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Obstetrics & Gynecology 2000;96:162-166
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Absent Umbilical Artery End-Diastolic Velocity in Growth-Restricted Fetuses: A Risk Factor for Neonatal Thrombocytopenia

AHMET A. BASCHAT, MD, ULRICH GEMBRUCH, MD, IRWIN REISS, MD, LUDWIG GORTNER, MD, CARL P. WEINER, MD and CHRIS R. HARMAN, MD

From the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, Maryland; and the Departments of Obstetrics and Gynecology and Pediatrics, Medical University Lübeck, Lübeck, Germany.


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
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Objective: To examine the relationship between umbilical artery (UA) end-diastolic flow and neonatal thrombocytopenia.

Methods: We prospectively examined 115 anatomically normal single fetuses with UA pulsatility indices more than two standard deviations above the gestational age mean and subsequent birth weights below the tenth percentile. Peripheral neonatal platelet counts in fetuses with positive UA end-diastolic velocity were compared with those of fetuses with absent or reversed UA end-diastolic velocity.

Results: Sixty-seven fetuses (58.3%) had positive UA end-diastolic velocity and 48 (41.7%) had absent or reversed UA end-diastolic velocity. Three neonates in the positive-flow group and 22 neonates in the absent- or reversed-flow group had platelet counts of less than 100,000/mm3 (relative risk 10.2; 95% confidence interval; 3.2, 32.3; P < .001). Absent or reversed end-diastolic velocity had a sensitivity of 88%, specificity of 71%, positive predictive value of 46%, and negative predictive value of 96% for predicting neonatal thrombocytopenia. Neonates with absent or reversed flow also had lower median platelet counts (101,500/mm3 versus 208,000/mm3, P < .001), hemoglobin levels (15.1 versus 16.4 g/dL, P < .01), and hematocrits (47.6 versus 51.1%, P < .05), as well as higher nucleated red blood cell counts (191 versus 15 per 100 white blood cells, P < .001).

Conclusion: Absent or reversed UA end-diastolic velocity in growth-restricted fetuses is associated with a statistically significant increase in risk of neonatal thrombocytopenia.

Umbilical artery (UA) blood flow is assessed by Doppler ultrasound in various fetal conditions, including fetal growth restriction (FGR), in which it has been used to help predict hypoxemia and acidemia.1,2 Increased UA blood flow resistance might indicate obliteration of small muscular arteries in tertiary stem villi or developmental abnormalities in the terminal villous vascular tree.1,3 Studies of sheep indicated that at least 70% placental embolization is necessary to cause absent or reversed UA end-diastolic velocity.4

Neonatal thrombocytopenia is a feature of FGR, and an inverse relationship between neonatal platelet counts and UA Doppler flow resistance has been documented.5,6 Villous endothelial damage predisposes to local platelet adherence, thrombosis, and vascular occlusion.3,5 Extensive intraplacental villous abnormalities found with absent or reversed UA end-diastolic velocity suggest a higher risk of overt thrombocytopenia. The use of qualitative UA waveform analysis to predict neonatal thrombocytopenia in such situations is relatively unexplored. We investigated the relationship between UA end-diastolic velocity and neonatal thrombocytopenia in growth-restricted fetuses.


   Materials and Methods
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We prospectively examined women with suspected FGR who were referred for tertiary care between 1994 and 1999. To preserve a close temporal relationship between Doppler and hematologic assessments, we included only fetuses examined within 24 hours before delivery. Other inclusion criteria were normal fetal anatomy and karyotype, sonographically measured abdominal circumference below the fifth percentile for gestational age by local reference values, abnormal UA Doppler flow velocimetry (pulsatility index7 [PI] more than two standard deviations [SDs] above the gestational age mean by local reference values), availability of neonatal follow-up data, and no indication for immediate delivery. Gestational age was estimated from the last menstrual period or by sonographic examination before 20 weeks’ gestation. Exclusion criteria were multiple gestations, maternal aspirin ingestion within 4 weeks of delivery, immune thrombocytopenia, and evidence of chorioamnionitis.

