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Prostanoid excretion in incipient singleton and twin pregnancies
Prostanoid excretion in incipient singleton and twin pregnancies Robin M.E van der Weiden, MD, Frans M. Helmerhorst, MD, Phi), and Marc J.N.C. Keirse, MD, DPhil Leiden, The Netherlands OBJECTIVE: Our purpose was to examine the urinary excretion of metabolites of prostacyclin, 6-keto-prostaglandin FI~ and 2,3-dinor-6-keto-prostaglandin FI,, and thromboxane A2, thromboxane B2 and 2,3-dinor-thromboxane B2, in early twin and singleton pregnancies resulting from in vitro fertilization-embryo transfer. STUDY DESIGN: Overnight urine samples were obtained from 23 women at regular intervals for 20 weeks after embryo transfer. Prostanoids were measured by high-pressure liquid chromatography-radioimmunoassay. RESULTS: All prostanoids, most markedly 6-keto-prostaglandin FI~ and 2,3-dinor-6-keto-prostaglandin FI~, increased in both singleton and twin pregnancies. This resulted in an increased ratio of prostacyclin over thromboxane A2 both in the dinor compounds (from 1.3 to 2.8) and the total metabolites (from 1.7 to 3.5). No marked differences were observed between twin and singleton pregnancies. CONCLUSIONS: Twin and singleton pregnancies show a similar increase in the prostacyclin to thromboxane A2 ratio in the first half of pregnancy. (AM J OBSTETGYNECOL1996;174:1614-7.)
Key words: In vitro fertilization, pregnancy, twin, urinary prostanoid metabolites, prostaglandins
Experimental data and clinical observations suggest that the uterine environment of incipient gestation can preordain pregnancy outcome) A variety of signaling molecules, such as cytokines, growth factors, and plateletactivating factor that are known to interact with prostanoids, are involved in preimplantation embryonic development2 and early pregnancy.~ The placenta in its early stages of development produces vasoactive prostanoids, prostacyclin (PGI2) and thromboxane A2 (TxA2),< 5 and observations in women with a history of recurrent abortion indicate that the balance between these compounds relates to the outcome of pregnancyfl Noort and Keirsev described pregnancy-related changes in the urinary excretion of PGI2 and TxA2 metabolites and suggested that these occurred toward the end of the first trimester, but these data were cross-sectional rather than longitudinal. Only one longitudinal study has been reported thus far. 6 It was conducted in women with a history of recurrent miscarriage; measurements were confined to the period between 4 and 18 weeks' gestation with few samples per patient and only one between weeks 12 and 18. All available data thus
From the Department of Obstetrics, Gynecology, and Reproduction, Leiden University Hospital. Received for publication January 4, 1995; revised October 19, 1995; accepted October31, 1995. Reprint requests: R.M.E van der Weiden, MD, Sint Franciscus Gasthuis, Kleiweg500, NL-3045 PM Rotterdam, The Netherlands. Copyright 9 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00 + 0 6/1/70439 1614
provide little information on prostanoid excretion at implantation, a process in which prostm]oids are thought to be implicated,s To gain further understanding of prostanoid involvement at this time during gestation, we measured urinary prostanoid excretion in women who achieved a twin or singleton pregnancy after embryo transfer (ET). Material and methods
The urinary excretion of the stable degradation products of PGI2 (6-keto-prostaglandin FI= [PGIlc,] and 2,3dinor-6-keto-prostaglandinFI=) and of TxA2 (thromboxane B2 [TxB2] and 2,3-dinor-TxB2) was measured in 27 women who became pregnant after in vitro fertilization (IVF). Three miscarried and one had an ectopic pregnancy, leaving 23 women with essentially normal pregnancies in the study. The IVF protocol included pituitary down-regulation with a gonadotropin-releasing hormone analog, starting on day 23 of the pretreatment cycle. Hyperstimulation was initiated, after the withdrawal bleeding, with human menopausal gonadotropin and ovulation was induced with 10,000 IU of human chorionic gonadotropin. Luteal support was given after oocyte pickup with 600 mg of progesterone (Progestan, Organon, Oss, The Netherlands) per day administered vaginally for up to 6 weeks after ET. Women collected urine produced overnight (from 12 midnight to 6 ~_,~) at 3- to 4-day intervals after ET and at weekly intervals after tile establishment of a clinical preg-
van der Weiden, Helmerhorst, and Keirse 1615
Volume 174, Number 5
AmJ Obstet Gynecol
2500
2000-
C
'E 1500O
1000-
500-
0 -20
0
20
40
60
80
100
120
140
days Fig. 1. Prostanoid me~bolite concentrations in twin pregnancy Day ~ Day of ET; so~d square, ~ketoPGFaa; opensquare, 2,~dinor-~keto-PGFl=; sold tnang~, TxB2; g 2,3-dinor-TxB2.
