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ORIGINAL RESEARCH |
From the Department of Reproductive Science and Medicine, Imperial College School of Medicine at St. Mary’s Hospital, London, United Kingdom.
Address reprint requests to: Lesley Regan, MD, FRCOG, ICSM at St. Mary’s, Department of Obstetrics & Gynaecology, Mint Wing, South Wharf Road, London W2 1NY, United Kingdom; E-mail: l.regan{at}ic.ac.uk.
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ABSTRACT |
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METHODS: One hundred seventy pregnant women with histories of recurrent miscarriage in association with antiphospholipid antibodies (32 lupus anticoagulant positive, 47 IgG anticardiolipin positive, 78 IgM anticardiolipin positive, and 13 lupus anticoagulant and anticardiolipin antibodies positive) treated with low-dose aspirin and heparin were recruited prospectively. Doppler assessment of the uterine arteries (presence or absence of notches and pulsatility index) were performed at 16–18 and 22–24 weeks. The main outcome measures were the delivery of a SGA infant and the development of preeclampsia.
RESULTS: There were 164 live births and six midtrimester losses. The prevalence of preeclampsia and SGA was similar at 10%. In predicting preeclampsia or SGA, uterine artery pulsatility index at either interval was of no value, and the diagnostic accuracy of the Doppler was limited to bilateral uterine artery notches at 22–24 weeks in the subgroup of women with positive lupus anticoagulant. In this subgroup, bilateral uterine artery notches at 22–24 weeks in predicting preeclampsia generated a high likelihood ratio for positive test (12.8, 95% confidence interval 2.2, 75), sensitivity (75%), specificity (94%), positive (75%) and negative (94%) predictive value. In predicting SGA, the corresponding figures were respectively 13.6 (95% confidence interval 1.9, 96), 80%, 94%, 80%, 94%. Uterine artery Doppler was of limited value in pregnancies associated with anticardiolipin antibodies in isolation.
CONCLUSION: In pregnancies associated with lupus anticoagulant, uterine artery Doppler at 22–24 weeks is a useful screening test in predicting preeclampsia and SGA infants.
Antiphospholipid antibodies, both lupus anticoagulant and IgG and IgM anticardiolipin antibodies are associated with recurrent fetal loss, preeclampsia, fetal growth restriction, placental abruption, and preterm delivery.1,2 The presumed mechanisms underlying these adverse pregnancy outcomes include direct damage of trophoblast cells by antiphospholipid antibodies, generation of thrombi in the intervillous space, and impairment of maternal spiral arterial blood flow.3,4
Failure of normal trophoblastic implantation, resulting in abnormal uteroplacental blood flow, is associated with later development of preeclampsia, fetal growth restriction, and placental abruption.5 The clinical studies of uterine artery Doppler screening are contradictory, and a recent meta-analysis6 has concluded that uterine artery flow velocity waveform ratio has limited diagnostic prediction for preeclampsia, intrauterine growth retardation, and perinatal death. Previous reports,7–9 although scarce, have suggested that uterine artery Doppler screening has the potential of predicting preeclampsia or small for gestational age (SGA) infants in women with primary antiphospholipid syndrome.
We conducted a prospective study designed to assess the value of midtrimester uterine artery Doppler in predicting preeclampsia and SGA infants in women with histories of recurrent miscarriage associated with antiphospholipid antibodies treated with low-dose aspirin and low-dose heparin.
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SUBJECTS AND METHODS |
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All women were treated with low-dose aspirin and low-dose heparin during pregnancy. Low-dose aspirin (75 mg daily) was commenced as soon as the urinary pregnancy test was positive. Self-administered subcutaneous low molecular weight heparin, enoxaparin sodium (20 mg daily, Clexane, Rhone-Poulence Rorer, Sussex, UK) was commenced when an intrauterine pregnancy was confirmed with ultrasound scan. Treatment with aspirin and heparin was discontinued at 34 completed weeks or at delivery if this occurred earlier.
After 12 completed weeks of gestation, women were invited to participate in the Doppler study. Informed consent was obtained from all the participants, and the local ethics committee approved the study. During the study period, 288 consecutive women with a singleton pregnancy attending the recurrent miscarriage clinic were considered eligible for the study. Of these 288 women, 112 were either not recruited or declined to participate in the Doppler study. Two women who required termination of pregnancy for fetal chromosomal abnormality were excluded from the study. Four women were lost to follow up and were excluded from the final analysis. Thus, 170 women were included and represent our total cohort. The demographic, clinical, and laboratory details of the two groups of women (those who had and those who did not have the Doppler examination) were comparable (Table 1
). Of the 170 women who initially agreed to participate in the study and for whom the pregnancy outcome details were available, 16 did not attend for the Doppler examination at 16 weeks and 13 (six because of midtrimester loss) women did not attend for the 24-week Doppler examination.
