Exp. Clin. Endocrino!. Endocrinol. Vol. 95, No. 1, 1, 1990, 1990, pp. pp. 105-109 105-109
J. A. Barth, Leipzig
Circulating Levels of Placental Protein 12 (PP 12) in Diabetic Pregnancy Complicated by Retinopathy*) V. BRIESE1), BRIEs11), G. N. THAN2), D. G. SZAB03), A. SZILAGYI2), SzILAGYI2), R.-R. STRACHE),
and 11.-H. BITTNER4) P. HEINKE1), HEINKE1),H. H.Horr1) Horr) and BTTNER4) With 1 Figure Summary. Placental protein 12 (PP 12) is a soluble tissue antigen Immunohistochemical studies have localized PP 12 in the placental syncytiotrophoblast, chorion and amnion, and also in the de. decidua. During normal pregnancy serum-PP 12 is already raised in the first trimester, there is then a peak at 18 weeks, a gradual fall until 32 weeks, and a moderate increase thereafter. The mean of the healthy control group at 18 weeks of pregnancy was 122.9 ± 47.5 g/l. The mean g/l. There was no signiof the diabetic group with retinopathy at the same time was 192.2 + 78.8 gfl. ficant difference between background retinopathy and the proliferative form of diabetic retinopathy. At all times during pregnancy the median values of PP 12 in diabetic pregnancies were significantly (p < 0.01) above the control values. Increased PP 12 levels in diabetic pregnancy complicated by retinopathy are probably caused by decidual, placental and amniotic leakages.
Key words: Placental protein 12 (PP 12) - PP 12 serum levels in high risk pregnancies - PP 12 in diabetic retinopathy
Introduction
The human decidua, placenta, fetus and fetal membranes secrete many proteins and steroids into the maternal circulation and their measurement has been used to assess fetal wellbeing. The development of specific and accurate diagnostic tests for the identification of the fetus at risk of dying or being damaged in utero has been an elusive goal. Recently, more studies monitoring diseases in pregnancies were carried out.
In investigations regarding complications in pregnancy, decidual function has received little attention. Placental protein 12 (PP 12), synthesized in the decidua, could be a suitable marker for the decidual function in pregnancy (Rutanen et al., 1985). *) Dedicated to Prof. H. Bibergeil on the occasion of his 85th birthday.
Downloaded by: National University of Singapore. Copyrighted material.
1) Central Institute of Diabetes "Gerhardt Katsch" (Director: OMR Prof. Dr. se. med. H. Bibergeil), Karlsburg/GDR, 2) Obstetrics and Gynecological Clinic (Director: Prof. Dr. sc. med. I. Osaba), Csaba), University University Medical Medical School, School, Pecs/Hungary, Pecs/Hungary,3) 3)Institute Instituteof of Biochemistry (Director: Prof. Dr. Sc. sc. med. med. H. H. Alkonyi), Alkonyi), Pecs/Hungary, Pecs/Hungary, and and 4) 4) ObsteObstetrics and Gynecological Clinic Clinic (Director: (Director: Prof. Prof. Dr. Dr. Sc. se. med. H. H. H. Büttner), Büttner), Wismar/ Wismar/ GDR
Exp. Clin. Endocrinol. 95 (1990) 1
106
Diabetic retinopathy is a complication of the microvascular system in a progressive also stage of disease. It was assumed that diabetic microvascular disease is also present in materno-fetal interface (Solerte et al., 1984). In our patients showing
evidence of retinopathy circulating levels of PP 12 were examined in order to verify the diagnostic tool in pregnancy.
