DOI 10.1515/jpm-2013-0227 J. Perinat. Med. 2014; 42(5): 629–633
Paweł Gutaj, Ewa Wender-Ożegowska*, Rafał Iciek, Agnieszka Zawiejska, Marek Pietryga and Jacek Brązert
Maternal serum placental growth factor and fetal SGA in pregnancy complicated by type 1 diabetes mellitus Abstract Aim: To analyze the role of maternal placental growth factor (PlGF) in the prediction of small for gestational age (SGA) birth weight in pregnancy complicated by type 1 diabetes mellitus (T1DM). Methods: A prospective observational study on 59 normotensive T1DM pregnant women, assessing maternal PlGF concentrations between the 10th–14th and 22nd–25th weeks of gestation. Results: Number of SGA vs. non-SGA newborns was 11 (18.6%) vs. 48 (81.4%), respectively. First trimester PlGF serum concentrations (pg/mL) were similar between SGA vs. non-SGA groups [data given as median (interquartile range)]: 65.5 (35.58–159.20) vs. 68.23 (11.59–150.03), respectively; P = 0.44. A trend for lower PlGF concentrations was observed in the second trimester in the SGA vs. non-SGA group: 63.34 (12.79–119.16) vs. 116.75 (33.93– 235.82); P = 0.07. In the SGA group, PlGF concentrations did not differ between the first and the second trimester: 65.5 (35.58–159.20) vs. 63.34 (12.79–119.16), respectively; P = 0.36. In the non-SGA group, PlGF concentrations were significantly higher at the gestational age of 22–25 weeks compared to 10–14 weeks [116.75 (33.93–235.82) vs. 68.23 (11.59–150.03); P = 0.03). Conclusions: Decreased PlGF serum concentration in midpregnancy, as well as a lack of physiological increase in PlGF levels between early and mid-gestation, may precede development of SGA in women with T1DM. Keywords: Intrauterine growth restriction; placental growth factor; small for gestational age; type 1 diabetes mellitus. *Corresponding author: Ewa Wender-Ożegowska, Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Polna St. 33, Poland, Tel./Fax: +48-61-84-19-334, E-mail: [email protected] Paweł Gutaj, Rafał Iciek, Agnieszka Zawiejska, Marek Pietryga and Jacek Brązert: Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, Poznan, Poland
Introduction The human placenta serves as an interface between the mother and the fetus. This interface relies on complex, well-organized, and dynamic vascular structures, which are formed de novo and are constantly expanding until delivery. Adequate placental vasculogenesis and angiogenesis are essential for the development of the fetus [5]. Aberrant vascular formation has been reported in pregnancies complicated by small for gestational age (SGA). Several histopathological changes have been identified in SGA placentas, such as decreased vascular density in villi and stroma, resulting in overall reduction of placental surface and volume. These structural abnormalities have been accompanied by changes in angiogenic factors, including placental growth factor (PlGF) [1]. It has been well documented that diabetes alters vascular function. Moreover, these effects are exerted on both existing vessels and vascular formation. As placental vasculature is affected by the diabetic environment, it could be a risk factor for SGA in diabetic mothers [4]. PlGF is produced by the trophoblast. It belongs to the vascular endothelial growth factor-1 family and plays an important role in vasculogenesis and angiogenesis in human placenta. Low concentrations of PlGF at certain periods of pregnancy may indicate placental dysfunction and may precede SGA [3, 7, 9, 10]. Some data suggests that maternal PlGF might be useful in detection of fetuses with SGA in non-diabetic patients. However, there are no studies examining this association in women with type 1 diabetes. The aim of this study was to analyze the role of maternal PlGF in prediction of fetal SGA in pregnancy complicated by T1DM. We hypothesized that abnormal fetal growth manifesting as SGA is associated with altered circulating PlGF levels.
