bishop score increased 6 hours after the gel application from an initial figure of 2.6 to 6.0 (p < 0.01 ). The trial was successful if vaginal delivery occurred within the infusion phase of 24 hours. In this respect the trial was successful in three, eight, and three patients in the three groups studied (30%, 80%, and 30%, respectively). However, in four patients in group 1 and one patient
Volume 159 Number I
Treatment of preeclampsia with PGA,
Table II. Maximum reductions (mean ± SD) in systolic and diastolic blood pressures in the three groups during treatment
Group I (n = 10) Group 2 (n = 10) Group 3 (n = 10)
Svsto/ic bl
DirL1tolic blood pressure
(mm Hg)
(mm Hg)
62.4 ± 25.24* 70.2 ± 19.27* 18.2 ± 04.10
47.4 ± 12.93* 56.3 ± 15.93* 12.4 ± 06.58t
Before treatment During treatment (minimum)
163
c==J 11'$
*Significant (p < 0.00 I). tSignificant (/J < 0.0 I).
in group 3, spontaneous vaginal delivery occurred within the postinfusion phase of 24 hours. Regardless of success or failure, spontaneous vaginal delivery occurred in all patients in group 1, in nine patients of group 2, and in five patients of group 3. Cesarean section was done in one patient in group 2 because of fetal distress caused by three turns of the umbilical cord around the fetal neck and in three patients of group 3 (two because of failed induction and one because of fetal distress). In two patients in the latter group delivery was assisted by forceps extraction. The mean induction-delivery interval (including the phase of cervical ripening by PGE" in group 2, with failures not included) was 20.9 hours in group 1, 17.4 hours in groups 2, and 22.0 hours in group 3. Abnormal fetal heart rate patterns were observed in two patients in group 1 (one with late decelerations and one with baseline tachycardia), in two patients of group 2 (one with bradycardia and one with tachycardia), and in four patients of group 3 (two with late decelerations, one with bradycardia, and one with variable decelerations). These patterns disappeared spontaneously when the dose was temporarily reduced or the infusion was interrupted. In group 1 (PGA, infusion alone) no abnormal uterine activity was observed, but in group 2 (preinfusion cervical ripening) one patient had hyperstimulation in two instances. In group 3 two patients had uterine hyperactivity; the first had persistent late decelerations that required cesarean section, and the second patient had a temporary phase of variable decelerations in the fetal heart rate. The mean birth weights of all newborn infants were 2.68, 2.65, and 2.62 kg, respectively, for the three groups. The means of the 1- and 5-minute Apgar scores were 8.1 and 9, 7.8 and 10.0, and 6.3 and 9.0, respectively. Only one fetal death occurred in a patient in group I with preeclampsia superimposed on essential hypertension and with severe intrauterine fetal growth retardation. Persistent late declerations were observed and cesarean section was immediately decided on. However, when the infusion was stopped, a marked rebound rise in blood pressure and an eclamptic seizure developed, and fetal heartbeats stopped. The mother was then treated med-
group I
Group II
Group ill
Fig. 3. Changes in the mean arterial blood pressure as a result of treatment in the three groups.
ically, and 8 hours later a stillborn fetus weighing 1.2 kg was spontaneously delivered vaginally. The mean duration of the third stage was within normal limits in all patients. Only one patient in group 3 had atonic postpartum hemorrhage. Follow-up evaluation of the su~jects for I week after delivery showed no fetal or maternal death. Only one patient, the previously mentioned patient with essential hypertension, had persistence of high blood pressure. Nausea, vomiting, diarrhea, and headache constituted the main side effects of PGA, but the symptoms were mild and not serious (three patients in group I and two patients in group 2). Comment
Several hypotheses have emerged in recent years that attempt to explain the pathogenesis of pregnancyinduced hypertension. The available evidence indicates that pregnancy-induced hypertension may be a deficiency disease of vasodepressor anti-plateletaggregating prostanoids, such as PCC or PGD,, or may be caused by the excessive release of vasoactive proaggregating prostanoids (such as thromboxanes) or a combination of both." '·" Correction of the disturbed biochemical parameters may be achieved through the administration of vasodepressor PCs, such as PGA, or prostacyclin, as a direct approach to maintaining a normal vascular homeostasis."· ' 0 · " PCs of the A type were previously believed to serve as possible renal antihypertensive hormones, but later evidence indicated that the measured PGA compounds
