http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.879706
ORIGINAL ARTICLE
Are there any relationships between umbilical artery Pulsatility Index and macrosomia in fetuses of type I diabetic mothers?
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
G. M. Maruotti1, G. Rizzo2, A. Sirico1, L. Sarno2, L. Cirigliano2, D. Arduini2, and P. Martinelli1 1
High Risk Pregnancy Centre, Department of Gynaecology and Obstetrics, University Federico II Naples, Naples, Italy and 2Department of Gynaecology and Obstetrics, Universita` di Roma Tor Vergata, Rome, Italy Abstract
Keywords
Objective: To establish whether there are relationships between umbilical artery Pulsatility Index (PI) and fetal macrosomia in pregnancies complicated by type I diabetes. Methods: In a retrospective observational study, 102 singleton pregnant women with type I diabetes were considered. Umbilical artery PI was measured by Doppler ultrasonography within one week from delivery and related to neonatal weight. Pregnancies were grouped according to birtweight in macrosomic group (4000 g) and normal growth group (54000 g). Relationships between umbilical artery PI and birth weight and birth weight centile were tested by Pearson’s correlation analysis. Further umbilical artery PI values were compared between macrosomic and normally grown fetuses. Results: Birth weight was 4000 g in 24 pregnancies (23.5%). A significant relationship was found between umbilical artery PI and neonatal weight (r ¼ 0.512; p50.01) and neonatal weight centile (r ¼ 0.400; p50.01). Umbilical artery PI were significantly lower (t ¼ 6.013; p50.001) in the macrosomic group (0.78; 95% confidence interval (CI) 0.73–0.84) than in the normal growth group (1.00; 95% CI 0.97–1.04). Conclusions: In pregnancies complicated by type I diabetes there is a significant relationship between umbilical artery PI value before delivery and absolute birth weight and birth weight centile. Macrosomic fetuses show a significant reduction in umbilical artery PI when compared with diabetic pregnancies without fetal overgrowth.
Doppler ultrasound, macrosomia, pregnancy, type I diabetes, umbilical artery
Objective Macrosomia is associated with a high incidence of perinatal mortality and morbidity and has been found to occur at a 10fold higher rate in diabetic pregnancies compared with a normal population [1]. Indeed, this condition carries an increased risk for shoulder dystocia, birth trauma (bone fracture and nerve palsy), perineal trauma and wound healing. The fetal overgrowth is also associated with an increase in fetal and neonatal death, caused mostly by asphyxia and infections, and neonatal morbidity, such as Apgar score less than 4, birth injury and meconium aspiration syndrome [2]. Moreover, macrosomia has been associated with the onset of diseases in offspring at adulthood, such as type 2 diabetes and obesity associated with metabolic syndrome [3–5]. Although there is no absolute consensus about the definition of macrosomia, usually it is defined as a birth weight greater than 4000 g in pregnancies complicated by diabetes [6].
Address for correspondence: Pasquale Martinelli, MD, High Risk Pregnancy Centre, Department of Gynaecology and Obstetrics, University Federico II Naples, Vico Acitillo 53, 80131 Naples, Italy. Tel: 39 81 746 2966. Fax: 39 81 746 2966. E-mail: [email protected]
History Received 13 November 2013 Revised 24 December 2013 Accepted 29 December 2013 Published online 3 February 2014
Increased fetal weight is considered to be associated with increased placental size and vascularization [7]. Umbilical artery (UA) Pulsatility Index (PI) is significantly associated with the development of placental vasculature and there are evidences of lower umbilical artery PI in macrosomic fetuses from non-diabetic pregnancies than the general population [8–10]. To the best of our knowledge, no data are up to now available of such relationship in pregnancies complicated by type I diabetic. The aim of our study was, therefore, to establish whether macrosomic fetuses at term in pregnancies complicated by type I diabetes show different values of umbilical artery Doppler PI from those of non-macrosomic fetuses.