The total sample for the present study comprised 473 pregnant women. PP 12 serum estimations were carried out in 420 healthy pregnant women between the 7th and 40th week of their pregnancy (published by Than et al., al., 1983). 1983). The The median median age age was was24 24(18-39 (18-39yrs). yrs).The Thedistribution distributionofofmaternal maternal weights as as well well as as birthweights birthweights of of newborns newborns was was normally. normally. Serum Serum samples samples were were collected collected from from 53 53 weights insulin-dependent (IDDM) diabetic pregnant women (50 samples 28-34 weeks; 53 samples 35-39 weeks). Diabetic disease was complicated by retinopathy. Retinopathy was evaluated by ophthalmoscopic examination. 28 diabetic patients were identified as having circinate deposits involving or threatening the macula. The circinate ring appeared clinically as intraretinal hard exsudates deposited circumferentially around a central focus of permeable retinal capillaries. Only two birthweights were above the 95th percentile and five were below the 5th percentile. Characteristics are described in Tables 1 and 2. The mean of the gestational age at delivery (37.6 (37M weeks) weeks) was was about about two two to three weeks before term, this being caused by fetal and maternal risk factors. Birthweights below the 5th percentile were found in 10%, probably caused by disturbed placental microvascularization followed of fetal malnutrition syndrome. In cases of pregnancy-induced hypertension we have seen mild and moderate forms of pre-eclampsia. Serum PP 12 concentrations were determined by double antibody radioimmunoassay as has been previously described (Szabo et al., 1981; Than et al., 1983).
Maternal and and neonatal neonatal characteristics characteristics in in diabetic diabetic retinopathy retinopathy Table 1 Maternal
Mean ± SD
Character Age (yrs) Gestational age at delivery (wk) Birth weight (g)
Chronic pyelonephritis Incidence of prematurity Pregnancy induced hypertension (PIH) Diabetic nephropathy Neonatal macrosomia Low for gestational age (5th centile)
25.3 ± 5.1 37.6 ± 1.5 37M 3112 ± 712.5
Range
19-34 34-40 1180-4160 1180-410
0/ /0 /0 3.9 3.9 6.5 4.3 2.0 7.7 10.1 10.1
Insulin requirement and glycosylated hemoglobin during, pregnancy complicated by diabetic retinopathy Table 2
Insulin Insulin requirement (units) HbA1 (rel. %) HbAJ
ist trimester Mean + ± SD
2nd trimester Mean ± SD
3rd 3rd trimester Mean ± SD
42.8 ± 12.4
58.8 ± 12.1
77.2 77.2 ±± 21.2 21.2
9.4± 1.8
9.0 9.0±± 1.2
8.2 ± 1M 1.6
Downloaded by: National University of Singapore. Copyrighted material.
Subjects and Methods
V. BRIEsxetetal., al.,Placental PlacentalProtein Protein12 12in inDiabetic Diabetic Pregnancy Pregnancy V. BRIEs
107
10%.
Sera from 20 healthy men and from 20 non-pregnant women served as controls. Serum samples
were stored at 20°C. Statistics. Statistical differences were calculated using the analysis of variance according to the Mann-Whitney Test. Values of p < 0.05 were considered statistically significant.
Results
In healthy pregnant women women PP PP 12 12 serum serum levels levels demonstrate demonstrateaacontinuous continuousincrease increase until weeks 16-20 followed by a fall thereafter up to the beginning of the 3rd trimester (Fig. 1). A steady increase increase occurred occurred up up to to term term reaching reaching aa mean meanvalue valueof of125.9 125.9± ± 47.6 g/l at term (Table 3). Serum-PP 12
r
(»gui (ugI11 30Q1 3011'
p' 0.01 p0.Ol
0.90
0.50
200.0
0.90 0.10 0.50
100.0 0.10
24.0 15.0
0
Itri.ti i
I
t
t
ti tiIl
t
t
II ti
12 16 20 24 26 32 36 40 8 1216202426323640 8
weeks ion weeks of of gestot gestotion
(median and and 90% 90% confidence confidence limits) limits)in innormal normalpregnant pregnantpatients patients(shaded (shaded Fig. 1 Serum PP 12 levels (median Pig.
area) and pregnant patients with diabetic retinopathy. PP 12 levels from normal pregnant patients were taken from Than et al. (1983).