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Main outcome variables for analysis were the development of hypertension with (preeclampsia) or without proteinuria and the delivery of SGA infant. A normal outcome was defined as delivery at term of an appropriately grown fetus with no evidence of hypertension during pregnancy. Preterm delivery was defined as delivery before 37 completed weeks of gestation. SGA was defined as fetal weight below the 10th centile adjusted for sex and gestation. Hypertension was defined as blood pressure at least 140/90 mmHg on two occasions 4 hours apart, or a single reading of diastolic blood pressure at least 110 mmHg. Preeclampsia was defined as hypertension along with the development of proteinuria (more than 300 mg of protein excreted per 24 hours).
Statistical analysis was performed using computer software (Statistical package for social scientist, SPSS, for Windows v. 6, SPSS Inc., Chicago, IL) and confidence interval (CI) analysis program. 
2 test or Fisher exact test were used with proportions. Wilcoxon matched-pairs signed-ranks test was used for paired comparisons of continuous data. There was no significant difference between the right and left uterine artery PI at 16 weeks. Although there was a significant difference in the right and left uterine artery PI at 24 weeks, this was not related to the outcome of interest (preeclampsia and SGA infant). Therefore, mean PI (mean of right and left uterine artery z score) was used for analysis. As the impedance indices change with gestation, absolute values were converted into delta values (z score), which were adjusted for gestation. This was done with the aid of a built-in calculation program in the fetal database program used in our maternity unit for routine clinical practice, which uses the previously published nomograms.11
The performance of the tests was evaluated by calculating sensitivity, specificity, positive and negative predictive values, likelihood ratios for abnormal {sensitivity/(1 — specificity)} and normal tests {(1 — sensitivity)/specificity} with their 95% CI. The likelihood ratio is a stable predictive property of a test because it combines information from both sensitivity and specificity and is independent of prevalence. The interpretation of likelihood ratios for positive and negative test results has been reported by Jaeschke et al.12 A likelihood ratio of 1 indicates that the test has no predictive value for the outcome event of interest. To achieve conclusive prediction of the outcome event of interest, a likelihood ratio of more than 10 or less than 0.1 would be required for a positive and negative test result, respectively. Moderate prediction can be achieved with likelihood ratios of 5–10 and 0.1–0.2, whereas likelihood ratios of 1–5 and 0.2–1 would generate only minimal prediction.
The area under the receiver operating characteristic (ROC) curve assessed the diagnostic accuracy of uterine artery PI in predicting adverse pregnancy outcome (preeclampsia or SGA infants). The area is 1 for a perfect test and 0.5 for an uninformative test. A two-parameter logistic regression analysis using mean uterine artery PI (as continuous independent variable) and bilateral uterine artery notching (as categorical independent variable), to estimate the risk of preeclampsia or SGA infant (dependent variable) was also performed. For this purpose, the dependent variable was coded as one or zero depending on whether the pregnancy was complicated (preeclampsia or SGA infants) or not. The categorical variable was coded as zero or one depending on the absence or presence of bilateral uterine artery notching. P < .05 was considered statistically significant.
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RESULTS |
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. Pregnancies associated with lupus anticoagulant and IgG anticardiolipin antibodies had the highest prevalence of complications and those associated with IgM anticardiolipin antibodies in isolation had the lowest rate of complications.
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The mean birth weight (standard deviation, SD) of 164 live born infants was 3244 (619) g, and the mean gestational age (SD) at delivery was 38 (3.9) weeks. Of the 164 live births, 11 (7%) infants had birth weights below the 5th centile, and 17 (10%) had birth weights below the 10th centile. In the subgroup of women who tested positive for lupus anticoagulant, the mean birth weight (SD) and the mean gestational age at delivery (SD) was 3147 (781) g and 37 (4) weeks, respectively. The proportions of infants with birth weight below the 5th centile and below the 10th centile in women with lupus anticoagulant were 10% and 16%, respectively. Of the 164 live births, 71 (43%) were delivered by cesarean, 40 by elective cesarean, and 31 by emergency cesarean, 75 (46%) had spontaneous vaginal births, and the remaining 18 (11%) had instrumental delivery.
In the entire study population, at 16 weeks’ gestation, 21% of women had bilateral uterine artery notches, and 26% had unilateral notch (16% left side, 10% right side). The corresponding values for 24 weeks’ gestation were respectively 10% and 12% (8%, 4%). The proportion of women with a high PI (greater than 95th centile) were 11% on the right, 8% on the left at 16 weeks and 5% on the right, 4% on the left at 24 weeks in the entire study population. However, in the subgroup of women with lupus anticoagulant, a greater proportion of women had uterine artery notches and high PI. The prevalence of uterine artery notches at 16 weeks’ gestation in women with lupus anticoagulant were 25% bilateral, 32% unilateral (18% left side, 14% right side) at 16 weeks’ gestation and 25% bilateral, 7% unilateral (7% left side) at 24 weeks’ gestation. In this subgroup, the proportion of women with high uterine artery PI (greater than 95th centile) at 16 weeks’ gestation were 14% (left side), 14% (right side), and the corresponding values at 24 weeks’ gestation were 14% and 11%, respectively.