Methods This is a multi-center retrospective observational study carried out from January 2006 to December 2012 at two referral centers for high-risk pregnancies in Naples and Rome. For this study, 102 patients with insulin-dependent diabetes were included. The clinical management of diabetes during pregnancy was similar between the two centers. Briefly, pregnant diabetic women self-monitored their capillary blood glucose
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
2
G. M. Maruotti et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
levels at home and insulin adjustments were performed at the biweekly visit, with the aim of maintaining blood glucose fasting levels 595 mg/dl, and 5140 and 5120 mg/dl at 1 and 2 h after meals, respectively. The quality of metabolic control was assessed by glycosylated hemoglobin concentration (Hba1ac%) in maternal blood. All included pregnancies were singleton, and accurately dated by early ultrasonographic examination. Exclusion criteria were the presence of fetal chromosomal or congenital diseases, maternal metabolic disease other than diabetes, a neonatal weight centile 10th and a gestational age of delivery less than 34 weeks of gestation. The birth weight centile has been calculated using the Italian Neonatal Study charts, based on a multi-center Italian study on 45 462 newborns [11]. Umbilical artery velocity waveforms recordings were obtained with Voluson E8 Expert ultrasound equipments (GE Medical Systems, Milwaukee, WI) equipped with 2–5 MHz transabdominal probes and using color and pulse wave Doppler functions. Umbilical artery waveforms were recorded from a free-floating loop of the umbilical cord during fetal quiescence and in the absence of fetal breathing using a previously reported technique [12]. PI was measured over at least three consecutive and uniform hearth cycles. All the ultrasound examinations considered were performed within three days before delivery. Included pregnancies were grouped according to birth weight in the macrosomic group (4000 g) and normal growth group (54000 g). Shapiro–Wilk’s test was used to analyze the normal distribution of the data. The unpaired Student’s t-test was used to evaluate differences between groups in umbilical artery (PI) values and in their clinical characteristics. Relationships between the umbilical artery PI and birth weight or birth weight centile were estimated by linear regression analysis. A p value 50.05 was considered as significant. Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS) Statistics v. 19 (IBM Inc., Armonk, New York).
Results Of the 102 included pregnancies 24 (23.5%) gave birth to a neonate with a birth weight 4000 g (macrosomic group) while 78 women gave birth to a baby whose weight was less than 4000 g (normal growth group). Regarding ethnicity, 94 women were Caucasian, 5 women were from Africa, 2 women from South America and 1 woman from Asia. There are no significant differences between the two groups according to the maternal characteristics and neonatal outcomes except for birth weight as reported in Table 1. Umbilical artery PI values resulted significantly lower in the macrosomic group when compared with controls
(PI ¼ 0.78; 95% confidence interval (CI) 0.73–0.84 versus PI ¼ 1.00; 95% CI 0.97–1.04; t ¼ 6,013; p50.001) (Figure 1). Linear regression analysis revealed a significant correlation between UA-PI and neonatal birth weight (constant ¼ 1.471; slope 0.000152; r ¼ 0.512; residual SD ¼ 0.00002; p50.01) (Figure 2). Similarly when neonatal weight centile was considered, linear regression analysis revealed a significant correlation with UA-PI (constant ¼ 1.157; slope ¼ 0.002663; r ¼ 0.400; residual SD ¼ 0.000611; p50.01) (Figure 3). The effect of gestational age on umbilical artery PI was tested by regression analysis. No significant relationships were found in both the macrosomic (r ¼ 0.169; p ¼ 0.429) and normal growth groups (r ¼ 0.390; p ¼ 0.736) (Figures 4 and 5). In order to assess the potential influence of maternal metabolic control on UA velocity waveforms, the Hb1ac% values measured at the time of Doppler recordings (available in 55 pregnancies) were related to UA-PI. Regression analysis showed no significant relationship between the two variables (r ¼ 0.10: p ¼ 0.843). Similarly, no relationship were found between maternal body mass index (BMI) and UA-PI (r ¼ 0.01; p ¼ 0.935)
Discussion In this study, we evidenced that in fetuses of type I diabetic mothers’ umbilical artery PI is significantly reduced in the presence of macrosomia and that there is significant inverse relationship between umbilical artery PI and absolute birth weight values or percentile. Previous studies have demonstrated an enhanced placental angiogenesis in women with diabetes. Increased surface area, capillary length and branching have been reported for placenta of type I and gestational diabetes mellitus (GDM) pregnancies [13–16]. Pietro et al. demonstrated that also mild gestational hyperglycemia causes an increase in terminal villi and capillaries. In placentas from diabetic mothers blood vessels walls appear thicker and the surrounding mesenchyme denser than in pregnant normoglycemic women [17]. This feature, associated with the erythrocyte deformation and increased blood viscosity due to the increased glycosylation of hemoglobin, leads to a poor local oxygen transport [18,19]. While the maternal–placental oxygen supply is reduced, fetal oxygen demand is increased by aerobic metabolism stimulated by fetal hyperinsulinemia, so the resulting relative placental hypoxia upregulates the transcription synthesis of proangiogenic and growth factors such as leptin, vascular endothelial growth factor and fibroblast growth factor 2 [20– 22]. This is also supported by recent 3D ultrasonographic studies showing an increased vascularization in the placenta of type I diabetic pregnancies already present in the first trimester and particularly evident in the presence of a poor
Table 1. Maternal and neonatal characteristics of the study population and controls. Characteristics Maternal age (years) BMI (kg/m2) Gestational age at delivery (days) Birth weight
Macrosomic group (n ¼ 24) 31.87 25.59 263.46 4276.67
(SD (SD (SD (SD
4.90) 3.93) 8.62) 199.45)
Normal growth group (n ¼ 78) 31.71 27.30 257.56 3163.90
(SD (SD (SD (SD
4.81) 5.45) 11.38) 444.04)
t
p
0.145 1.387 2.336 17.2
0.885 0.169 0.021 50.001
DOI: 10.3109/14767058.2013.879706
Type I diabetic mothers
3
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
Figure 1. Mean UA-PI and % 95th CI in the case and control groups.