nancy until 20 weeks' gestation. Samples were kept at -80 ~ C and analyzed within 6 months after collection. The stable degradation products of PGI 2 and TxA2 were extracted with methyl tert-butyl ether from 5 ml urine samples and spiked with tritium-labeled prostanoids for recovery determination. They were evaporated to dryness and separated by high-pressure liquid chromatography for separate radioimmunoassay of 6_keto_PGFl~ ' 2,3_dinor_6_keto_PGFl~ ' TxB2,L 3 and 2,3dinor-TxB2. Conditions for high-pressure liquid chromatography and for radioimmunoassay were as described by Noort and Keirse. ~ Prostanoid levels were expressed in nanograms per gram of creatinine. The sum of 6-ketoPGFI~ and 2,3-dinor-6-keto-PGFl~was taken as indicative for total PGI 2 production and the sum of TxB 2 and 2,3dinor-TxB2 for total TxA2 production. 6 Prostanoid concentrations and their ratios were analyzed for each Woman, and a mean was calculated for samples obtained in the periods from days 0 to 9 (day 0 = day of embryo transfer), days 10 to 19, days 20 to 39, days 40 to 60, days 60 to 99, and days 100 to 120 of gestation. The Wilcoxon two-sample (rank-sum) test was used to assess interindividual differences and the signed rank test for within-woman differences.
Results The excretion rate of the four prostanoid metabolites, 6-keto-PGFl~, 2,3-dinor-6-keto-PGFl=, TxB 2, and 2,3-dinor-TxB2 after ET and during pregnancy is shown in Table I. There was considerable interindividual variation in the concentrations of all prostanoids measured. Except for TxB 2 excretion, which showed virtually no in-
crease over the period of gestation studied, all prostanoids increased in the course of pregnancy. A typical example is shown in Fig. 1. No statistically significant differences were found in prostanoid concentrations between singleton and twin pregnancies. Although the ratios of 2,3-dinor-6-ketoPGFI= versus 2,3-dinor-TxB2 and of the combined PGI 2 versus TxA2 metabolites increased in singleton and twin pregnancies, these were not different between singleton and twin pregnancies (Table II). In both singleton and twin pregnancies significant differences between the periods day 0 to day 9 and, to a lesser extent, days'10 to 19 with later periods were most marked for the concentrations of 6-keto-PGFlc~ and 2,3dinor-6-keto-PGFl= (Table I). The ratio of total PGI 2 versus total thromboxane was significantly higher than the ratio of the dinor metabolites in both singleton and twin pregnancies. However, the pattern of increase in the ratio of total PGI 2 versus total TxAz metabolites closely refleeted the increase in the ratio of dinor metabolites.