164 Toppozada et al.
may represent analytic artifacts.'' Initially, PGA was administered by intravenous infusion to male volunteers for the control of different types of hypertension which confirmed its hypotensive properties and beneficial renal effects.'" The vasodepressor effects are probably achieved through peripheral arteriolar dilatation that is induced by a direct action and does not involve cholinergic, histaminergic, or adrenergic nerve endings.'' The fact that pregnancy-induced hypertension is a temporary form of hypertension made a limited infusion period of PGA, a potentially useful therapeutic measure in this disease. Clinical application confirmed the anticipated hypotensive response and showed further advantages in terms of improved renal function and mild oxytocic properties.,_., Furthermore, the weak anti-platelet aggregation effect of this agent represented another favorable aspect of the compound in patients with severe pregnancy-induced hypertension.1.·. The present study was aimed at answering two specific questions: (I) Does PGA, represent a better therapeutic modality than what is presently used as a nonsurgical line of treatment? (2) Do we need additional cervical ripening by vaginal PGE 2 gel to supplement the weak oxytocic property of PGA,, particularly in patients with unripe cervices? The induction of labor in patients with preeclampsia is clinically indicated when intrauterine fetal existence is attended with certain risks that outweigh those of prematurity or if the toxemic process imposes immediate maternal dangers and does not respond to proper treatmenl. PGA, alone (group I) induced labor in only 30% of patients during the infusion phase of 24 hours, and 40% more were delivered the next day because of the progress of an already initiated labor. In a previous study, the same dose schedule was successful in terminating pregnancy in all cases because the patients were either in early labor or had a farnrable Bishop score compared with scores of unripe cervices in the present study." Accordingly, preinduction cervical ripening by PGE 2 gel appears to be a valuable supplement to the weakly oxytocic PGA, therapy whenever the inducibility score is low. During PGA, infusions the observed fetal heart rate changes were generally of a temporary nature and were within the expected range of occurrence in patients with severe pregnancy-induced hypertension and placental insufficiency.'" Moreover, the fact that the condition of all newborn infants was rather good provides further reassurance concerning the fetal safety of this form of therapy. Concerning the maternal safety, the maintenance of a normotensive blood pressure and the lack of serious side effects during infusion preclude an increased risk during the induction phase. The infrequent and mild side effects observed appear to be ac-
July 1988 Am .J Obstet Gynecol
ceptable in return for the achieved clinical response. Delivery in itself represents an end point of danger in most cases, but postpartum continuation of the infusions for several hours may prove to be beneficial in the event of the rare development of postpartum eclampsia. Group 3, with oxytocin induction, presented the least favorable results and the highest rate of failure, the longest induction-delivery interval, and an increased incidence of operative delivery despite the higher initial Bishop score. Also, oxytocin did not offer an effective hypotensive response and was associated with more serious fetal heart rate patterns. Moreover, the potential hazards of oxytocin infusion for prolonged periods in pregnancy-induced hypertension represent an additional drawback. From the data obtained from the present study and from previous experience with PGA, infusion in patients with pregnancy induced hypertension, it can be concluded that this prostaglandin offers a new and useful modality in the management of pregnancy induced hypertension. Blood pressure is reduced and maintained at normotensive levels, renal function is improved, and labor is induced with a relatively safe approach for both mother and fetus. Whenever the cervix is unripe, additional priming with PGE 2 gel is indicated. We wish to acknowledge the continuous encouragement and support we received from Professor Sune Bergstrom, the Karolinska Institute, Stockholm, Sweden. REFERENCES I. Wood SM. Drugs in the treatment of hypertension in pregnancy. In: Studd .J, ed. Progress in obstetrics and gynaecology. Edinburgh: Churchill Livingstone, 1982 vol 2:94-107. 2. Kelly JV. Drugs in the treatment of toxemia of pregnancy. Clin Obstet c;ynecol 1977;20:'.~95-409. '.{. Ylikorkala 0, Makita U'.\I. Prostacvclin and thromboxane in gynecology and obstetrics. A~ .J 0BSTET GY:\ECOL 1985; 152:'.H8-29. 4. Toppozada MK, El-Damarawy H, Kamel M. Renal prostaglandins for induction of labor-a dual clinical advanProstaglandins tage in toxemia of pregnancy. 1976;12:581-97. 5. Toppozada '.\1K, Ghoncim A, Habib Y, El-Ziadi L, ElDamarawy 11. Effect of prostaglandin A, on renal hemodynaniics in pregnancy toxemia. A:-.i .J OBSTET GY:\ECOL 1979; J 35:581-5. 6. Toppozada '.\1K, Shaala S, Moussa H. Therapeutic use of p(;A, infusions in severe preeclampsia. A major clinical potential. Clin Exp Hypertens [B] 1983; 82:217-32. 7. Pritchard .JA, Stone SR. Clinical and laboratory observat_i'._>ns on eclampsia. A~1.J 011STET GY:\ECOL I 967;99:7546;).