Figure 2. Linear regression analysis between UA-PI and neonatal birth weight in the entire population (% 95th CI).
metabolic control [23]. Furthermore, it has been demonstrated that placental weight also tends to be heavier in diabetic pregnancies; the weight gain is more marked in placenta than in the fetus, so the placental-to-fetal weight ratio is higher than in normal pregnancies. Placentomegaly is also correlated with fetal macrosomia, confirming the correlation between placental and fetal weight [7]. Previous studies investigated the correlation between UA-PI and birth weight. In 2003, Owen et al. analyzed in 274 non-diabetic pregnancies the correlation between
umbilical artery PI and systolic/diastolic ratio with estimated fetal weight (EFW) and no correlation was found [8]. In this study, 22 pregnancies (8%) with birth weight below 10th centile were included and moreover not any difference in UA-PI between macrosomic and non-macrosomic fetuses was investigated. In 2005, Lam et al. analyzed the usefulness of UA-PI in the prediction of large for gestational age babies compared with EFW in 181 pregnancies and demonstrated a significant inverse correlation between UA-PI and birth weight centile [9]. In 2011, Ebbing et al. studied Umbilical
4
G. M. Maruotti et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
Figure 3. Linear regression analysis between UA-PI and neonatal weight centile in the entire population (% 95th CI).
Figure 4. Linear regression analysis between UA-PI and the gestational age at delivery in the group of pregnancies with macrosomic fetuses (% 95th CI).
vein blood flow and Doppler measurements of the ductus venosus, left portal vein and the hepatic, splenic, superior mesenteric, cerebral and umbilical arteries in a population of 29 non-diabetic women who gave birth to a baby with birth weight 90th centile compared with a reference population of 161 women with low-risk pregnancies. Data analysis showed that mean UA-PI and SD were significantly lower in the macrosomic pregnancies [10]. To the best of our knowledge, our study is the first to evaluate the characteristics of umbilical artery Doppler velocimetry according to the presence of macrosomia in a cohort of diabetic pregnant women with type I diabetes.
Furthermore, it is the only study about umbilical artery Doppler in macrosomic fetuses that considers for the diagnosis of macrosomia a birth weight 44000 g, while other studies define macrosomia as a birth weight centile490 ; this point is essential because a newborn of 2800 at 34 weeks can be considered macrosomic, but it is difficult that its placental weight and vascularization, and then its UA-PI, could be compared with that of a 4000 g newborn. For the same reason, we intentionally excluded from the study very preterm newborn or fetal growth restricted babies in order to remove possible biases which could be due to the presence of abnormal increased UA-PI in these controls. The absence of
DOI: 10.3109/14767058.2013.879706
Type I diabetic mothers
5
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
Figure 5. Linear regression analysis between UA-PI and the gestational age at delivery in the control group (% 95th CI).
relationship between gestational age and umbilical artery PI in our study population corroborates the direct link between birth weight and umbilical artery impedance to flow. A limitation of this study is the lack of simultaneous informations of fetal arterial and venous hemodynamics that can be affected in macrosomic fetuses of diabetic mothers. Further the relationships between fetal weight and umbilical artery at earlier gestational age deserve further investigations In conclusion, our study shows that macrosomic growth of fetuses of type I diabetic mother is associated with reduced umbilical artery impedance to flow. The role, if any, of umbilical artery PI in predicting macrosomia together other ultrasonographic measurements in diabetic pregnancies remains to be established.
Declaration of interest The authors report no declarations of interest.