All ultrasound examinations were done with 4- or 5-MHz sector-probes (128 XP/10 ob or Sequoia 512; Acuson Corp., Mountain View, CA) with the high-pass filter set at 100 Hz to separate vessel wall vibrations from flow velocity waveforms. Measurements were obtained during fetal rest and apnea. Color Doppler imaging was used to optimize placement of the pulsed wave Doppler gate by adjusting the velocity scale to identify the area and direction of maximum blood flow. The insonation angle was kept as close to 0° as possible and the sample volume was adjusted to cover the entire vessel. This approach maximizes detection of end-diastolic velocities and accuracy of Doppler measurements.8 Measurements were taken from the frozen image after at least five consecutive uniform flow velocity waveforms with high signal-to-noise ratios were obtained from the midsection of the umbilical cord. Diagnoses of absent or reversed end-diastolic velocity were based on multiple measurements, with consideration given to the best waveform achieved. We saw no clipping of the waveform at baseline with this ultrasound technique.

Neonatal evaluation included assigning of Apgar scores by the attending pediatric team and determination of umbilical cord arterial pH and blood gas levels. Complete blood counts including neonatal platelet counts were done in the hospital laboratory using a peripheral venous sample collected in an ethylenediaminetetra-acetic acid–coated tube within 1 hour of delivery. Nucleated red blood cell (RBC) count per 100 white blood cells also was done using peripheral blood smears. Acidemia was defined as a cord artery pH level or base excess below the tenth percentile.9 Thrombocytopenia was defined as an automated platelet count of less than 100,000/mm3 and was confirmed using a peripheral blood smear.5,6,10

One hundred fifteen fetuses met inclusion criteria and were subdivided on the basis of their last Doppler examinations before delivery. Validity of the three principal waveform patterns (positive, absent, or reversed end-diastolic flow) for predicting thrombocytopenia was examined. In this analysis, absent and reversed end-diastolic velocity were tested in isolation and in combination. For final analysis, fetuses were divided into two groups: those with end-diastolic flow present and those with absent or reversed end-diastolic flow. Pulsatility index elevation was corrected for gestational age by conversion of individual measurements into their z scores ({Delta}PI = SDs from the gestational age mean). Statistical analysis was done using Abstat 1.9 (Anderson Bell Corp., Arvada, CO). The Student t test or Mann-Whitney U test was used for continuous variables according to distribution. Fisher exact and {chi}2 analyses were used for categoric variables. Multiple linear regression was used to assess the relationship between {Delta}PI, umbilical cord artery blood gas values, birth weight percentile, gestational age at delivery, and platelet count. The 95% confidence interval (CI) was calculated and P < .05 was considered statistically significant.


   Results
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Abstract
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 Results
Discussion
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End-diastolic velocity was positive in the UAs of 67 fetuses (58.3%). Of the remaining 48 (41.7%), 17 had absent and 31 had reversed end-diastolic velocity. The study population was predominantly white, and the two groups did not differ with respect to maternal age, parity, pregnancy complications, or race. There was a high incidence of preeclampsia in both groups (Table 1Go). Gestational ages at delivery and birth weights were significantly lower in the group of fetuses with absent or reversed end-diastolic flow, and most neonates in that group had birth weights below the third percentile. Neonates in the absent- or reversed-flow group had lower umbilical cord artery pH, oxygen pressure (tension), bicarbonate, and base excess values were more likely to have 1-minute Apgar scores of less than 7 and acidemia at birth (Table 2Go).


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  		Table 1. Maternal Characteristics
 

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  		Table 2. Delivery Outcomes
 
Neonates with absent or reversed UA end-diastolic velocity had significantly lower hemoglobin levels and hematocrits and significantly higher nucleated RBC counts. Nucleated RBC counts were statistically significantly higher in neonates with thrombocytopenia (median 258, range 3–3180) than in those with normal platelet counts at birth (median 32.5, range 0–1660; P < .001). Blood counts and 95% CIs are summarized in Table 3Go.


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  		Table 3. Neonatal Blood Values
 
Multiple linear regression using birth weight percentile, gestational age, umbilical cord artery blood gas values, and {Delta}PI as independent variables and platelet count as the dependent variable identified that UA {Delta}PI had the strongest association with platelet counts in the whole study group (R2 = 0.21, P < .05). However, subgroup analysis revealed that the UA pH level had the only significant correlation with the neonatal platelet counts within the absent- or reversed-velocity group (R2 = 0.18, P < .05), whereas no significant associations were identified in the group with positive flow.