Downloaded by: National University of Singapore. Copyrighted material.
Highly purified PP 12 (Lot. ZA)(A) (A)rabbit rabbitserum serum (Behring(Behring(Lot. No No 64/91) M/91) and anti-PP anti-PP 12 12 (Lot. (Lot. No No 461 41 ZA) werke AG, Marburg/Lahn) were. were used usedfor forradioimmunoassay. radioimmunoassay Radioiodination was carried out using the Marchalonis Marchalonis method method (1969) (199) using using 125J 1251and and lactoperoxidase-H202. lactoperoxidase-11202.The Thehighest highest specific specific activity activity was 1.73 TBq/g (MTA Isotop Institute, Budapest, Hungary). Sephadex G-100 chromatography was used to separate the labelled protein from the free isotopic iodine. All50 50 sd-samples wereanalysed analysedinintriplicate. triplicate.The The standard standard curve curve gave gave aa range range of of 7.5l-samples were iodine. All 1,000 1,000 g/l, PP 12 diluted with phosphate buffer and PP 12 free dog serum. The antibody dilution was 1:2,000. 1: 2,000.AAdouble-antibody double-antibodyradioimmunoassay radioimmunoassaywas wasemployed employedusing usinganti-rabbit anti-rabbitgamma-globulin gamma-globulin goat serum (Behringwerke AG, Cat. No. OTOP 14/15) with a dilution of 1:10. 1 10. The incubation time was 28 was 28h. h. The sensitivity of assay expressed as the concentration which caused a reduction of 10% bound g/l. The PP 12, in in relation relationto tozero zerobinding bindingwas was1515 zg/l. Theintraintra-and andinterassay interassay variations variations were were less less than
Exp. Clin. Endocrinol. 95 (1990) 1
108
Table 3 Maternal PP 12 serum concentrations (g/l) in normal pregnancy and pregnant patients
with diabetic retinopathy
79
11-15 17-21 23-27 29-33 35-39
normal normal pregnancy Mean Mean ± SD 71.2
32.0 32.0
121.3 121.3 ± 42.9 122.9 ± 47.5 98.2 ± 35.1 98.2 35.1 108.0 ± 43.3 123.9 ± 47.6
diabetic pregnancy Mean ± SD
211.9 ± 79.8** 218.8
89.5**
192.2 ± 78.8** 218.1 ± 101.3** 216.1
211.5 ± 91.7** 207.7 ±±77.0** 207.7 77.0"
** p < 0.01
In contrast, elevated PP 12 serum levels were found in all diabetic pregnant patients with retinopathy (p < 0.01). We have found no significant differences between background retinopathy and the proliferative form of retinopathy as far as maternal PP 12 serum levels are concerned. Additionally, there was no relation between maternal PP 12 serum concentrations, mother's age and birth weights. Discussion
PP 12 is one of the recently recognized water soluble soluble placenta placenta proteins,an proteins,an alpha-1 alpha-1 assumed to to be be specific specific to to placenta, placenta,according accordingto toclassical classicalimmuimmu globulin which has been assumed nological methods (Bohn and Kraus, 1980). PP 12 is a glycoprotein with mol wt estimates of 25,200 (ultracentrifugation) and 51,000 (sodium dodecyl sulfate polyacrylamide gel electrophoresis) Immunohistochemical studies have localized PP 12 in the placental syncytiotrophoblast, chorion and amnion, and also in the the decidua decidua (Inaba (Inaba et et al., al., 1980). 