- Email: [email protected]
First-trimester maternal serum levels of placenta growth factor as predictor of preeclampsia and fetal growth restriction
First-Trimester Maternal Serum Levels of Placenta Growth Factor as Predictor of Preeclampsia and Fetal Growth Restriction Charas Y. T. Ong, MD, Adolfo W. Liao, MD, Ana M. Cacho, MD, Kevin Spencer, FRCPath, and Kypros H. Nicolaides, MD OBJECTIVE: To determine whether the reported decrease in maternal serum placenta growth factor concentration in preeclampsia is evident from the first trimester and before clinical onset of the disease. We also examined levels in pregnancies that subsequently resulted in fetal growth restriction (FGR). METHODS: Placenta growth factor concentration was measured in stored maternal serum samples obtained at 11–14 weeks of gestation from 131 women who subsequently developed preeclampsia, 137 women who subsequently developed FGR, and 400 randomly selected controls who did not develop preeclampsia or FGR. Preeclampsia was defined as diastolic blood pressure of 90 mmHg or more on two occasions 4 hours apart, accompanied by proteinuria (more than 300 mg of total protein in a 24-hour urine collection or a positive test for albumin on reagent strip) in women with no pre-existing hypertensive or renal disease. Fetal growth restriction was considered present if a woman subsequently delivered a live infant with a birth weight below the fifth centile for gestation. RESULTS: In the control group, maternal serum placenta growth factor concentration increased with gestation. Compared with the controls (median multiple of the median 0.98, standard deviation [SD] 0.51), levels in the preeclampsia group (median multiple of the median 1.09, SD 0.52) were not significantly different (t ⴝ 1.83, P ⴝ .07), but in the FGR group (median multiple of the median 1.57, SD 0.74), levels were significantly increased (t ⴝ 10.85, P < .001). CONCLUSION: The previously reported decrease in serum placenta growth factor levels in women with preeclampsia might not precede clinical onset of the disease and is not apparent in the first trimester of pregnancy. Levels are significantly increased in pregnancies resulting in FGR.
From the Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, London; and Endocrine Unit, Clinical Biochemistry Department, Harold Wood Hospital, Romford, Essex, United Kingdom. Supported by a grant from the Fetal Medicine Foundation (U.K. Charity No. 1037116).
608
(Obstet Gynecol 2001;98:608 –11. © 2001 by the American College of Obstetricians and Gynecologists.)
Placenta growth factor, a homodimeric glycoprotein belonging to the family of vascular endothelial growth factors, is expressed predominantly by cyto- and syncytiotrophoblasts in the placenta and is capable of inducing proliferation, migration, and activation of endothelial cells.1–3 Placenta growth factor has been suggested as one possible marker and mediator of endothelial cell dysfunction in preeclampsia.4,5 One study found that maternal serum placenta growth factor concentrations in 30 patients with preeclampsia at a mean gestation of 36 weeks were about three times lower than in 30 normotensive women matched for gestation.4 Similarly, another study found that maternal serum placenta growth factor concentrations in 28 patients with preeclampsia at a mean gestation of 30 weeks were about ten times lower than in 28 normotensive women matched for maternal age, parity, and gestation.5 The development of preeclampsia and/or fetal growth restriction (FGR) is thought to be a consequence of impaired trophoblastic invasion of the maternal spiral arteries in early pregnancy, resulting in a high-resistance uteroplacental circulation and reduced placental perfusion.6,7 However, there are no reports of maternal serum placenta growth factor levels in pregnancies complicated by FGR in the absence of preeclampsia. The aim of this study was to investigate whether the reported decrease in maternal serum placenta growth factor concentration in preeclampsia is evident from the first trimester and before clinical onset of the disease. In addition, we examined levels of placenta growth factor in pregnancies that subsequently resulted in FGR in the absence of preeclampsia. MATERIALS AND METHODS At King’s College Hospital, London, and Harold Wood Hospital, Essex, women registered for antenatal care are
VOL. 98, NO. 4, OCTOBER 2001 © 2001 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/01/$20.00 PII S0029-7844(01)01528-9
Table 1. Characteristics of the Preeclampsia, Fetal Growth Restriction, and Control Groups
Maternal age (y) Maternal weight (kg) White race Cigarette smoking Primigravid Gestation at sampling (wk) Gestation at delivery (wk) Birth weight (g)
Preeclampsia group (n ⫽ 131)
Fetal growth restriction group (n ⫽ 137)
Controls (n ⫽ 400)
29.0 ⫾ 5.6 74.1 ⫾ 15.9 98 (74.8%) 18 (13.7%) 67 (51.1%) 12 ⫾ 0.8 37.1 ⫾ 3.7* 2775 ⫾ 873*
28.4 ⫾ 6.0 59.0 ⫾ 12.3* 109 (79.6%) 46 (33.6%)* 55 (40.1%) 12 ⫾ 0.8 39.6 ⫾ 2.5* 2460 ⫾ 413*
28.2 ⫾ 5.3 67.9 ⫾ 13.7 336 (84.0%) 56 (14.0%) 197 (49.3%) 12 ⫾ 0.8 40.1 ⫾ 1.2 3488 ⫾ 396
Data are presented as mean ⫾ standard deviation or n (%). * Significantly lower, P ⬍ .001.