Neonates with absent or reversed UA end-diastolic velocity had a tenfold increase in incidence of thrombocytopenia compared with those with end-diastolic velocity present (relative risk [RR] 10.3; CI 3.2, 32.3; P < .001). There was no significant difference between absent or reversed end-diastolic velocity in terms of predicting neonatal thrombocytopenia. Both waveform patterns were associated with similar increases in RR. Absent or reversed end-diastolic velocity identified 22 of 25 neonates with thrombocytopenia at birth and had a higher sensitivity than either waveform pattern in isolation (Table 4Go).


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  		Table 4. Umbilical Artery Flow Pattern and Prediction of Thrombocytopenia
 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
This study illustrated an association between neonatal thrombocytopenia and absent or reversed UA end-diastolic velocity in pregnant women referred for evaluation of severe FGR. The association can be inferred from previous studies,5,6,11 but this investigation specifically documented that qualitative UA waveform analysis is useful for identifying neonates at high risk for thrombocytopenia at birth. Thrombocytopenia is rare if UA end-diastolic velocity is preserved. However, loss or reversal of end-diastolic velocity was associated with a tenfold increase in incidence. Platelet count was not tested by cordocentesis in fetuses remote from delivery, so it is possible that this relationship is present for a variable time before birth.

Thrombocytopenia at birth in growth-restricted neonates might be multifactorial, involving decreased fetal platelet production, increased placental or fetal platelet sequestration, and active consumption. Those mechanisms all act to increase platelet turnover, with a consequent decrease in platelet counts.12 Absent or reversed UA end-diastolic velocity is a manifestation of placental disease associated with disturbance of villous architecture and blood flow, as well as abnormal placental respiratory function. With the principal mechanisms for thrombocytopenia in mind, there are several possible ways in which absent or reversed end-diastolic velocity can be related to development of thrombocytopenia in utero.

Significant fetal hypoxemia or acidemia, which often accompanies absent or reversed UA end-diastolic velocity,2 might have a direct depressant effect on megakaryocyte proliferation. Megakaryocytopoietic defects without evidence of increased platelet destruction have been found in growth-restricted neonates.13 Platelet production is under more complex control and might not necessarily parallel the proliferation of erythrocyte precursors observed with intrauterine hypoxemia.14,15 Under such circumstances, preferential devotion of marrow to erythropoiesis could lead to decreased platelet production.16 The strong association we noted between thrombocytopenia and increased nucleated RBC counts is consistent with previous reports11,15 and suggests that chronic hypoxemia or acidemia contributes to the development of thrombocytopenia.

Absent or reversed UA end-diastolic flow indicates a marked decrease in villous blood flow, in turn influenced by several factors.1,2,17 Release of humoral factors especially from platelets (eg, platelet activating factor) can alter villous vascular tone.1,2,4,6,17 Chronic platelet activation and placental arteriolar constriction are inferred by the increased platelet activating factor–hydrolase levels in growth-restricted fetuses.16 Abnormal villous vessel walls are a feature of the placental disease in FGR.1,3 The prothrombotic potential of abnormal flow, vessel tone, and vessel walls in the placenta circulation might exceed compensatory mechanisms, resulting in placental thrombosis.4–6,17 Red blood cells and platelets can be consumed through placental thrombosis or microangiopathic hemolysis.11 Intraplacental thrombosis is a plausible common pathway for platelet and RBC consumption, progressive villous vascular occlusion, and subsequently increased UA flow resistance.11 That mechanism is supported by the observation that in growth-restricted fetuses, abnormal UA Doppler studies, platelet turnover, and degree of thrombocytopenia appear related to placental pathology.6 Lower hematologic indices might reflect erythrocyte consumption, explaining why neonates with absent or reversed UA end-diastolic velocity have lower hematocrits despite higher nucleated RBC counts.11,13

Episodic placental thrombosis has specific implications for outcome in FGR. Progressive loss of placental function, with its metabolic implications and rapid fluctuations in fetal cardiac afterload or blood pressure coupled with thrombocytopenia might increase the risk of perinatal brain damage. In that setting, thrombocytopenia and increased nucleated RBC counts can be considered markers for adverse neurologic outcome.15 The significant correlation between placental resistance, cord pH level, and platelet counts and the association between thrombocytopenia, low hematocrit, and high nucleated RBC counts suggest a complex interaction in which platelets fundamentally influence the vicious cycle of placental injury, growth restriction, vascular damage, and abnormal blood flow.