References 1. Landon MB, Catalano PM, Gabbe SG. Diabetes mellitus. In: Gabbe SG, Niebyl JR, Simpson Jl, eds. Obstetrics, normal and problem pregnancies. 4th ed. New York (NY): Churchill Livingstone; 2002:1089–97. 2. Zhang X, Decker A, Platt RW, Kramer MS. How big is too big? The perinatal consequences of fetal macrosomia. Am J Obstet Gynecol 2008;198:517.e1–517.e6. 3. Hales CN, Barker DJP. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5–20. 4. Grissa O, Ate`gbo JM, Yessoufou A, et al. Antioxidant status and circulating lipids are altered in human gestational diabetes and macrosomia. Trans Res 2007;150:164–71. 5. Khan NA, Yessoufou A, Kim M, Hichami A. N-3 fatty acids modulate Th1 and Th2 dichotomy in diabetic pregnancy and macrosomia. J Autoimmun 2006;26:268–77. 6. Boyd ME, Usher RH, McLean FH. Fetal macrosomia: prediction, risks, proposed management. Obstet Gynecol 1983;61:715–22.
7. Taricco E, Randelli T, Nobile de Santis MS, Cetin I. Foetal and placental weights in relation to maternal characteristics in gestational diabetes. Placenta 2003;24:343–7. 8. Owen P, Murphy J, Farrell T. Is there a relationship between estimated fetal weight and umbilical artery Doppler impedance indices? Ultrasound Obstet Gynecol 2003;22:157–9. 9. Lam H, Leung WC, Lee CP, Lao TT. Relationship between cerebroplacental Doppler ratio and birth weight in postdates pregnancies. Ultrasound Obstet Gynecol 2005;25:265–9. 10. Ebbing C, Rasmussen S, Kiserud T. Fetal hemodynamic development in macrosomic growth. Ultrasound Obstet Gynecol 2011;38: 303–8. 11. Bertino E, Spada E, Occhi L, et al. Neonatal anthropometric charts: the Italian neonatal study compared with other European studies. J Pediatr Gastroenterol Nutr 2010;51:353–61. 12. Arduini D, Rizzo G. Normal values of Pulsatility Index from fetal vessels: a cross-sectional study on 1556 healthy fetuses. J Perinat Med 1990;18:165–72. 13. Jauniaux E, Burton GJ. Villous histomorphometry and placental bed biopsy investigation in type I diabetic pregnancies. Placenta 2006;27:468–74. 14. Jirkovska´ M, Kubı´nova´ L, Jana´cek J, et al. Topological properties and spatial organization of villous capillaries in normal and diabetic placentas. J Vasc Res 2002;39:268–78. 15. Leach L, Gray C, Staton S, et al. Vascular endothelial cadherin and beta-catenin in human fetoplacental vessels of pregnancies complicated by type 1 diabetes: associations with angiogenesis and perturbed barrier function. Diabetologia 2004;47:695–709. 16. Mayhew TM. Enhanced fetoplacental angiogenesis in pre-gestational diabetes mellitus: the extra growth is exclusively longitudinal and not accompanied by microvascular remodelling. Diabetologia 2002;45:1434–9. 17. Pietro L, Daher S, Rudge MV, et al. Vascular endothelial growth factor (VEGF) and VEGF-receptor expression in placenta of hyperglycemic pregnant women. Placenta 2010;31:770–80. 18. Iino K, Yoshinari M, Doi Y, et al. Reduced tissue oxygenation and its reversibility by glycemic control in diabetic patients. Diabetes Res Clin Pract 1997;34:163–8. 19. Taricco E, Radaelli T, Rossi G, et al. Effects of gestational diabetes on fetal oxygen and glucose levels in vivo. BJOG 2009;116: 1729–35.
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20. Jos´ko J, Mazurek M. Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. Med Sci Monit 2004;10:RA89–98. 21. Bouloumie´ A, Drexler HC, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res 1998;83: 1059–66.
J Matern Fetal Neonatal Med, Early Online: 1–6
22. Burleigh DW, Stewart K, Grindle KM, et al. Influence of maternal diabetes on placental fibroblast growth factor-2 expression, proliferation, and apoptosis. J Soc Gynecol Investig 2004;11:36–41. 23. Rizzo G, Capponi A, Pietrolucci ME, et al. First trimester placental volume and three dimensional power doppler ultrasonography in type I diabetic pregnancies. Prenat Diagn 2012;32:480–4.
ORIGINAL ARTICLE
Are there any relationships between umbilical artery Pulsatility Index and macrosomia in fetuses of type I diabetic mothers?