There was a significant reduction in the uterine artery PI, adjusted for gestation (z score) between the first (16–18 weeks) and second visit (22–24 weeks) (Figure 1). Receiver operating characteristic analysis was performed for uterine artery PI (z scores) at 16 and 24 weeks as a diagnostic test to predict preeclampsia and SGA infants. The area under the ROC curve did not exceed 0.5 for any of the Doppler indices. In predicting preeclampsia, the area under the ROC curve (95% CI) for mean uterine artery PI (z score) was 0.43 (0.3, 0.6) at 16 weeks and 0.5 (0.3, 0.7) at 24 weeks. The corresponding values in the prediction of SGA infants were 0.48 (0.34, 0.64) and 0.49 (0.33, 0.66), respectively.
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and 4 show the performance of uterine artery notches at 16 and 24 weeks in predicting preeclampsia and SGA infants.
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). Neither uterine artery PI (z score) nor persistence of bilateral notches at 16 or 24 weeks predicted preeclampsia or SGA infants.
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DISCUSSION |
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In this large prospective study, we investigated the value of midtrimester uterine artery Doppler (PI and/or diastolic notch) in predicting preeclampsia and/or SGA in women with a history of recurrent miscarriage associated with antiphospholipid antibodies, receiving aspirin and heparin. Overall, the prevalence of preeclampsia and SGA was similar at 10%. Uterine artery PI at 16 or 24 weeks and uterine artery notching at 16 weeks were of no value in predicting preeclampsia and/or SGA. There was a statistically significant association between the persistence of bilateral uterine artery notching at 24 weeks and subsequent development of SGA infant and preeclampsia. However, despite this significant association, the performance of Doppler in predicting preeclampsia and/or SGA in the whole study population was poor. The high negative predictive values of the test again are of little value given the low prevalence of the disease. At this level of prevalence (10%), even if the test had no predictive performance at all, the negative predictive value would be expected to be at least 90%. Other studies evaluating midtrimester uterine artery Doppler in predicting subsequent development of preeclampsia and SGA infants also report a high specificity and negative predictive value, but low sensitivity and positive predictive value.15
In a recent meta-analysis, Chien et al6 concluded that the use of uterine artery flow velocity waveform ± diastolic notch has limited diagnostic prediction for preeclampsia, intrauterine growth retardation, and perinatal death in both low- and high-risk populations. However, the role of uterine artery diastolic notch alone in predicting preeclampsia in a high-risk population requires further investigation. In our study, we found that pregnancies associated with lupus anticoagulant or IgG anticardiolipin antibodies were at higher risk of preeclampsia and SGA compared with those associated with IgM anticardiolipin antibodies alone. Uterine artery notching at 22–24 weeks predicted preclampsia and SGA in pregnancies associated with lupus anticoagulant, but not in those associated with IgG anticardiolipin antibodies or IgM anticardiolipin antibodies. This may result from the varying severity of the disease process among the different subtypes of antiphospholipid antibodies, lupus anticoagulant representing the most severe end of the spectrum. The high positive likelihood ratio and the low negative likelihood ratio suggest that bilateral uterine artery notching at 22–24 weeks in predicting preeclampsia and SGA in women with lupus anticoagulant is a promising screening test. However, because of the small number of women with lupus anticoagulant in this study, currently, we cannot recommend routine Doppler screening. The CIs for likelihood ratios are too wide to suggest a policy, and larger studies are required to confirm our findings.
Several factors are likely to influence the performance of screening tests and these include anatomical site measured, indices used to describe an abnormal waveform, and outcome measures for which the test is predictive. In our study, the waveforms were obtained from a standard reference point (apparent crossover of the external iliac artery and the main uterine artery), which gives reliable and reproducible measurements.10 Doppler characteristics evaluated in predicting adverse pregnancy outcome were uterine artery PI and the presence of notches. PI was preferred to other impedance indices as the entire waveform is taken into consideration in calculating the impedance index, unlike the resistance index or systolic/diastolic ratio. We used a rigid definition of preeclampsia and SGA, and care was taken to identify the nonproteinuric hypertension (not likely to be influenced by placental perfusion) as a separate category. Not surprisingly, uterine artery Doppler did not predict nonproteinuric hypertension.
One important confounding factor in the present study is the effect of treatment. Low-dose aspirin acts by irreversibly blocking the action of cyclooxygenase in platelets, thereby inhibiting platelet thromboxane synthesis and preventing thrombosis. Heparin binds to antiphospholipid antibodies, thereby protecting the trophoblast and promoting successful implantation in addition to its anticoagulant effect.16,17 Furthermore, data from both human and animal studies have suggested a blood pressure lowering effect of heparin, the postulated mechanisms being reduction in plasma aldosterone level and lowering elevated vascular calcium uptake, regulation of endothelin-1 production by endothelial cells, and altered vascular reactivity.18–22 In the present study, the screening test was performed at the time of continued treatment but the final outcome measures (pregnancy complications) assessed after the cessation of treatment. The reduction in the uterine artery PI (z score) between the first and the second visit, in women with high initial z score, is likely to be caused by the effect of "regression to mean," although beneficial effects of aspirin and/or heparin on the uterine perfusion cannot be excluded.
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Footnotes |
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Received December 11, 2000. Received in revised form April 24, 2001. Accepted May 4, 2001.
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REFERENCES |
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