Materials and methods The study group consisted of 59 normotensive Caucasian women with T1DM. The study was conducted at our department and patients
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630 Gutaj et al., Maternal PlGF and SGA in diabetic pregnancy were enrolled prospectively to this study from 2010 until 2012. The study was performed under a protocol of a larger scientific project examining genetic and biochemical background of perinatal complications in women with type 1 diabetes (Polish Scientific Committee Grant N N407187936). Clinical and biochemical data were collected during at least three admissions to our department: (i) between the 10th–14th weeks of gestation; (ii) between the 22nd–25th weeks of gestation; and (iii) near the delivery (maximally 7 days before) and postpartum. First-trimester crown-rump length measurements were used for pregnancy dating. Exclusion criteria at baseline (10th–14th weeks of gestation) were smoking, chronic hypertension, pregnancy after in vitro fertilization, and multiple pregnancy. At baseline, women were assessed for the presence of diabetic vascular complications. Every patient was consulted by an ophthalmologist and screened for diabetic retinopathy. The diagnosis of diabetic nephropathy was based on either the patient’s past medical history or the presence of proteinuria that exceeded 300 mg in a 24 h urine sample. During the first two hospitalizations, blood samples for PlGF measurements were collected and centrifuged. When separated, sera were stored at –80°C until analysis. PlGF concentrations were determined using commercially available kits (Quantikine ELISA; R&D Systems Europe, Abingdon, UK) according to the manufacturer’s instructions. Laboratory staff members were blinded to the clinical characteristics of patients. Women who developed gestational hypertension or preeclampsia were excluded from the study group. Diagnosis of SGA was based on sex and age specific growth curves. Newborns with birth weight below the 10th percentile for gestational age were classified as SGA. Infectious causes of SGA, such as Toxoplasma gondii, rubella, cytomegalovirus, herpes simplex virus type 1 and type 2, and parvovirus B19 were excluded in every patient. Every women taking part in the study was screened for hepatitis B and C, treponema pallidum, human immunodeficiency virus, and all participants were seronegative. Mothers who delivered newborns with congenital anomalies confirmed at birth were excluded from the analysis. In one patient included in the study, intrauterine fetal death occurred due to severe placental insufficiency at 26 weeks of gestation. After delivery, the patients were divided into two groups for comparative analysis. The first group consisted of women who delivered SGA newborns, and the second group consisted of women who delivered non-SGA newborns. The non-SGA group consisted of either appropriate-for-gestational age or large-for-gestational age newborns. Data concerning placental weight was extracted from hospital records. Statistical analyses were performed using MedCalc for Windows, version 12.1.3.0 (MedCalc Software, Mariakerke, Belgium). Student t-test for independent samples was used to measure the significance of the difference between two independent samples when data presented normal distribution; data expressed as means ± 1 standard deviation. Mann-Whitney test was used to measure the significance of the difference between two independent samples when data did not present normal distribution; data expressed as medians (interquartile range-IQR). Wilcoxon test was used to measure the significance of the difference between two paired samples when data did not have normal distribution; data expressed as medians (IQR). Fisher exact test was used for comparison of categorical variables. Multiple regression was used to analyze the relationship between
dependent variable and one or more independent variables. The levels of significance were indicated by P-values. All P-values of
Paweł Gutaj, Ewa Wender-Ożegowska*, Rafał Iciek, Agnieszka Zawiejska, Marek Pietryga and Jacek Brązert
Maternal serum placental growth factor and fetal SGA in pregnancy complicated by type 1 diabetes mellitus Abstract Aim: To analyze the role of maternal placental growth factor (PlGF) in the prediction of small for gestational age (SGA) birth weight in pregnancy complicated by type 1 diabetes mellitus (T1DM). Methods: A prospective observational study on 59 normotensive T1DM pregnant women, assessing maternal PlGF concentrations between the 10th–14th and 22nd–25th weeks of gestation. Results: Number of SGA vs. non-SGA newborns was 11 (18.6%) vs. 48 (81.4%), respectively. First trimester PlGF serum concentrations (pg/mL) were similar between SGA vs. non-SGA groups [data given as median (interquartile range)]: 65.5 (35.58–159.20) vs. 68.23 (11.59–150.03), respectively; P = 0.44. A trend for lower PlGF concentrations was observed in the second trimester in the SGA vs. non-SGA group: 63.34 (12.79–119.16) vs. 116.75 (33.93– 235.82); P = 0.07. In the SGA group, PlGF concentrations did not differ between the first and the second trimester: 65.5 (35.58–159.20) vs. 63.34 (12.79–119.16), respectively; P = 0.36. In the non-SGA group, PlGF concentrations were significantly higher at the gestational age of 22–25 weeks compared to 10–14 weeks [116.75 (33.93–235.82) vs. 68.23 (11.59–150.03); P = 0.03). Conclusions: Decreased PlGF serum concentration in midpregnancy, as well as a lack of physiological increase in PlGF levels between early and mid-gestation, may precede development of SGA in women with T1DM. Keywords: Intrauterine growth restriction; placental growth factor; small for gestational age; type 1 diabetes mellitus. *Corresponding author: Ewa Wender-Ożegowska, Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Polna St. 33, Poland, Tel./Fax: +48-61-84-19-334, E-mail: [email protected] Paweł Gutaj, Rafał Iciek, Agnieszka Zawiejska, Marek Pietryga and Jacek Brązert: Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, Poznan, Poland
Introduction The human placenta serves as an interface between the mother and the fetus. This interface relies on complex, well-organized, and dynamic vascular structures, which are formed de novo and are constantly expanding until delivery. Adequate placental vasculogenesis and angiogenesis are essential for the development of the fetus [5]. Aberrant vascular formation has been reported in pregnancies complicated by small for gestational age (SGA). Several histopathological changes have been identified in SGA placentas, such as decreased vascular density in villi and stroma, resulting in overall reduction of placental surface and volume. These structural abnormalities have been accompanied by changes in angiogenic factors, including placental growth factor (PlGF) [1]. It has been well documented that diabetes alters vascular function. Moreover, these effects are exerted on both existing vessels and vascular formation. As placental vasculature is affected by the diabetic environment, it could be a risk factor for SGA in diabetic mothers [4]. PlGF is produced by the trophoblast. It belongs to the vascular endothelial growth factor-1 family and plays an important role in vasculogenesis and angiogenesis in human placenta. Low concentrations of PlGF at certain periods of pregnancy may indicate placental dysfunction and may precede SGA [3, 7, 9, 10]. Some data suggests that maternal PlGF might be useful in detection of fetuses with SGA in non-diabetic patients. However, there are no studies examining this association in women with type 1 diabetes. The aim of this study was to analyze the role of maternal PlGF in prediction of fetal SGA in pregnancy complicated by T1DM. We hypothesized that abnormal fetal growth manifesting as SGA is associated with altered circulating PlGF levels.