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
G. M. Maruotti1, G. Rizzo2, A. Sirico1, L. Sarno2, L. Cirigliano2, D. Arduini2, and P. Martinelli1 1
High Risk Pregnancy Centre, Department of Gynaecology and Obstetrics, University Federico II Naples, Naples, Italy and 2Department of Gynaecology and Obstetrics, Universita` di Roma Tor Vergata, Rome, Italy Abstract
Keywords
Objective: To establish whether there are relationships between umbilical artery Pulsatility Index (PI) and fetal macrosomia in pregnancies complicated by type I diabetes. Methods: In a retrospective observational study, 102 singleton pregnant women with type I diabetes were considered. Umbilical artery PI was measured by Doppler ultrasonography within one week from delivery and related to neonatal weight. Pregnancies were grouped according to birtweight in macrosomic group (4000 g) and normal growth group (54000 g). Relationships between umbilical artery PI and birth weight and birth weight centile were tested by Pearson’s correlation analysis. Further umbilical artery PI values were compared between macrosomic and normally grown fetuses. Results: Birth weight was 4000 g in 24 pregnancies (23.5%). A significant relationship was found between umbilical artery PI and neonatal weight (r ¼ 0.512; p50.01) and neonatal weight centile (r ¼ 0.400; p50.01). Umbilical artery PI were significantly lower (t ¼ 6.013; p50.001) in the macrosomic group (0.78; 95% confidence interval (CI) 0.73–0.84) than in the normal growth group (1.00; 95% CI 0.97–1.04). Conclusions: In pregnancies complicated by type I diabetes there is a significant relationship between umbilical artery PI value before delivery and absolute birth weight and birth weight centile. Macrosomic fetuses show a significant reduction in umbilical artery PI when compared with diabetic pregnancies without fetal overgrowth.
Doppler ultrasound, macrosomia, pregnancy, type I diabetes, umbilical artery
Objective Macrosomia is associated with a high incidence of perinatal mortality and morbidity and has been found to occur at a 10fold higher rate in diabetic pregnancies compared with a normal population [1]. Indeed, this condition carries an increased risk for shoulder dystocia, birth trauma (bone fracture and nerve palsy), perineal trauma and wound healing. The fetal overgrowth is also associated with an increase in fetal and neonatal death, caused mostly by asphyxia and infections, and neonatal morbidity, such as Apgar score less than 4, birth injury and meconium aspiration syndrome [2]. Moreover, macrosomia has been associated with the onset of diseases in offspring at adulthood, such as type 2 diabetes and obesity associated with metabolic syndrome [3–5]. Although there is no absolute consensus about the definition of macrosomia, usually it is defined as a birth weight greater than 4000 g in pregnancies complicated by diabetes [6].
Address for correspondence: Pasquale Martinelli, MD, High Risk Pregnancy Centre, Department of Gynaecology and Obstetrics, University Federico II Naples, Vico Acitillo 53, 80131 Naples, Italy. Tel: 39 81 746 2966. Fax: 39 81 746 2966. E-mail: [email protected]
History Received 13 November 2013 Revised 24 December 2013 Accepted 29 December 2013 Published online 3 February 2014
Increased fetal weight is considered to be associated with increased placental size and vascularization [7]. Umbilical artery (UA) Pulsatility Index (PI) is significantly associated with the development of placental vasculature and there are evidences of lower umbilical artery PI in macrosomic fetuses from non-diabetic pregnancies than the general population [8–10]. To the best of our knowledge, no data are up to now available of such relationship in pregnancies complicated by type I diabetic. The aim of our study was, therefore, to establish whether macrosomic fetuses at term in pregnancies complicated by type I diabetes show different values of umbilical artery Doppler PI from those of non-macrosomic fetuses.