1980). Based Basedon onthese thesefindings findingsInaba Inaba et al. (1982) proposed that PP PP 12 12 be be regarded regarded as as one one of of the the trophoblast-neutrophiltrophoblast-neutrophilcarcinoma-associated antigens (TNCA). During normal pregnancy serum-PP 12 is already raised in the first trimester, there is then a peak at 18 weeks, a gradual fall until 32 weeks, and a moderate increase thereafter. We reported here about high circulating PP 12 levels in insulin-dependent diabetic pregnant women complicated by benign and proliferative retinopathy. The increased PP 12 levels could be caused by placental and amniotic leakages or decidual deteriorations followed by an increased PP 12 passage through the placenta and amnion, respectively. The knowledge of diabetic retinopathy as a microvascular disease favoured the hypothesis of decidual deteriorations (Moloney and Drury, 1982). On the other hand, it may be that increased PP 12 production is a main factor in the immunoprotection during diabetic pregnancy. PP 12 obviously belongs to a multifactorial immunological defence system incorporating both specific and nonspecific factors. Several findings suggest that the immune system is at least partly dependent upon normal insulin metabolism and it is of interest that numerous immunological functions may be disturbed in subjects with upcontrolled uncontrolled diabetes. A pregnancy complicated by diabetes must therefore be regarded as a disturbed pregnancy from the immunological point of view. Therefore, it appeared appropriate to study serum placental protein concentrations of pregnant patients with diabetes mellitus. Future prospective studies are planned in diabetic pregnancy to clarify the meaning of high maternal serum concentrations concentrations in in pregnancy-specific pregnancy-specificas aswell wellas asassociated associatedproproteins.
Downloaded by: National University of Singapore. Copyrighted material.
WK
V. Brus et al., Placental Protein 12 in Diabetic Pregnancy
109
References BOHN, H.; KRAUS, W.: Isolierung und Charakterisierung eines neuen plazentaspezifischen Preotejas (PP 12). Arch. Gynecol. 229 (1980) 279-291.
INABA, N.; RENK, T.; Bo, H.: Immunohistocheinical localization of placental proteins (PP89 101112) in human term placentae. Arch. Gynecol. 230 (1980) 109. INABA, N.; ISHIGE, H.; IzICHI, M.; SEr0H, N.; KATOH, T.; SEKIYA, S.; SmorAKE, S.; OrnAWA, R.; TAKAMIZAWA, H.; NITOH, A.; RENK, T.; Bo, H.: Possible new marker in trophoblastic diseases. Am. J. Obstet. Gynecol. 143 (1982) 973-974. MA.RaHALONIS, J. J.: An enzymic method for the trace iodinations of immunoglobulins and other
proteins. Biochem. J. 113 (199) 299-305. pathy. Am. J. Ophthalmol. 93 (1982) 745-75e. [] RurA, E. M.; K0I5rIIcEN, R.; WAIILSrRÖM, T.: Synthesis of placental protein 12 by human decidua. Endocrinology 116 (1985) 1304-1307. S0LERrE, S. B.; ADAMO, S.; VIOLA, C.; Scirwn&, G P C; CRIPPA, A.; FERRARI, E.: Acutephase protein reactants pattern and alpha2-macroglobulin in diabetes mellitus. Pathophysiological aspects in diabetic microangiopathy. La Ricerca Clin. Lab. 14 (1984) 575-579. SzABo, D.; THAN, G. N.; BOGNAE, Z.: Development of a radioimmunoass&y for placental protein 12. IRCS Med. Sci. 9 (1981) THAN, G, N,; CZABA, I. F.; SZABO, D. G.; BOGNAr, Y. J.; ARANY, A.; Bomc, H.: Levels of placenta-
specific tissue protein 12 (PP 12) in serum during normal pregnancy and in patients with trophoblastic tumour. Arch. Gynecol. 234 (1983) 39-4e. (Accepted 25 April 1989)
Author's adress: Dr. sc. med. V. BRTSE, Central Institute of Diabetes "Gerhardt Katsch", Karlsburg, DDR-2201
Downloaded by: National University of Singapore. Copyrighted material.