offered the option of attending a one-stop clinic for assessment of risk of trisomy 21 by a combination of measurement of fetal nuchal translucency thickness and determination of maternal serum free -hCG and pregnancy-associated plasma protein A levels at 11–14 weeks of gestation.8 A sample of blood collected at this clinic is stored for subsequent analysis as part of a research program to identify potential markers for screening of pregnancy complications. Women gave informed consent to participate in the study, which was approved by the hospital ethics committees. Pregnancy outcome was obtained from all patients and entered into a database, which was searched to identify those who developed preeclampsia and those who developed FGR in the absence of preeclampsia. Preeclampsia was defined as diastolic blood pressure of 90 mmHg or more on two occasions 4 hours apart, accompanied by proteinuria (more than 300 mg of total protein in a 24-hour urine collection or a 1⫹ albumin on reagent strip) in women with no pre-existing hypertensive or renal disease.9 Fetal growth restriction was considered present if a woman subsequently delivered a live infant with a birth weight below the fifth centile for gestation.10 The database then was searched to identify healthy women with normal singleton pregnancies who delivered appropriately grown infants at term, and from these women a control group of 400 women was selected at random. Maternal blood was collected from the antecubital vein, and serum was stored at ⫺20C until the time of assay. Serum placenta growth factor concentrations were measured using a quantitative enzyme immunoassay technique (R & D Systems Europe Ltd, Abingdon, UK). All blood samples were collected between May 1998 and July 1999. The interassay precision was 7% and the intra-assay precision was 6% at 80 pg/mL. The interassay and intra-assay precisions were calculated to be the same at 200 pg/mL (4%) and at 600 pg/mL (3%).
VOL. 98, NO. 4, OCTOBER 2001
Data on maternal serum placenta growth factor concentration in the preeclampsia and FGR groups were compared with those on levels in the control group. In the control group, regression was done to describe the relationship between placenta growth factor concentration and gestational age in weeks; each placenta growth factor value then was expressed as multiple of the normal median for gestation. The unpaired t test was used to determine the significance of the difference between the groups in normalized log-transformed multiples of the median values. RESULTS Demographic characteristics, gestational ages at the time of sampling and at delivery, and birth weights are shown in Table 1. In the control group, maternal serum placenta growth factor concentration increased with gestation (median placenta growth factor level ⫽ 2.889398 ⫻ exp [gestation in weeks ⫻ 0.0227736]; R ⫽ 0.39, P ⬍ .001). The individual values in the preeclampsia and FGR groups are plotted on the reference range for gestation in Figure 1. Compared with the controls (median multiple of the median 0.98, standard deviation [SD] 0.51), levels in the preeclampsia group (median multiple of the median 1.09, SD 0.52) were not significantly different (t ⫽ 1.83, P ⫽ .07), but in the FGR group (median multiple of the median 1.57, SD 0.74), levels were significantly increased (t ⫽ 10.85, P ⬍ .001). The sensitivities and false-positive rates (receiver operating characteristic curve) for the detection of FGR by measurement of maternal serum placenta growth factor concentration in the first trimester are shown in Figure 2. DISCUSSION The findings of this study, that the maternal serum concentration of placenta growth factor at 11–14 weeks of gestation is increased in pregnancies that result in
Ong et al
Placenta Growth Factor Levels
609
Figure 1. Maternal serum placental growth factor (PlGF) concentration at 10 –14 weeks of gestation in women who subsequently developed preeclampsia (left) or fetal growth restriction (right), plotted on the reference range (median and 95th and fifth centiles) for gestation. Ong. Placenta Growth Factor Levels. Obstet Gynecol 2001.