Methods This is a multi-center retrospective observational study carried out from January 2006 to December 2012 at two referral centers for high-risk pregnancies in Naples and Rome. For this study, 102 patients with insulin-dependent diabetes were included. The clinical management of diabetes during pregnancy was similar between the two centers. Briefly, pregnant diabetic women self-monitored their capillary blood glucose
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
2
G. M. Maruotti et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
levels at home and insulin adjustments were performed at the biweekly visit, with the aim of maintaining blood glucose fasting levels 595 mg/dl, and 5140 and 5120 mg/dl at 1 and 2 h after meals, respectively. The quality of metabolic control was assessed by glycosylated hemoglobin concentration (Hba1ac%) in maternal blood. All included pregnancies were singleton, and accurately dated by early ultrasonographic examination. Exclusion criteria were the presence of fetal chromosomal or congenital diseases, maternal metabolic disease other than diabetes, a neonatal weight centile 10th and a gestational age of delivery less than 34 weeks of gestation. The birth weight centile has been calculated using the Italian Neonatal Study charts, based on a multi-center Italian study on 45 462 newborns [11]. Umbilical artery velocity waveforms recordings were obtained with Voluson E8 Expert ultrasound equipments (GE Medical Systems, Milwaukee, WI) equipped with 2–5 MHz transabdominal probes and using color and pulse wave Doppler functions. Umbilical artery waveforms were recorded from a free-floating loop of the umbilical cord during fetal quiescence and in the absence of fetal breathing using a previously reported technique [12]. PI was measured over at least three consecutive and uniform hearth cycles. All the ultrasound examinations considered were performed within three days before delivery. Included pregnancies were grouped according to birth weight in the macrosomic group (4000 g) and normal growth group (54000 g). Shapiro–Wilk’s test was used to analyze the normal distribution of the data. The unpaired Student’s t-test was used to evaluate differences between groups in umbilical artery (PI) values and in their clinical characteristics. Relationships between the umbilical artery PI and birth weight or birth weight centile were estimated by linear regression analysis. A p value 50.05 was considered as significant. Statistical analysis was carried out using the Statistical Package for Social Sciences (SPSS) Statistics v. 19 (IBM Inc., Armonk, New York).
Results Of the 102 included pregnancies 24 (23.5%) gave birth to a neonate with a birth weight 4000 g (macrosomic group) while 78 women gave birth to a baby whose weight was less than 4000 g (normal growth group). Regarding ethnicity, 94 women were Caucasian, 5 women were from Africa, 2 women from South America and 1 woman from Asia. There are no significant differences between the two groups according to the maternal characteristics and neonatal outcomes except for birth weight as reported in Table 1. Umbilical artery PI values resulted significantly lower in the macrosomic group when compared with controls
(PI ¼ 0.78; 95% confidence interval (CI) 0.73–0.84 versus PI ¼ 1.00; 95% CI 0.97–1.04; t ¼ 6,013; p50.001) (Figure 1). Linear regression analysis revealed a significant correlation between UA-PI and neonatal birth weight (constant ¼ 1.471; slope 0.000152; r ¼ 0.512; residual SD ¼ 0.00002; p50.01) (Figure 2). Similarly when neonatal weight centile was considered, linear regression analysis revealed a significant correlation with UA-PI (constant ¼ 1.157; slope ¼ 0.002663; r ¼ 0.400; residual SD ¼ 0.000611; p50.01) (Figure 3). The effect of gestational age on umbilical artery PI was tested by regression analysis. No significant relationships were found in both the macrosomic (r ¼ 0.169; p ¼ 0.429) and normal growth groups (r ¼ 0.390; p ¼ 0.736) (Figures 4 and 5). In order to assess the potential influence of maternal metabolic control on UA velocity waveforms, the Hb1ac% values measured at the time of Doppler recordings (available in 55 pregnancies) were related to UA-PI. Regression analysis showed no significant relationship between the two variables (r ¼ 0.10: p ¼ 0.843). Similarly, no relationship were found between maternal body mass index (BMI) and UA-PI (r ¼ 0.01; p ¼ 0.935)
Discussion In this study, we evidenced that in fetuses of type I diabetic mothers’ umbilical artery PI is significantly reduced in the presence of macrosomia and that there is significant inverse relationship between umbilical artery PI and absolute birth weight values or percentile. Previous studies have demonstrated an enhanced placental angiogenesis in women with diabetes. Increased surface area, capillary length and branching have been reported for placenta of type I and gestational diabetes mellitus (GDM) pregnancies [13–16]. Pietro et al. demonstrated that also mild gestational hyperglycemia causes an increase in terminal villi and capillaries. In placentas from diabetic mothers blood vessels walls appear thicker and the surrounding mesenchyme denser than in pregnant normoglycemic women [17]. This feature, associated with the erythrocyte deformation and increased blood viscosity due to the increased glycosylation of hemoglobin, leads to a poor local oxygen transport [18,19]. While the maternal–placental oxygen supply is reduced, fetal oxygen demand is increased by aerobic metabolism stimulated by fetal hyperinsulinemia, so the resulting relative placental hypoxia upregulates the transcription synthesis of proangiogenic and growth factors such as leptin, vascular endothelial growth factor and fibroblast growth factor 2 [20– 22]. This is also supported by recent 3D ultrasonographic studies showing an increased vascularization in the placenta of type I diabetic pregnancies already present in the first trimester and particularly evident in the presence of a poor
Table 1. Maternal and neonatal characteristics of the study population and controls. Characteristics Maternal age (years) BMI (kg/m2) Gestational age at delivery (days) Birth weight
Macrosomic group (n ¼ 24) 31.87 25.59 263.46 4276.67
(SD (SD (SD (SD
4.90) 3.93) 8.62) 199.45)
Normal growth group (n ¼ 78) 31.71 27.30 257.56 3163.90
(SD (SD (SD (SD
4.81) 5.45) 11.38) 444.04)
t
p
0.145 1.387 2.336 17.2
0.885 0.169 0.021 50.001
DOI: 10.3109/14767058.2013.879706
Type I diabetic mothers
3
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
Figure 1. Mean UA-PI and % 95th CI in the case and control groups.