MOLO]EY, I. M.; DRURY, M. I.: The effect of pregnancy on the natural course of diabetic retino-
J. A. Barth, Leipzig
Circulating Levels of Placental Protein 12 (PP 12) in Diabetic Pregnancy Complicated by Retinopathy*) V. BRIESE1), BRIEs11), G. N. THAN2), D. G. SZAB03), A. SZILAGYI2), SzILAGYI2), R.-R. STRACHE),
and 11.-H. BITTNER4) P. HEINKE1), HEINKE1),H. H.Horr1) Horr) and BTTNER4) With 1 Figure Summary. Placental protein 12 (PP 12) is a soluble tissue antigen Immunohistochemical studies have localized PP 12 in the placental syncytiotrophoblast, chorion and amnion, and also in the de. decidua. During normal pregnancy serum-PP 12 is already raised in the first trimester, there is then a peak at 18 weeks, a gradual fall until 32 weeks, and a moderate increase thereafter. The mean of the healthy control group at 18 weeks of pregnancy was 122.9 ± 47.5 g/l. The mean g/l. There was no signiof the diabetic group with retinopathy at the same time was 192.2 + 78.8 gfl. ficant difference between background retinopathy and the proliferative form of diabetic retinopathy. At all times during pregnancy the median values of PP 12 in diabetic pregnancies were significantly (p < 0.01) above the control values. Increased PP 12 levels in diabetic pregnancy complicated by retinopathy are probably caused by decidual, placental and amniotic leakages.
Key words: Placental protein 12 (PP 12) - PP 12 serum levels in high risk pregnancies - PP 12 in diabetic retinopathy
Introduction
The human decidua, placenta, fetus and fetal membranes secrete many proteins and steroids into the maternal circulation and their measurement has been used to assess fetal wellbeing. The development of specific and accurate diagnostic tests for the identification of the fetus at risk of dying or being damaged in utero has been an elusive goal. Recently, more studies monitoring diseases in pregnancies were carried out.
In investigations regarding complications in pregnancy, decidual function has received little attention. Placental protein 12 (PP 12), synthesized in the decidua, could be a suitable marker for the decidual function in pregnancy (Rutanen et al., 1985). *) Dedicated to Prof. H. Bibergeil on the occasion of his 85th birthday.
Downloaded by: National University of Singapore. Copyrighted material.
1) Central Institute of Diabetes "Gerhardt Katsch" (Director: OMR Prof. Dr. se. med. H. Bibergeil), Karlsburg/GDR, 2) Obstetrics and Gynecological Clinic (Director: Prof. Dr. sc. med. I. Osaba), Csaba), University University Medical Medical School, School, Pecs/Hungary, Pecs/Hungary,3) 3)Institute Instituteof of Biochemistry (Director: Prof. Dr. Sc. sc. med. med. H. H. Alkonyi), Alkonyi), Pecs/Hungary, Pecs/Hungary, and and 4) 4) ObsteObstetrics and Gynecological Clinic Clinic (Director: (Director: Prof. Prof. Dr. Dr. Sc. se. med. H. H. H. Büttner), Büttner), Wismar/ Wismar/ GDR
Exp. Clin. Endocrinol. 95 (1990) 1
106
Diabetic retinopathy is a complication of the microvascular system in a progressive also stage of disease. It was assumed that diabetic microvascular disease is also present in materno-fetal interface (Solerte et al., 1984). In our patients showing
evidence of retinopathy circulating levels of PP 12 were examined in order to verify the diagnostic tool in pregnancy.