Comment The uterine environment at the inception of gestation is of crucial importance for the further evolution of pregnancy. A key event in h u m a n embryo implantation and subsequent placental development is angiogenesis. Angiogenesis starts during the menstrual cycle and is boosted at the time that the blastocyst approaches the implantation sitefl Prostanoids are natural candidates in the mediation of angiogenesis not only by their own account, but also by interfering with the action of other signaling molecules, such as the cytokines. 1' ~ Raised con-
1616
van der Weiden, Helmerhorst, and Keirse
May 1996 AmJ Obstet G~lecol
Table I. Excretion of prostanoid metabolites in w o m e n with singleton and twin pregnancies resulting from IVF-ET (ET on day 0)
Singleton pregnancy Prostanoid and period 6-Keto-PGFI~ Days 0-9 Days 10-19 Days 40-60 Days 100-120 TxB2 Days 0-9 Days 10-19 Days 40-60 Days 100-120 2,3-Dinor-6-keto-PGFl~ Days 0-9 Days 10-19 Days 40-60 Days 100-120 2,3-Dinor-TxB 2 Days 0-9 Days 10-19 Days 40-60 Days 100-120
Twin pregnancy
Median
Range
Median
Range
176.9 160.2 320.8 384.9
96.9-285.7 86.6-457.0 98.7-434.2* 178.1-735.81-
145.9 198.9 215.8 424.5
109.3-164.2 110.1-259.7 151.9-386.1" 232.6-719.95
38.6 46.3 49.3 63.5
14.2-86.1 24.9-109.4 12.6-233.8 13.3-265.9
39.4 34.1 63.8 64.7
11.8-48.9 14.6-56.3 29.2-314.9 39.4-626.2
206.0 235.8 398.7 709.9
137.7-751.2 195.2-944.3 149.9-1109.8' 270.2-3224.6t-
234.2 297.3 564.3 1142.4
163.3-290.2 106.3-777.8 205.7-1165.2" 636.3-1455.1++
214.0 246.8 272.0 331.2
134.9486.9 29.2-576.0 44.4-1135.6 123.2-1151.1
158.0 240.7 199.3 366.4
82.2-222.9 91.2-268.0 140.1-1779.4 212.7-3098.7"
*p < 0.02, significance versus days 0 to 9. +p < 0.001, significance versus days 0 to 9. Sp < 0.01, significance versus days 0 to 9.
Table II. Ratios of urinary prostanoids metabolites m w o m e n with singleton and twin pregnancies achieved by IVF-ET (ET on day 0)
Singleton pregnancy Prostanoid and period Ratio dinor-6-keto-PGFaa versus dinor-TxB9 Days 0-9 Days 10-19 Days 20-39 Days 40-59 Days 60-99 Days 100-120 Ratio PGI 2 versus TxA2 metabolites Days 0-9 Days 10-19 Days 20-39 Days 40-59 Days 60-99 Days 100-120
Twin pregnancy
Median
Range
Median
Range
1.26 1.36 1.19 1.59 1.76 2.80
0.77-1.72 0.66-1.90 0.6%4.99 0.23-7.06 0.75-9.54 0.37-13.48'
1.38 2.41 2.46 2.70 2.96 2.19
0.84-3.54 0.51-3.40 0.26-6.07 0.39-6.20 0.2%6.78 0.31-6.63
1.66 1.69 1.73 2.29 2.44 3.45
1.19-2.37 0.95-2.74 1.27-5.74 0.51-8.02 1.43-10.59 0.7%14.96t
1.83 3.11 2.47 2.68 3.15 3.59
1.22-3.36 0.78-3.57 0.3645.87 0.54-5.82 0.40-7.21 0.38-7.35
*p < 0.05, significance versus days 0 to 9. tP < 0.02, significance versus days 0 to 9.