Figure 2. Linear regression analysis between UA-PI and neonatal birth weight in the entire population (% 95th CI).
metabolic control [23]. Furthermore, it has been demonstrated that placental weight also tends to be heavier in diabetic pregnancies; the weight gain is more marked in placenta than in the fetus, so the placental-to-fetal weight ratio is higher than in normal pregnancies. Placentomegaly is also correlated with fetal macrosomia, confirming the correlation between placental and fetal weight [7]. Previous studies investigated the correlation between UA-PI and birth weight. In 2003, Owen et al. analyzed in 274 non-diabetic pregnancies the correlation between
umbilical artery PI and systolic/diastolic ratio with estimated fetal weight (EFW) and no correlation was found [8]. In this study, 22 pregnancies (8%) with birth weight below 10th centile were included and moreover not any difference in UA-PI between macrosomic and non-macrosomic fetuses was investigated. In 2005, Lam et al. analyzed the usefulness of UA-PI in the prediction of large for gestational age babies compared with EFW in 181 pregnancies and demonstrated a significant inverse correlation between UA-PI and birth weight centile [9]. In 2011, Ebbing et al. studied Umbilical
4
G. M. Maruotti et al.
J Matern Fetal Neonatal Med, Early Online: 1–6
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
Figure 3. Linear regression analysis between UA-PI and neonatal weight centile in the entire population (% 95th CI).
Figure 4. Linear regression analysis between UA-PI and the gestational age at delivery in the group of pregnancies with macrosomic fetuses (% 95th CI).
vein blood flow and Doppler measurements of the ductus venosus, left portal vein and the hepatic, splenic, superior mesenteric, cerebral and umbilical arteries in a population of 29 non-diabetic women who gave birth to a baby with birth weight 90th centile compared with a reference population of 161 women with low-risk pregnancies. Data analysis showed that mean UA-PI and SD were significantly lower in the macrosomic pregnancies [10]. To the best of our knowledge, our study is the first to evaluate the characteristics of umbilical artery Doppler velocimetry according to the presence of macrosomia in a cohort of diabetic pregnant women with type I diabetes.
Furthermore, it is the only study about umbilical artery Doppler in macrosomic fetuses that considers for the diagnosis of macrosomia a birth weight 44000 g, while other studies define macrosomia as a birth weight centile490 ; this point is essential because a newborn of 2800 at 34 weeks can be considered macrosomic, but it is difficult that its placental weight and vascularization, and then its UA-PI, could be compared with that of a 4000 g newborn. For the same reason, we intentionally excluded from the study very preterm newborn or fetal growth restricted babies in order to remove possible biases which could be due to the presence of abnormal increased UA-PI in these controls. The absence of
DOI: 10.3109/14767058.2013.879706
Type I diabetic mothers
5
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
Figure 5. Linear regression analysis between UA-PI and the gestational age at delivery in the control group (% 95th CI).
relationship between gestational age and umbilical artery PI in our study population corroborates the direct link between birth weight and umbilical artery impedance to flow. A limitation of this study is the lack of simultaneous informations of fetal arterial and venous hemodynamics that can be affected in macrosomic fetuses of diabetic mothers. Further the relationships between fetal weight and umbilical artery at earlier gestational age deserve further investigations In conclusion, our study shows that macrosomic growth of fetuses of type I diabetic mother is associated with reduced umbilical artery impedance to flow. The role, if any, of umbilical artery PI in predicting macrosomia together other ultrasonographic measurements in diabetic pregnancies remains to be established.
Declaration of interest The authors report no declarations of interest.