FGR but is not altered in those resulting in preeclampsia, suggest that the underlying mechanism for these complications is different, even if both conditions are thought to be due to failure of trophoblastic invasion of the spiral arteries.
Figure 2. Receiver operating characteristic curve showing detection rates of fetal growth restriction against falsepositive rates. Ong. Placenta Growth Factor Levels. Obstet Gynecol 2001.
610
Ong et al
Placenta Growth Factor Levels
In about one-third of pregnancies resulting in FGR, maternal serum placenta growth factor concentration is above the 95th centile of the normal range. Given that FGR is associated with impaired trophoblastic invasion of the maternal spiral arteries,11,12 our results suggest that the increased maternal serum placenta growth factor concentration might be a marker of impairment in placental angiogenesis. Contrary to previous reports that in women with established preeclampsia there is a decrease in serum placenta growth factor levels,4,5 our findings suggest that altered maternal serum levels might not precede clinical onset of the disease and are not apparent in the first trimester of pregnancy. Therefore, the decreased maternal serum levels in women with preeclampsia are likely to be a consequence rather than the cause of the disease. It is possible that in women with preeclampsia there is placental hypoxia-mediated decrease in production of placenta growth factor. In vitro studies have demonstrated that hypoxia alters the morphology and function of trophoblasts12,13 and results in downregulation of placenta growth factor expression by these cells.2,14 In placentas from pregnancies with FGR, placenta growth factor messenger RNA and protein levels are higher than in normal placentas. Furthermore, hyperoxia has been found to upregulate placenta growth factor expression.14 The presence of possible placental hyperoxia and fetal hypoxia in FGR has been suggested by the finding that in this condition the oxygen content of maternal blood leaving the intervillous space is higher than in normal pregnancies.15 Placental hyperoxia also
OBSTETRICS & GYNECOLOGY
has been suggested as the underlying mechanism for the finding of ultrastructural studies that in placentas from fetal growth–restricted pregnancies, there is reduced cytotrophoblast proliferation and serious impairment of placental angiogenesis.16 If it is true that in FGR there is placental hyperoxia that upregulates placenta growth factor, our results suggest that such hyperoxia might be evident from the first trimester of pregnancy and several months before clinical onset of the disease.
9.
10.
11.
REFERENCES 1. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 1991;88:9267–71. 2. Shore VH, Wang TH, Wang CL, Torry RJ, Caudle MR, Torry DS. Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast. Placenta 1997;18:657– 65. 3. Zieche M, Maglione D, Ribatti D. Placenta growth factor-I is chemotactic, mitogenic, and angiogenic. Lab Invest 1997;76:517–31. 4. Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 1998;179: 1539 – 44. 5. Reuvekamp A, Velsing-Aarts FV, Poulina IE, Capello JJ, Duits AJ. Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol 1999;106:1019 –22. 6. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-forgestational age infants. Br J Obstet Gynaecol 1986;93: 1049 –59. 7. Campbell S, Diaz-Recasens J, Griffin DR, Cohen-Overbeek TE, Pearce JM, Willson K, et al. New doppler technique for assessing uteroplacental blood inflow. Lancet 1983;1:675–7. 8. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening programme for trisomy 21 at 10 –14 weeks using fetal nuchal translucency, maternal serum free  human
VOL. 98, NO. 4, OCTOBER 2001
12.
13.
14.
15.
16.
chorionic gonadotropin and pregnancy associated plasma protein A. Ultrasound Obstet Gynecol 1999;13:231–7. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988;158:892– 8. Yudkin PL, Aboualfa M, Eyre JA, Redman CW, Wilkinson AR. New birthweight and head circumference centiles for gestational ages 24 to 42 weeks. Early Hum Dev 1987;15:45–52. Pijnenborg R, Anthony J, Davey DA, Tiltman A, Vercruysse L, van Assche A. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol 1991;98:648 –55. Genbacev O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 1996;97: 540 –50. Esterman A, Greco MA, Mitani Y, Finlay TH, Ismail-Beigi F, Dancis J. The effect of hypoxia on human trophoblast in culture: Morphology, glucose transport and metabolism. Placenta 1997;18:129 –36. Khaliq A, Dunk C, Jiang J, Shams M, Li XF, Acevedo C, et al. Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: Molecular evidence for “placental hyperoxia” in intrauterine growth restriction. Lab Invest 1999;79:151–70. Pardi G, Cetin I, Marconi AM, Bozzetti P, Buscaglia M, Makowski EL. Venous drainage of the human uterus: Respiratory gas studies in normal and fetal growthretarded pregnancies. Am J Obstet Gynecol 1992;166: 699 –706. Kingdom JC, Kaufmann P. Oxygen and placental villous development: Origins of fetal hypoxia. Placenta 1997;18: 613–21.