Although our data do not allow identification of the precise underlying mechanism, they illustrate that a degree of placental abnormality manifesting itself in absent or reversed UA end-diastolic velocity is associated with overt thrombocytopenia at birth. Further research into the relationship between uteroplacental blood flow, hematologic indices, and perinatal outcome is of potential importance to managing perinatologists, neonatologists and hematologists because it might influence delivery planning, postnatal management, and diagnostic work-up.


   Footnotes
 
PII S0029-7844(00)00904-2

Received October 28, 1999. Received in revised form March 17, 2000. Accepted March 30, 2000.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Kingdom JCP, Burrell SJ, Kaufmann P. Pathology and clinical implications of abnormal umbilical artery Doppler waveforms. Ultrasound Obstet Gynecol 1997;9:271–86.[Medline]

2. Bilardo C, Nicolaides KH, Campbell S. Doppler measurements of fetal and uteroplacental circulations: Relationship with umbilical venous blood gases measured at cordocentesis. Am J Obstet Gynecol 1990;162:115–20.[Medline]

3. Giles WB, Trudinger BJ, Baird PJ. Fetal umbilical artery flow velocity waveforms and placental resistance: Pathological correlation. Br J Obstet Gynaecol 1985;92:31–8.[Medline]

4. Morrow RJ, Adamson SL, Bull SB, Ritchie JW. Effect of placental embolization on the umbilical artery velocity waveform in fetal sheep. Am J Obstet Gynecol 1989;161:1055–60.[Medline]

5. Wilcox G, Trudinger B, Cook CM, Wilcox W, Conelly A. Reduced fetal platelet counts in pregnancies with abnormal Doppler umbilical flow waveforms. Obstet Gynecol 1989;73:639–43.[Abstract/Free Full Text]

6. Wilcox GR, Trudinger BJ. Fetal platelet consumption: A feature of placental insufficiency. Obstet Gynecol 1991;77:616–21.[Abstract/Free Full Text]

7. Gosling RG, King DH. Ultrasound angiology. In: Marcus AW, Adamson L, eds. Arteries and veins. Edinburgh, United Kingdom: Churchill Livingstone, 1975:61–98.

8. Londrey GL, Spadone DP, Hodgson KJ, Ramsey DE, Barkmeier LD, Sumner DS. Does color-flow imaging improve the accuracy of duplex carotid evaluation? J Vasc Surg 1991;13:659–63.[Medline]

9. Eskes TK, Jongsma HW, Houx PC. Percentiles for gas values in human umbilical cord blood. Eur J Obstet Gynecol Reprod Biol 1983;14:341–6.[Medline]

10. Andrew M, Kelton J. Neonatal thrombocytopenia. Clin Perinatol 1984;11:359–91.[Medline]

11. Bernstein PS, Minior VK, Divon MY. Nucleated red blood cell counts in small for gestational age fetuses with abnormal umbilical artery Doppler studies. Am J Obstet Gynecol 1997;177:1079–84.[Medline]

12. Scissione AC, Bessos H, Callan N, Blakemore K, Kickler T. Indicators of platelet turnover in thrombocytopenic infants. Br J Obstet Gynaecol 1997;104:743–5.[Medline]

13. Weiner CP, Williamson RA. Evaluation of severe growth retardation using cordocentesis—Hematologic and metabolic alterations by etiology. Obstet Gynecol 1989;73:225–9.[Abstract/Free Full Text]

14. Vainchenker W, Debili N, Methia N, Mouthon MA, Wendling F. Hematopoiesis and its regulation: Comparison between erythropoiesis and megakaryocytopoiesis. Bull Acad Natl Med 1994;178: 753–78.[Medline]

15. Korst LM, Phelan JP, Wang YM, Ahn MO. Neonatal platelet counts in fetal brain injury. Am J Perinatol 1999;16:79–83.[Medline]

16. Meberg A, Jakobsen E, Halvorsen K. Humoral regulation of erythropoiesis and thrombopoiesis in appropriate and small for gestational age infants. Acta Paediatr Scand 1982;71:769–73.[Medline]

17. Ohshige A, Yoshimura T, Maeda T, Ito M, Okamura H. Increased platelet activating factor acetylhydrolase activity in the umbilical venous plasma of growth restricted fetuses. Obstet Gynecol 1993; 93:180–3.




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