centrations of 6-keto-PGFlc, have been foun d at the site of implantation in rabbits ~~and mice. z~In w o m e n both firsttrimester decidual cells and placental tissue possess the key enzymes for PGI 2 and TxA 2 synthesis. ~ The vasoactive prostanoids PGI z and TxAz could exert their actions not only at the implantation site but also on the d e v e l o p m e n t of the uteroplacental vasculature as a d e t e r m i n a n t of successful pregnancy outcome. Prostanoid excretion measured in our study provides a
reasonable reflection of PGI 2 and TxA 2 production in vitro. 6-Keto-PGFla and TxB 2 are the stable hydrolysis products, respectively, of PGI 2 mad TxA2, whereas the dinor c o m p o u n d s 2, 3-dinor-6-keto-PGFlc, and 2,3-dinorTxBz are known to be their major urinary metaholites.lS, 14We observed a twofold increase in 6-keto-PGFl= levels and a threefold increase in 2,3-dinor-6-keto-PGFl~ levels in singleton pregnancies between the day of ET and day 120 of gestation. T h e m u c h smaller increase in the
Volume 174, Nmnber 5 AmJ Obstet Gynecol
excretion o f T x B 2 and 2,3-dinor-TxB 2 resulted in a significant elevation of the PGI2-to-TxA 2 ratio with advancing gestation, c o n f i r m i n g cross-sectional observations in normal singleton pregnancies. 7 Increases in the excretion of PGI 2 metabolites were m o r e p r o n o u n c e d in twin pregnancies than in singleton pregnancies. Increases in the excretion of TxA 2 metabolites, on the o t h e r hand, were roughly of the same o r d e r of magnitude. O n the whole, ratios between PGI 2 and TxA 2 metabolites thus t e n d e d to be h i g h e r in twin than in singleton pregnancies, but this was only so in the early stages o f p r e g n a n c y w h e n most of the physiologic adaptations are known to occur. After the first trimester o f pregnancy, the ratios o f both the d i n o r c o m p o u n d s and the total PG12 versus TxA 2 metabolites hardly differed between twin and singleton pregnancies. This suggests that uterine and placental size per se have little bearing on the PGIe versus t h r o m b o x a n e balance in pregnancy. We thank Mr. A. van Leeuwen for technical assistance with the prostanoid measurements. REFERENCES
1. Robertson SA, Guilbert LJ, Seamark RF, Wegmann TG. Cytokines in gestation. Crit Rev Immunol 1994;14:23992. 2. Schultz GA, Heyner S. Growth factors in preimplantation mammalian embryos. Oxf Rev Reprod Biol 1994;15:4381.
van der Weiden, Helmerhorst, and Keirse
1617
3. Clark DA. C~okines, decidua and early pregnancy. Oxf Rev Reprod Biol 1994;15:83-ll 1. 4. Keirse MJNC, Erwich ~JHM, Klok G. Does or can human placenta produce prostacyclin? Placenta 1986;7:37-42. 5. Erwich ~JHM, Klok G, Keirse MJNC. Prostaglandin endoperoxide metabolism changes in the developing human placenta. Eur~ Obstet GynecoI Reprod BioI 1987;26:195-6. 6. Tulppala M, Viinika L, Ylikorkala O. Thromboxane dominance and prostacyclin deficiency in habitual abortion. Lancet 1991;337:879-81. 7. Noort WA, Keirse MJNC. Prostacyclin versus thromboxane metabolite excretion: changes in pregnancy and labor. EurJ Obstet Gynecol Reprod Biol 1990;35:15-21. 8. van der Weiden RMF, Helmerhorst FM, Keirse MJNC. Influence of prostaglandins and platelet activating factor on implantation. Hum Reprod 1991;6:436-42. 9. Finn CA. Implantation, menstruation and inflammation. Biol Rev Camb Philos Soc 1986;61:313-28. 10. Hoffman LH, Davenport GR, Brash AR. Endometrial prostaglandins and phospholipase activity related to implantation in rabbits: effects of dexamethasone. Biol Reprod 1984; 38:544-55. 11. Kinoshita K, Satoh K, Ishihara O, Tsutsumi O, Nakayama M, Kashimura F, et al. Involvement ofprostaglandins in implantation in the pregnant mouse. Adv Prostaglandin Thromboxane Leukotriene Res 1985;15:605-7. 12. Asboth G, Gimes G, Hertelendy F, Toth M. The relation between thromboxane and prostaglandin synthesis in human decidua tissue: a comparison of eicosanoid synthesis in minced tissue with that in a cell-free preparation. Biochim Biophys Acta 1989;1002i101-8. 13. Rosenkranz B, Fischer C, Weimer KE, Fr61ich JC. Metabolism of prostacyclin and 6-keto-prostaglandin FI= in man. J Biol Chem 1980;21:10194-8. 14. Roberts LJ, Sweetman BJ, OatesJA. Metabolism of thromboxane A2 in man. J Biol Chem 1981;256:8384-93.