Address reprint requests to: Kypros H. Nicolaides, MD, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, Denmark Hill, London SE5 9RS, United Kingdom; E-mail: [email protected]. Received January 29, 2001. Received in revised form May 23, 2001. Accepted June 7, 2001.
Ong et al
Placenta Growth Factor Levels
611
From the Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, London; and Endocrine Unit, Clinical Biochemistry Department, Harold Wood Hospital, Romford, Essex, United Kingdom. Supported by a grant from the Fetal Medicine Foundation (U.K. Charity No. 1037116).
608
(Obstet Gynecol 2001;98:608 –11. © 2001 by the American College of Obstetricians and Gynecologists.)
Placenta growth factor, a homodimeric glycoprotein belonging to the family of vascular endothelial growth factors, is expressed predominantly by cyto- and syncytiotrophoblasts in the placenta and is capable of inducing proliferation, migration, and activation of endothelial cells.1–3 Placenta growth factor has been suggested as one possible marker and mediator of endothelial cell dysfunction in preeclampsia.4,5 One study found that maternal serum placenta growth factor concentrations in 30 patients with preeclampsia at a mean gestation of 36 weeks were about three times lower than in 30 normotensive women matched for gestation.4 Similarly, another study found that maternal serum placenta growth factor concentrations in 28 patients with preeclampsia at a mean gestation of 30 weeks were about ten times lower than in 28 normotensive women matched for maternal age, parity, and gestation.5 The development of preeclampsia and/or fetal growth restriction (FGR) is thought to be a consequence of impaired trophoblastic invasion of the maternal spiral arteries in early pregnancy, resulting in a high-resistance uteroplacental circulation and reduced placental perfusion.6,7 However, there are no reports of maternal serum placenta growth factor levels in pregnancies complicated by FGR in the absence of preeclampsia. The aim of this study was to investigate whether the reported decrease in maternal serum placenta growth factor concentration in preeclampsia is evident from the first trimester and before clinical onset of the disease. In addition, we examined levels of placenta growth factor in pregnancies that subsequently resulted in FGR in the absence of preeclampsia. MATERIALS AND METHODS At King’s College Hospital, London, and Harold Wood Hospital, Essex, women registered for antenatal care are
VOL. 98, NO. 4, OCTOBER 2001 © 2001 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/01/$20.00 PII S0029-7844(01)01528-9
Table 1. Characteristics of the Preeclampsia, Fetal Growth Restriction, and Control Groups
Maternal age (y) Maternal weight (kg) White race Cigarette smoking Primigravid Gestation at sampling (wk) Gestation at delivery (wk) Birth weight (g)
Preeclampsia group (n ⫽ 131)
Fetal growth restriction group (n ⫽ 137)
Controls (n ⫽ 400)
29.0 ⫾ 5.6 74.1 ⫾ 15.9 98 (74.8%) 18 (13.7%) 67 (51.1%) 12 ⫾ 0.8 37.1 ⫾ 3.7* 2775 ⫾ 873*
28.4 ⫾ 6.0 59.0 ⫾ 12.3* 109 (79.6%) 46 (33.6%)* 55 (40.1%) 12 ⫾ 0.8 39.6 ⫾ 2.5* 2460 ⫾ 413*
28.2 ⫾ 5.3 67.9 ⫾ 13.7 336 (84.0%) 56 (14.0%) 197 (49.3%) 12 ⫾ 0.8 40.1 ⫾ 1.2 3488 ⫾ 396
Data are presented as mean ⫾ standard deviation or n (%). * Significantly lower, P ⬍ .001.