The total sample for the present study comprised 473 pregnant women. PP 12 serum estimations were carried out in 420 healthy pregnant women between the 7th and 40th week of their pregnancy (published by Than et al., al., 1983). 1983). The The median median age age was was24 24(18-39 (18-39yrs). yrs).The Thedistribution distributionofofmaternal maternal weights as as well well as as birthweights birthweights of of newborns newborns was was normally. normally. Serum Serum samples samples were were collected collected from from 53 53 weights insulin-dependent (IDDM) diabetic pregnant women (50 samples 28-34 weeks; 53 samples 35-39 weeks). Diabetic disease was complicated by retinopathy. Retinopathy was evaluated by ophthalmoscopic examination. 28 diabetic patients were identified as having circinate deposits involving or threatening the macula. The circinate ring appeared clinically as intraretinal hard exsudates deposited circumferentially around a central focus of permeable retinal capillaries. Only two birthweights were above the 95th percentile and five were below the 5th percentile. Characteristics are described in Tables 1 and 2. The mean of the gestational age at delivery (37.6 (37M weeks) weeks) was was about about two two to three weeks before term, this being caused by fetal and maternal risk factors. Birthweights below the 5th percentile were found in 10%, probably caused by disturbed placental microvascularization followed of fetal malnutrition syndrome. In cases of pregnancy-induced hypertension we have seen mild and moderate forms of pre-eclampsia. Serum PP 12 concentrations were determined by double antibody radioimmunoassay as has been previously described (Szabo et al., 1981; Than et al., 1983).
Maternal and and neonatal neonatal characteristics characteristics in in diabetic diabetic retinopathy retinopathy Table 1 Maternal
Mean ± SD
Character Age (yrs) Gestational age at delivery (wk) Birth weight (g)
Chronic pyelonephritis Incidence of prematurity Pregnancy induced hypertension (PIH) Diabetic nephropathy Neonatal macrosomia Low for gestational age (5th centile)
25.3 ± 5.1 37.6 ± 1.5 37M 3112 ± 712.5
Range
19-34 34-40 1180-4160 1180-410
0/ /0 /0 3.9 3.9 6.5 4.3 2.0 7.7 10.1 10.1
Insulin requirement and glycosylated hemoglobin during, pregnancy complicated by diabetic retinopathy Table 2
Insulin Insulin requirement (units) HbA1 (rel. %) HbAJ
ist trimester Mean + ± SD
2nd trimester Mean ± SD
3rd 3rd trimester Mean ± SD
42.8 ± 12.4
58.8 ± 12.1
77.2 77.2 ±± 21.2 21.2
9.4± 1.8
9.0 9.0±± 1.2
8.2 ± 1M 1.6
Downloaded by: National University of Singapore. Copyrighted material.
Subjects and Methods
V. BRIEsxetetal., al.,Placental PlacentalProtein Protein12 12in inDiabetic Diabetic Pregnancy Pregnancy V. BRIEs
107
10%.
Sera from 20 healthy men and from 20 non-pregnant women served as controls. Serum samples
were stored at 20°C. Statistics. Statistical differences were calculated using the analysis of variance according to the Mann-Whitney Test. Values of p < 0.05 were considered statistically significant.
Results
In healthy pregnant women women PP PP 12 12 serum serum levels levels demonstrate demonstrateaacontinuous continuousincrease increase until weeks 16-20 followed by a fall thereafter up to the beginning of the 3rd trimester (Fig. 1). A steady increase increase occurred occurred up up to to term term reaching reaching aa mean meanvalue valueof of125.9 125.9± ± 47.6 g/l at term (Table 3). Serum-PP 12
r
(»gui (ugI11 30Q1 3011'
p' 0.01 p0.Ol
0.90
0.50
200.0
0.90 0.10 0.50
100.0 0.10
24.0 15.0
0
Itri.ti i
I
t
t
ti tiIl
t
t
II ti
12 16 20 24 26 32 36 40 8 1216202426323640 8
weeks ion weeks of of gestot gestotion
(median and and 90% 90% confidence confidence limits) limits)in innormal normalpregnant pregnantpatients patients(shaded (shaded Fig. 1 Serum PP 12 levels (median Pig.
area) and pregnant patients with diabetic retinopathy. PP 12 levels from normal pregnant patients were taken from Than et al. (1983).