Key words: In vitro fertilization, pregnancy, twin, urinary prostanoid metabolites, prostaglandins
Experimental data and clinical observations suggest that the uterine environment of incipient gestation can preordain pregnancy outcome) A variety of signaling molecules, such as cytokines, growth factors, and plateletactivating factor that are known to interact with prostanoids, are involved in preimplantation embryonic development2 and early pregnancy.~ The placenta in its early stages of development produces vasoactive prostanoids, prostacyclin (PGI2) and thromboxane A2 (TxA2),< 5 and observations in women with a history of recurrent abortion indicate that the balance between these compounds relates to the outcome of pregnancyfl Noort and Keirsev described pregnancy-related changes in the urinary excretion of PGI2 and TxA2 metabolites and suggested that these occurred toward the end of the first trimester, but these data were cross-sectional rather than longitudinal. Only one longitudinal study has been reported thus far. 6 It was conducted in women with a history of recurrent miscarriage; measurements were confined to the period between 4 and 18 weeks' gestation with few samples per patient and only one between weeks 12 and 18. All available data thus
From the Department of Obstetrics, Gynecology, and Reproduction, Leiden University Hospital. Received for publication January 4, 1995; revised October 19, 1995; accepted October31, 1995. Reprint requests: R.M.E van der Weiden, MD, Sint Franciscus Gasthuis, Kleiweg500, NL-3045 PM Rotterdam, The Netherlands. Copyright 9 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00 + 0 6/1/70439 1614
provide little information on prostanoid excretion at implantation, a process in which prostm]oids are thought to be implicated,s To gain further understanding of prostanoid involvement at this time during gestation, we measured urinary prostanoid excretion in women who achieved a twin or singleton pregnancy after embryo transfer (ET). Material and methods
The urinary excretion of the stable degradation products of PGI2 (6-keto-prostaglandin FI= [PGIlc,] and 2,3dinor-6-keto-prostaglandinFI=) and of TxA2 (thromboxane B2 [TxB2] and 2,3-dinor-TxB2) was measured in 27 women who became pregnant after in vitro fertilization (IVF). Three miscarried and one had an ectopic pregnancy, leaving 23 women with essentially normal pregnancies in the study. The IVF protocol included pituitary down-regulation with a gonadotropin-releasing hormone analog, starting on day 23 of the pretreatment cycle. Hyperstimulation was initiated, after the withdrawal bleeding, with human menopausal gonadotropin and ovulation was induced with 10,000 IU of human chorionic gonadotropin. Luteal support was given after oocyte pickup with 600 mg of progesterone (Progestan, Organon, Oss, The Netherlands) per day administered vaginally for up to 6 weeks after ET. Women collected urine produced overnight (from 12 midnight to 6 ~_,~) at 3- to 4-day intervals after ET and at weekly intervals after tile establishment of a clinical preg-
van der Weiden, Helmerhorst, and Keirse 1615
Volume 174, Number 5
AmJ Obstet Gynecol
2500
2000-
C
'E 1500O
1000-
500-
0 -20
0
20
40
60
80
100
120
140
days Fig. 1. Prostanoid me~bolite concentrations in twin pregnancy Day ~ Day of ET; so~d square, ~ketoPGFaa; opensquare, 2,~dinor-~keto-PGFl=; sold tnang~, TxB2; g 2,3-dinor-TxB2.
nancy until 20 weeks' gestation. Samples were kept at -80 ~ C and analyzed within 6 months after collection. The stable degradation products of PGI 2 and TxA2 were extracted with methyl tert-butyl ether from 5 ml urine samples and spiked with tritium-labeled prostanoids for recovery determination. They were evaporated to dryness and separated by high-pressure liquid chromatography for separate radioimmunoassay of 6_keto_PGFl~ ' 2,3_dinor_6_keto_PGFl~ ' TxB2,L 3 and 2,3dinor-TxB2. Conditions for high-pressure liquid chromatography and for radioimmunoassay were as described by Noort and Keirse. ~ Prostanoid levels were expressed in nanograms per gram of creatinine. The sum of 6-ketoPGFI~ and 2,3-dinor-6-keto-PGFl~was taken as indicative for total PGI 2 production and the sum of TxB 2 and 2,3dinor-TxB2 for total TxA2 production. 6 Prostanoid concentrations and their ratios were analyzed for each Woman, and a mean was calculated for samples obtained in the periods from days 0 to 9 (day 0 = day of embryo transfer), days 10 to 19, days 20 to 39, days 40 to 60, days 60 to 99, and days 100 to 120 of gestation. The Wilcoxon two-sample (rank-sum) test was used to assess interindividual differences and the signed rank test for within-woman differences.