offered the option of attending a one-stop clinic for assessment of risk of trisomy 21 by a combination of measurement of fetal nuchal translucency thickness and determination of maternal serum free -hCG and pregnancy-associated plasma protein A levels at 11–14 weeks of gestation.8 A sample of blood collected at this clinic is stored for subsequent analysis as part of a research program to identify potential markers for screening of pregnancy complications. Women gave informed consent to participate in the study, which was approved by the hospital ethics committees. Pregnancy outcome was obtained from all patients and entered into a database, which was searched to identify those who developed preeclampsia and those who developed FGR in the absence of preeclampsia. Preeclampsia was defined as diastolic blood pressure of 90 mmHg or more on two occasions 4 hours apart, accompanied by proteinuria (more than 300 mg of total protein in a 24-hour urine collection or a 1⫹ albumin on reagent strip) in women with no pre-existing hypertensive or renal disease.9 Fetal growth restriction was considered present if a woman subsequently delivered a live infant with a birth weight below the fifth centile for gestation.10 The database then was searched to identify healthy women with normal singleton pregnancies who delivered appropriately grown infants at term, and from these women a control group of 400 women was selected at random. Maternal blood was collected from the antecubital vein, and serum was stored at ⫺20C until the time of assay. Serum placenta growth factor concentrations were measured using a quantitative enzyme immunoassay technique (R & D Systems Europe Ltd, Abingdon, UK). All blood samples were collected between May 1998 and July 1999. The interassay precision was 7% and the intra-assay precision was 6% at 80 pg/mL. The interassay and intra-assay precisions were calculated to be the same at 200 pg/mL (4%) and at 600 pg/mL (3%).
VOL. 98, NO. 4, OCTOBER 2001
Data on maternal serum placenta growth factor concentration in the preeclampsia and FGR groups were compared with those on levels in the control group. In the control group, regression was done to describe the relationship between placenta growth factor concentration and gestational age in weeks; each placenta growth factor value then was expressed as multiple of the normal median for gestation. The unpaired t test was used to determine the significance of the difference between the groups in normalized log-transformed multiples of the median values. RESULTS Demographic characteristics, gestational ages at the time of sampling and at delivery, and birth weights are shown in Table 1. In the control group, maternal serum placenta growth factor concentration increased with gestation (median placenta growth factor level ⫽ 2.889398 ⫻ exp [gestation in weeks ⫻ 0.0227736]; R ⫽ 0.39, P ⬍ .001). The individual values in the preeclampsia and FGR groups are plotted on the reference range for gestation in Figure 1. Compared with the controls (median multiple of the median 0.98, standard deviation [SD] 0.51), levels in the preeclampsia group (median multiple of the median 1.09, SD 0.52) were not significantly different (t ⫽ 1.83, P ⫽ .07), but in the FGR group (median multiple of the median 1.57, SD 0.74), levels were significantly increased (t ⫽ 10.85, P ⬍ .001). The sensitivities and false-positive rates (receiver operating characteristic curve) for the detection of FGR by measurement of maternal serum placenta growth factor concentration in the first trimester are shown in Figure 2. DISCUSSION The findings of this study, that the maternal serum concentration of placenta growth factor at 11–14 weeks of gestation is increased in pregnancies that result in
Ong et al
Placenta Growth Factor Levels
609
Figure 1. Maternal serum placental growth factor (PlGF) concentration at 10 –14 weeks of gestation in women who subsequently developed preeclampsia (left) or fetal growth restriction (right), plotted on the reference range (median and 95th and fifth centiles) for gestation. Ong. Placenta Growth Factor Levels. Obstet Gynecol 2001.
FGR but is not altered in those resulting in preeclampsia, suggest that the underlying mechanism for these complications is different, even if both conditions are thought to be due to failure of trophoblastic invasion of the spiral arteries.
Figure 2. Receiver operating characteristic curve showing detection rates of fetal growth restriction against falsepositive rates. Ong. Placenta Growth Factor Levels. Obstet Gynecol 2001.