Materials and methods The study group consisted of 59 normotensive Caucasian women with T1DM. The study was conducted at our department and patients
Brought to you by | University of Iowa Libraries Authenticated Download Date | 5/29/15 12:55 PM
630 Gutaj et al., Maternal PlGF and SGA in diabetic pregnancy were enrolled prospectively to this study from 2010 until 2012. The study was performed under a protocol of a larger scientific project examining genetic and biochemical background of perinatal complications in women with type 1 diabetes (Polish Scientific Committee Grant N N407187936). Clinical and biochemical data were collected during at least three admissions to our department: (i) between the 10th–14th weeks of gestation; (ii) between the 22nd–25th weeks of gestation; and (iii) near the delivery (maximally 7 days before) and postpartum. First-trimester crown-rump length measurements were used for pregnancy dating. Exclusion criteria at baseline (10th–14th weeks of gestation) were smoking, chronic hypertension, pregnancy after in vitro fertilization, and multiple pregnancy. At baseline, women were assessed for the presence of diabetic vascular complications. Every patient was consulted by an ophthalmologist and screened for diabetic retinopathy. The diagnosis of diabetic nephropathy was based on either the patient’s past medical history or the presence of proteinuria that exceeded 300 mg in a 24 h urine sample. During the first two hospitalizations, blood samples for PlGF measurements were collected and centrifuged. When separated, sera were stored at –80°C until analysis. PlGF concentrations were determined using commercially available kits (Quantikine ELISA; R&D Systems Europe, Abingdon, UK) according to the manufacturer’s instructions. Laboratory staff members were blinded to the clinical characteristics of patients. Women who developed gestational hypertension or preeclampsia were excluded from the study group. Diagnosis of SGA was based on sex and age specific growth curves. Newborns with birth weight below the 10th percentile for gestational age were classified as SGA. Infectious causes of SGA, such as Toxoplasma gondii, rubella, cytomegalovirus, herpes simplex virus type 1 and type 2, and parvovirus B19 were excluded in every patient. Every women taking part in the study was screened for hepatitis B and C, treponema pallidum, human immunodeficiency virus, and all participants were seronegative. Mothers who delivered newborns with congenital anomalies confirmed at birth were excluded from the analysis. In one patient included in the study, intrauterine fetal death occurred due to severe placental insufficiency at 26 weeks of gestation. After delivery, the patients were divided into two groups for comparative analysis. The first group consisted of women who delivered SGA newborns, and the second group consisted of women who delivered non-SGA newborns. The non-SGA group consisted of either appropriate-for-gestational age or large-for-gestational age newborns. Data concerning placental weight was extracted from hospital records. Statistical analyses were performed using MedCalc for Windows, version 12.1.3.0 (MedCalc Software, Mariakerke, Belgium). Student t-test for independent samples was used to measure the significance of the difference between two independent samples when data presented normal distribution; data expressed as means ± 1 standard deviation. Mann-Whitney test was used to measure the significance of the difference between two independent samples when data did not present normal distribution; data expressed as medians (interquartile range-IQR). Wilcoxon test was used to measure the significance of the difference between two paired samples when data did not have normal distribution; data expressed as medians (IQR). Fisher exact test was used for comparison of categorical variables. Multiple regression was used to analyze the relationship between
dependent variable and one or more independent variables. The levels of significance were indicated by P-values. All P-values of