Downloaded by: National University of Singapore. Copyrighted material.
Highly purified PP 12 (Lot. ZA)(A) (A)rabbit rabbitserum serum (Behring(Behring(Lot. No No 64/91) M/91) and anti-PP anti-PP 12 12 (Lot. (Lot. No No 461 41 ZA) werke AG, Marburg/Lahn) were. were used usedfor forradioimmunoassay. radioimmunoassay Radioiodination was carried out using the Marchalonis Marchalonis method method (1969) (199) using using 125J 1251and and lactoperoxidase-H202. lactoperoxidase-11202.The Thehighest highest specific specific activity activity was 1.73 TBq/g (MTA Isotop Institute, Budapest, Hungary). Sephadex G-100 chromatography was used to separate the labelled protein from the free isotopic iodine. All50 50 sd-samples wereanalysed analysedinintriplicate. triplicate.The The standard standard curve curve gave gave aa range range of of 7.5l-samples were iodine. All 1,000 1,000 g/l, PP 12 diluted with phosphate buffer and PP 12 free dog serum. The antibody dilution was 1:2,000. 1: 2,000.AAdouble-antibody double-antibodyradioimmunoassay radioimmunoassaywas wasemployed employedusing usinganti-rabbit anti-rabbitgamma-globulin gamma-globulin goat serum (Behringwerke AG, Cat. No. OTOP 14/15) with a dilution of 1:10. 1 10. The incubation time was 28 was 28h. h. The sensitivity of assay expressed as the concentration which caused a reduction of 10% bound g/l. The PP 12, in in relation relationto tozero zerobinding bindingwas was1515 zg/l. Theintraintra-and andinterassay interassay variations variations were were less less than
Exp. Clin. Endocrinol. 95 (1990) 1
108
Table 3 Maternal PP 12 serum concentrations (g/l) in normal pregnancy and pregnant patients
with diabetic retinopathy
79
11-15 17-21 23-27 29-33 35-39
normal normal pregnancy Mean Mean ± SD 71.2
32.0 32.0
121.3 121.3 ± 42.9 122.9 ± 47.5 98.2 ± 35.1 98.2 35.1 108.0 ± 43.3 123.9 ± 47.6
diabetic pregnancy Mean ± SD
211.9 ± 79.8** 218.8
89.5**
192.2 ± 78.8** 218.1 ± 101.3** 216.1
211.5 ± 91.7** 207.7 ±±77.0** 207.7 77.0"
** p < 0.01
In contrast, elevated PP 12 serum levels were found in all diabetic pregnant patients with retinopathy (p < 0.01). We have found no significant differences between background retinopathy and the proliferative form of retinopathy as far as maternal PP 12 serum levels are concerned. Additionally, there was no relation between maternal PP 12 serum concentrations, mother's age and birth weights. Discussion
PP 12 is one of the recently recognized water soluble soluble placenta placenta proteins,an proteins,an alpha-1 alpha-1 assumed to to be be specific specific to to placenta, placenta,according accordingto toclassical classicalimmuimmu globulin which has been assumed nological methods (Bohn and Kraus, 1980). PP 12 is a glycoprotein with mol wt estimates of 25,200 (ultracentrifugation) and 51,000 (sodium dodecyl sulfate polyacrylamide gel electrophoresis) Immunohistochemical studies have localized PP 12 in the placental syncytiotrophoblast, chorion and amnion, and also in the the decidua decidua (Inaba (Inaba et et al., al., 1980). 