Results The excretion rate of the four prostanoid metabolites, 6-keto-PGFl~, 2,3-dinor-6-keto-PGFl=, TxB 2, and 2,3-dinor-TxB2 after ET and during pregnancy is shown in Table I. There was considerable interindividual variation in the concentrations of all prostanoids measured. Except for TxB 2 excretion, which showed virtually no in-
crease over the period of gestation studied, all prostanoids increased in the course of pregnancy. A typical example is shown in Fig. 1. No statistically significant differences were found in prostanoid concentrations between singleton and twin pregnancies. Although the ratios of 2,3-dinor-6-ketoPGFI= versus 2,3-dinor-TxB2 and of the combined PGI 2 versus TxA2 metabolites increased in singleton and twin pregnancies, these were not different between singleton and twin pregnancies (Table II). In both singleton and twin pregnancies significant differences between the periods day 0 to day 9 and, to a lesser extent, days'10 to 19 with later periods were most marked for the concentrations of 6-keto-PGFlc~ and 2,3dinor-6-keto-PGFl= (Table I). The ratio of total PGI 2 versus total thromboxane was significantly higher than the ratio of the dinor metabolites in both singleton and twin pregnancies. However, the pattern of increase in the ratio of total PGI 2 versus total TxAz metabolites closely refleeted the increase in the ratio of dinor metabolites.
Comment The uterine environment at the inception of gestation is of crucial importance for the further evolution of pregnancy. A key event in h u m a n embryo implantation and subsequent placental development is angiogenesis. Angiogenesis starts during the menstrual cycle and is boosted at the time that the blastocyst approaches the implantation sitefl Prostanoids are natural candidates in the mediation of angiogenesis not only by their own account, but also by interfering with the action of other signaling molecules, such as the cytokines. 1' ~ Raised con-
1616
van der Weiden, Helmerhorst, and Keirse
May 1996 AmJ Obstet G~lecol
Table I. Excretion of prostanoid metabolites in w o m e n with singleton and twin pregnancies resulting from IVF-ET (ET on day 0)
Singleton pregnancy Prostanoid and period 6-Keto-PGFI~ Days 0-9 Days 10-19 Days 40-60 Days 100-120 TxB2 Days 0-9 Days 10-19 Days 40-60 Days 100-120 2,3-Dinor-6-keto-PGFl~ Days 0-9 Days 10-19 Days 40-60 Days 100-120 2,3-Dinor-TxB 2 Days 0-9 Days 10-19 Days 40-60 Days 100-120
Twin pregnancy
Median
Range
Median
Range
176.9 160.2 320.8 384.9
96.9-285.7 86.6-457.0 98.7-434.2* 178.1-735.81-
145.9 198.9 215.8 424.5
109.3-164.2 110.1-259.7 151.9-386.1" 232.6-719.95
38.6 46.3 49.3 63.5
14.2-86.1 24.9-109.4 12.6-233.8 13.3-265.9
39.4 34.1 63.8 64.7
11.8-48.9 14.6-56.3 29.2-314.9 39.4-626.2
206.0 235.8 398.7 709.9
137.7-751.2 195.2-944.3 149.9-1109.8' 270.2-3224.6t-
234.2 297.3 564.3 1142.4
163.3-290.2 106.3-777.8 205.7-1165.2" 636.3-1455.1++
214.0 246.8 272.0 331.2
134.9486.9 29.2-576.0 44.4-1135.6 123.2-1151.1
158.0 240.7 199.3 366.4
82.2-222.9 91.2-268.0 140.1-1779.4 212.7-3098.7"
*p < 0.02, significance versus days 0 to 9. +p < 0.001, significance versus days 0 to 9. Sp < 0.01, significance versus days 0 to 9.