8. Downing I, Shepherd GL, Lewis P.J. Reduced prostacyclin production in prceclampsia. Lancet 1980;2: 1374-5. 9. Lewis PJ. Does prostacyclin deficiency play a role in preedampsia? In: Lewis ~J. Moncada S, O'Grady.J, eds. Prostacyclin in pregnancy. !\:cw York: Raven Press, 1983:21520. IO. Pipkin FB, Symonds EM. Pregnancy induced hypcrten-
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sion. In: Bygdeman M, Berger GS, Keith G, eds. Prostaglandins and their inhibitors in clinical obstetrics and gynecology. Lancaster, England: MTP Press, 1986:33766. 11. Toppozada M, Khowessah M, Shaala S, Shalaby T. Effect of prostacyclin infusion in se\'ere pre-eclampsia. Clin Exp Hypertens [BJ 1987;B5(3):331-47. 12. Middleditch BS. PGA: fact or artefact. Prostaglandins 1975;9:409. 13. Carr AA. Hemodynamic and renal effect of prostaglandin A, in subjects with essential hypertension. Am J Med Sci 1970;259:2 I.
Treatment of preeclampsia with PGA,
14. Smith ER, Mc:\forrow JV, Co\'ino B, Lee JB. In: Rammwell PW, Shaw JF. eds. Prostaglandin symposium of Worcester. New York: Wilev Interscience, 1968:259-66. 15. Nishizawa EE. Prostaglandin analogs in the treatment of thrombosis. In: Prostaglandins in hematology. Proceedings of the international symposium. Philadelphia: Spectrum. 1977:321-9. 16. Liu DT. Blackwell RJ, Tukel S. The relevance of antenatal and intrapartum foetal heart rate patterns to foetal outcome. Br J Obstet c;ynaecol 1978:85:270-7.
Abdominal ultrasound examination of the first-trimester fetus J. J.
Green, MS, RDMS, and J. C. Hobbins, MD
New Haven, Connecticut The first-trimester fetus can now be comprehensively studied with ultrasound. Various biometric measurements correlate well with gestational age, such as crown-rump length (r2 = 0.938) and cranial apex to ear diameter (r2 = 0.983). On the other hand, yolk sac diameter (r2 = 0.129) and abdominal perimeter (r2 = 0.58) correlate poorly with gestational age. By 10 weeks' gestation, kidneys can be visualized in 60% of cases; 98% will be seen at 11 weeks; and 100% of cases will be visible by 12 weeks. The bladder appears later, and by 12 weeks' gestation this organ can be identified in 50% of cases. It is likely that renal agenesis can be diagnosed (or excluded) reliably in the first trimester. With improving technology, prenatal diagnosis of some fetal anomalies is now possible in the first trimester. (AM J OssTET GYNECOL 1988;159:165-75.)
Key words: L:ltrasound, first trimester, fetus In the past 5 years there has been a virtual explosion in prenatal diagnosis that has enabled the detection of fetal defects whose diagnosis seemed unattainable. The two major reasons for this progress have been the improved resolution of diagnostic ultrasound and triumphs in molecular genetics. Until the advent of chorion villus sampling, the main diagnostic thrust had been in the second trimester. Very recently, however, further improvement in ultrasound technology has allowed detailed study of the first-trimester embryo. Moving prenatal diagnosis back to the first trimester has obvious benefits that, along with logistic, economic, and humane advantages, open up the possibility of fetal treatment at a time in immunologic development when the fetus has less chance of "graft" rejection. In this attempt to apprise the reader of the vast scope of first trimester diagnosis, original data of the authors will be melded with the published experience of other invesFrom the Department of Obstetrics and Gynecology, Yale University School of Medicine. Received for publication ,\,larch 19, 1987; rei•ised November 23, 1987; accepted March 5, 1988. Reprint requests: Jacqueline Creen, MS, RDMS, Department of Obstetrics and G)'l1ecolog;·, Yale L'niversity School of Medicine, 333 Cedar St., New Haven, CT 06510.
tigators. All of the authors' studies were performed in clinicallv well-dated, uncomplicated pregnancies. Dating was validated by ultrasound measurement of crown-rump length. All studies were performed with an Aloka 5 MHz Sector scanner (280 SL) applied abdominallv. First trimester biometry
Crown-rump length. One of the first biometric indices used to date pregnancv was the crown-rump length of the embryo. In 1975 Robinson and Fleming' published data correlating crown-rump length with gestational age. Despite the fact that their imestigation of the active first-trimester fetus was conducted with a static scanner, that work represents one of the most reproducible studies undertaken before the advent of real-time imagery. Others'·" have since studied crownrump length with real-time ultrasound and found a very reasonable correlation between this measurement and gestational age until 13 weeks, after which considerable variability was encountered. Fig. 1 was constructed at Yale from data from 500 clinically well-dated pregnancies. The r' of 0.943 represents a high degree of correlation between crown-rump length and dates in the first trimester. 165