1980). Based Basedon onthese thesefindings findingsInaba Inaba et al. (1982) proposed that PP PP 12 12 be be regarded regarded as as one one of of the the trophoblast-neutrophiltrophoblast-neutrophilcarcinoma-associated antigens (TNCA). During normal pregnancy serum-PP 12 is already raised in the first trimester, there is then a peak at 18 weeks, a gradual fall until 32 weeks, and a moderate increase thereafter. We reported here about high circulating PP 12 levels in insulin-dependent diabetic pregnant women complicated by benign and proliferative retinopathy. The increased PP 12 levels could be caused by placental and amniotic leakages or decidual deteriorations followed by an increased PP 12 passage through the placenta and amnion, respectively. The knowledge of diabetic retinopathy as a microvascular disease favoured the hypothesis of decidual deteriorations (Moloney and Drury, 1982). On the other hand, it may be that increased PP 12 production is a main factor in the immunoprotection during diabetic pregnancy. PP 12 obviously belongs to a multifactorial immunological defence system incorporating both specific and nonspecific factors. Several findings suggest that the immune system is at least partly dependent upon normal insulin metabolism and it is of interest that numerous immunological functions may be disturbed in subjects with upcontrolled uncontrolled diabetes. A pregnancy complicated by diabetes must therefore be regarded as a disturbed pregnancy from the immunological point of view. Therefore, it appeared appropriate to study serum placental protein concentrations of pregnant patients with diabetes mellitus. Future prospective studies are planned in diabetic pregnancy to clarify the meaning of high maternal serum concentrations concentrations in in pregnancy-specific pregnancy-specificas aswell wellas asassociated associatedproproteins.
Downloaded by: National University of Singapore. Copyrighted material.
WK
V. Brus et al., Placental Protein 12 in Diabetic Pregnancy
109
References BOHN, H.; KRAUS, W.: Isolierung und Charakterisierung eines neuen plazentaspezifischen Preotejas (PP 12). Arch. Gynecol. 229 (1980) 279-291.
INABA, N.; RENK, T.; Bo, H.: Immunohistocheinical localization of placental proteins (PP89 101112) in human term placentae. Arch. Gynecol. 230 (1980) 109. INABA, N.; ISHIGE, H.; IzICHI, M.; SEr0H, N.; KATOH, T.; SEKIYA, S.; SmorAKE, S.; OrnAWA, R.; TAKAMIZAWA, H.; NITOH, A.; RENK, T.; Bo, H.: Possible new marker in trophoblastic diseases. Am. J. Obstet. Gynecol. 143 (1982) 973-974. MA.RaHALONIS, J. J.: An enzymic method for the trace iodinations of immunoglobulins and other
proteins. Biochem. J. 113 (199) 299-305. pathy. Am. J. Ophthalmol. 93 (1982) 745-75e. [] RurA, E. M.; K0I5rIIcEN, R.; WAIILSrRÖM, T.: Synthesis of placental protein 12 by human decidua. Endocrinology 116 (1985) 1304-1307. S0LERrE, S. B.; ADAMO, S.; VIOLA, C.; Scirwn&, G P C; CRIPPA, A.; FERRARI, E.: Acutephase protein reactants pattern and alpha2-macroglobulin in diabetes mellitus. Pathophysiological aspects in diabetic microangiopathy. La Ricerca Clin. Lab. 14 (1984) 575-579. SzABo, D.; THAN, G. N.; BOGNAE, Z.: Development of a radioimmunoass&y for placental protein 12. IRCS Med. Sci. 9 (1981) THAN, G, N,; CZABA, I. F.; SZABO, D. G.; BOGNAr, Y. J.; ARANY, A.; Bomc, H.: Levels of placenta-
specific tissue protein 12 (PP 12) in serum during normal pregnancy and in patients with trophoblastic tumour. Arch. Gynecol. 234 (1983) 39-4e. (Accepted 25 April 1989)
Author's adress: Dr. sc. med. V. BRTSE, Central Institute of Diabetes "Gerhardt Katsch", Karlsburg, DDR-2201
Downloaded by: National University of Singapore. Copyrighted material.
MOLO]EY, I. M.; DRURY, M. I.: The effect of pregnancy on the natural course of diabetic retino-