610
Ong et al
Placenta Growth Factor Levels
In about one-third of pregnancies resulting in FGR, maternal serum placenta growth factor concentration is above the 95th centile of the normal range. Given that FGR is associated with impaired trophoblastic invasion of the maternal spiral arteries,11,12 our results suggest that the increased maternal serum placenta growth factor concentration might be a marker of impairment in placental angiogenesis. Contrary to previous reports that in women with established preeclampsia there is a decrease in serum placenta growth factor levels,4,5 our findings suggest that altered maternal serum levels might not precede clinical onset of the disease and are not apparent in the first trimester of pregnancy. Therefore, the decreased maternal serum levels in women with preeclampsia are likely to be a consequence rather than the cause of the disease. It is possible that in women with preeclampsia there is placental hypoxia-mediated decrease in production of placenta growth factor. In vitro studies have demonstrated that hypoxia alters the morphology and function of trophoblasts12,13 and results in downregulation of placenta growth factor expression by these cells.2,14 In placentas from pregnancies with FGR, placenta growth factor messenger RNA and protein levels are higher than in normal placentas. Furthermore, hyperoxia has been found to upregulate placenta growth factor expression.14 The presence of possible placental hyperoxia and fetal hypoxia in FGR has been suggested by the finding that in this condition the oxygen content of maternal blood leaving the intervillous space is higher than in normal pregnancies.15 Placental hyperoxia also
OBSTETRICS & GYNECOLOGY
has been suggested as the underlying mechanism for the finding of ultrastructural studies that in placentas from fetal growth–restricted pregnancies, there is reduced cytotrophoblast proliferation and serious impairment of placental angiogenesis.16 If it is true that in FGR there is placental hyperoxia that upregulates placenta growth factor, our results suggest that such hyperoxia might be evident from the first trimester of pregnancy and several months before clinical onset of the disease.
9.
10.
11.
REFERENCES 1. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A 1991;88:9267–71. 2. Shore VH, Wang TH, Wang CL, Torry RJ, Caudle MR, Torry DS. Vascular endothelial growth factor, placenta growth factor and their receptors in isolated human trophoblast. Placenta 1997;18:657– 65. 3. Zieche M, Maglione D, Ribatti D. Placenta growth factor-I is chemotactic, mitogenic, and angiogenic. Lab Invest 1997;76:517–31. 4. Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 1998;179: 1539 – 44. 5. Reuvekamp A, Velsing-Aarts FV, Poulina IE, Capello JJ, Duits AJ. Selective deficit of angiogenic growth factors characterises pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol 1999;106:1019 –22. 6. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-forgestational age infants. Br J Obstet Gynaecol 1986;93: 1049 –59. 7. Campbell S, Diaz-Recasens J, Griffin DR, Cohen-Overbeek TE, Pearce JM, Willson K, et al. New doppler technique for assessing uteroplacental blood inflow. Lancet 1983;1:675–7. 8. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. A screening programme for trisomy 21 at 10 –14 weeks using fetal nuchal translucency, maternal serum free  human
VOL. 98, NO. 4, OCTOBER 2001
12.
13.
14.
15.
16.
chorionic gonadotropin and pregnancy associated plasma protein A. Ultrasound Obstet Gynecol 1999;13:231–7. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988;158:892– 8. Yudkin PL, Aboualfa M, Eyre JA, Redman CW, Wilkinson AR. New birthweight and head circumference centiles for gestational ages 24 to 42 weeks. Early Hum Dev 1987;15:45–52. Pijnenborg R, Anthony J, Davey DA, Tiltman A, Vercruysse L, van Assche A. Placental bed spiral arteries in the hypertensive disorders of pregnancy. Br J Obstet Gynaecol 1991;98:648 –55. Genbacev O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest 1996;97: 540 –50. Esterman A, Greco MA, Mitani Y, Finlay TH, Ismail-Beigi F, Dancis J. The effect of hypoxia on human trophoblast in culture: Morphology, glucose transport and metabolism. Placenta 1997;18:129 –36. Khaliq A, Dunk C, Jiang J, Shams M, Li XF, Acevedo C, et al. Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: Molecular evidence for “placental hyperoxia” in intrauterine growth restriction. Lab Invest 1999;79:151–70. Pardi G, Cetin I, Marconi AM, Bozzetti P, Buscaglia M, Makowski EL. Venous drainage of the human uterus: Respiratory gas studies in normal and fetal growthretarded pregnancies. Am J Obstet Gynecol 1992;166: 699 –706. Kingdom JC, Kaufmann P. Oxygen and placental villous development: Origins of fetal hypoxia. Placenta 1997;18: 613–21.
Address reprint requests to: Kypros H. Nicolaides, MD, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical School, Denmark Hill, London SE5 9RS, United Kingdom; E-mail: [email protected]. Received January 29, 2001. Received in revised form May 23, 2001. Accepted June 7, 2001.
Ong et al
Placenta Growth Factor Levels
611