Table II. Ratios of urinary prostanoids metabolites m w o m e n with singleton and twin pregnancies achieved by IVF-ET (ET on day 0)
Singleton pregnancy Prostanoid and period Ratio dinor-6-keto-PGFaa versus dinor-TxB9 Days 0-9 Days 10-19 Days 20-39 Days 40-59 Days 60-99 Days 100-120 Ratio PGI 2 versus TxA2 metabolites Days 0-9 Days 10-19 Days 20-39 Days 40-59 Days 60-99 Days 100-120
Twin pregnancy
Median
Range
Median
Range
1.26 1.36 1.19 1.59 1.76 2.80
0.77-1.72 0.66-1.90 0.6%4.99 0.23-7.06 0.75-9.54 0.37-13.48'
1.38 2.41 2.46 2.70 2.96 2.19
0.84-3.54 0.51-3.40 0.26-6.07 0.39-6.20 0.2%6.78 0.31-6.63
1.66 1.69 1.73 2.29 2.44 3.45
1.19-2.37 0.95-2.74 1.27-5.74 0.51-8.02 1.43-10.59 0.7%14.96t
1.83 3.11 2.47 2.68 3.15 3.59
1.22-3.36 0.78-3.57 0.3645.87 0.54-5.82 0.40-7.21 0.38-7.35
*p < 0.05, significance versus days 0 to 9. tP < 0.02, significance versus days 0 to 9.
centrations of 6-keto-PGFlc, have been foun d at the site of implantation in rabbits ~~and mice. z~In w o m e n both firsttrimester decidual cells and placental tissue possess the key enzymes for PGI 2 and TxA 2 synthesis. ~ The vasoactive prostanoids PGI z and TxAz could exert their actions not only at the implantation site but also on the d e v e l o p m e n t of the uteroplacental vasculature as a d e t e r m i n a n t of successful pregnancy outcome. Prostanoid excretion measured in our study provides a
reasonable reflection of PGI 2 and TxA 2 production in vitro. 6-Keto-PGFla and TxB 2 are the stable hydrolysis products, respectively, of PGI 2 mad TxA2, whereas the dinor c o m p o u n d s 2, 3-dinor-6-keto-PGFlc, and 2,3-dinorTxBz are known to be their major urinary metaholites.lS, 14We observed a twofold increase in 6-keto-PGFl= levels and a threefold increase in 2,3-dinor-6-keto-PGFl~ levels in singleton pregnancies between the day of ET and day 120 of gestation. T h e m u c h smaller increase in the
Volume 174, Nmnber 5 AmJ Obstet Gynecol
excretion o f T x B 2 and 2,3-dinor-TxB 2 resulted in a significant elevation of the PGI2-to-TxA 2 ratio with advancing gestation, c o n f i r m i n g cross-sectional observations in normal singleton pregnancies. 7 Increases in the excretion of PGI 2 metabolites were m o r e p r o n o u n c e d in twin pregnancies than in singleton pregnancies. Increases in the excretion of TxA 2 metabolites, on the o t h e r hand, were roughly of the same o r d e r of magnitude. O n the whole, ratios between PGI 2 and TxA 2 metabolites thus t e n d e d to be h i g h e r in twin than in singleton pregnancies, but this was only so in the early stages o f p r e g n a n c y w h e n most of the physiologic adaptations are known to occur. After the first trimester o f pregnancy, the ratios o f both the d i n o r c o m p o u n d s and the total PG12 versus TxA 2 metabolites hardly differed between twin and singleton pregnancies. This suggests that uterine and placental size per se have little bearing on the PGIe versus t h r o m b o x a n e balance in pregnancy. We thank Mr. A. van Leeuwen for technical assistance with the prostanoid measurements. REFERENCES
1. Robertson SA, Guilbert LJ, Seamark RF, Wegmann TG. Cytokines in gestation. Crit Rev Immunol 1994;14:23992. 2. Schultz GA, Heyner S. Growth factors in preimplantation mammalian embryos. Oxf Rev Reprod Biol 1994;15:4381.
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