References 1. Landon MB, Catalano PM, Gabbe SG. Diabetes mellitus. In: Gabbe SG, Niebyl JR, Simpson Jl, eds. Obstetrics, normal and problem pregnancies. 4th ed. New York (NY): Churchill Livingstone; 2002:1089–97. 2. Zhang X, Decker A, Platt RW, Kramer MS. How big is too big? The perinatal consequences of fetal macrosomia. Am J Obstet Gynecol 2008;198:517.e1–517.e6. 3. Hales CN, Barker DJP. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5–20. 4. Grissa O, Ate`gbo JM, Yessoufou A, et al. Antioxidant status and circulating lipids are altered in human gestational diabetes and macrosomia. Trans Res 2007;150:164–71. 5. Khan NA, Yessoufou A, Kim M, Hichami A. N-3 fatty acids modulate Th1 and Th2 dichotomy in diabetic pregnancy and macrosomia. J Autoimmun 2006;26:268–77. 6. Boyd ME, Usher RH, McLean FH. Fetal macrosomia: prediction, risks, proposed management. Obstet Gynecol 1983;61:715–22.
7. Taricco E, Randelli T, Nobile de Santis MS, Cetin I. Foetal and placental weights in relation to maternal characteristics in gestational diabetes. Placenta 2003;24:343–7. 8. Owen P, Murphy J, Farrell T. Is there a relationship between estimated fetal weight and umbilical artery Doppler impedance indices? Ultrasound Obstet Gynecol 2003;22:157–9. 9. Lam H, Leung WC, Lee CP, Lao TT. Relationship between cerebroplacental Doppler ratio and birth weight in postdates pregnancies. Ultrasound Obstet Gynecol 2005;25:265–9. 10. Ebbing C, Rasmussen S, Kiserud T. Fetal hemodynamic development in macrosomic growth. Ultrasound Obstet Gynecol 2011;38: 303–8. 11. Bertino E, Spada E, Occhi L, et al. Neonatal anthropometric charts: the Italian neonatal study compared with other European studies. J Pediatr Gastroenterol Nutr 2010;51:353–61. 12. Arduini D, Rizzo G. Normal values of Pulsatility Index from fetal vessels: a cross-sectional study on 1556 healthy fetuses. J Perinat Med 1990;18:165–72. 13. Jauniaux E, Burton GJ. Villous histomorphometry and placental bed biopsy investigation in type I diabetic pregnancies. Placenta 2006;27:468–74. 14. Jirkovska´ M, Kubı´nova´ L, Jana´cek J, et al. Topological properties and spatial organization of villous capillaries in normal and diabetic placentas. J Vasc Res 2002;39:268–78. 15. Leach L, Gray C, Staton S, et al. Vascular endothelial cadherin and beta-catenin in human fetoplacental vessels of pregnancies complicated by type 1 diabetes: associations with angiogenesis and perturbed barrier function. Diabetologia 2004;47:695–709. 16. Mayhew TM. Enhanced fetoplacental angiogenesis in pre-gestational diabetes mellitus: the extra growth is exclusively longitudinal and not accompanied by microvascular remodelling. Diabetologia 2002;45:1434–9. 17. Pietro L, Daher S, Rudge MV, et al. Vascular endothelial growth factor (VEGF) and VEGF-receptor expression in placenta of hyperglycemic pregnant women. Placenta 2010;31:770–80. 18. Iino K, Yoshinari M, Doi Y, et al. Reduced tissue oxygenation and its reversibility by glycemic control in diabetic patients. Diabetes Res Clin Pract 1997;34:163–8. 19. Taricco E, Radaelli T, Rossi G, et al. Effects of gestational diabetes on fetal oxygen and glucose levels in vivo. BJOG 2009;116: 1729–35.
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G. M. Maruotti et al.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Virginia on 05/27/14 For personal use only.
20. Jos´ko J, Mazurek M. Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. Med Sci Monit 2004;10:RA89–98. 21. Bouloumie´ A, Drexler HC, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res 1998;83: 1059–66.
J Matern Fetal Neonatal Med, Early Online: 1–6
22. Burleigh DW, Stewart K, Grindle KM, et al. Influence of maternal diabetes on placental fibroblast growth factor-2 expression, proliferation, and apoptosis. J Soc Gynecol Investig 2004;11:36–41. 23. Rizzo G, Capponi A, Pietrolucci ME, et al. First trimester placental volume and three dimensional power doppler ultrasonography in type I diabetic pregnancies. Prenat Diagn 2012;32:480–4.
