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Keywords:

  • assisted reproduction;
  • Doppler ultrasonography;
  • placenta;
  • uteroplacental hemodynamics

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objective

To determine whether low-dose aspirin improves uteroplacental hemodynamics in unselected in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) subjects when medication is started concomitantly with controlled ovarian hyperstimulation.

Methods

Thirty-seven pregnant women who had undergone IVF/ICSI and had been randomized to receive 100 mg aspirin (n = 17) or placebo (n = 20) daily, started concomitantly with controlled ovarian hyperstimulation, were included in this study. Doppler ultrasound examination was performed at 6, 10, 13 and 18 weeks' gestation. Uterine artery (UtA) pulsatility index (PI) was calculated and bilateral UtA notching was noted. Subplacental arcuate artery PI was obtained at 6 and 10 weeks' gestation. Umbilical artery (UA) PI and mean velocity were calculated at 10, 13 and 18 weeks' gestation. In the aspirin group there was one early pregnancy miscarriage, and one patient discontinued the study medication owing to early pregnancy bleeding. A total of 15 women in the aspirin group and 20 women in the placebo group underwent the complete ultrasound protocol.

Results

At 6 weeks' gestation, arcuate artery PI and at 18 weeks' gestation, UtA PI were lower (P < 0.05) in the aspirin group than in the placebo group. At 18 weeks' gestation, bilateral UtA notching tended to be more common in the placebo group (40%) than in the aspirin group (13%) (P = 0.06). UA PI and mean velocity did not differ significantly between the groups.

Conclusion

Low-dose aspirin reduces uteroplacental vascular impedance in early and mid pregnancy in unselected IVF/ICSI subjects when medication is started concomitantly with controlled ovarian hyperstimulation. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Abnormal implantation and invasion of the trophoblastic cells can lead to structural and occlusive changes in the spiral arteries and underperfusion of placental circulation. This is one plausible mechanism in the pathogenesis of pre-eclampsia. These fundamental disturbances in the development of the uteroplacental circulation may occur as early as the first trimester, when trophoblastic invasion starts.

Pre-eclampsia is associated with an imbalance between the production of intravascular prostacyclin and thromboxane. Low-dose acetylsalicylic acid (aspirin) irreversibly inhibits the cyclo-oxygenase enzyme in platelets, preventing the synthesis of thromboxane1, 2. By decreasing platelet aggregation and inhibiting vasoconstriction, low-dose aspirin may enhance uterine blood flow and tissue perfusion and thus improve uteroplacental vasculature. However, randomized studies have demonstrated that low-dose aspirin when started after 12 weeks of gestation does not significantly reduce the incidence of pre-eclampsia even in the high-risk population3–7.

Increased uterine artery (UtA) pulsatility index (PI) and bilateral notching of the blood-flow waveform, which reflect elevated uteroplacental vascular impedance, have been used to predict subsequent adverse pregnancy outcome. UtA Doppler screening of a low-risk population at 20–24 weeks' gestation can identify most women who will subsequently develop severe pre-eclampsia and/or intrauterine growth restriction (IUGR) due to impaired placentation8–10.

The aim of the present randomized double-blind prospective study was to test our hypothesis that low-dose aspirin therapy (100 mg daily) improves the uteroplacental circulation in unselected subjects undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) when medication is started concomitantly with controlled ovarian hyperstimulation.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Within the study period a total of 176 women who underwent IVF (n = 109) or ICSI (n = 67) treatment in Oulu University Hospital, Oulu, Finland, were included in this study. Inclusion criteria were: (1) age < 40 years; (2) < 4 previous ovarian stimulations; and (3) no contraindications for aspirin. Prior to the start of the long gonadotropin-releasing hormone agonist protocol, each subject signed written informed consent, and the local ethics committee approved the research protocol. Randomization was carried out in blocks of four with sealed envelopes by the pharmacist at Oulu University Hospital. The women were treated with identical-looking tablets of aspirin or placebo (Bayer AG, Leverkusen, Germany). The subjects were randomized on the first day of gonadotropin stimulation to receive 100 mg oral aspirin (n = 87) or placebo (n = 89) daily in one dose. Embryo transfer was performed successfully in 80 patients in the aspirin group and in 83 patients in the placebo group. Forty-one (23.3%) subjects subsequently had clinical pregnancy, but there were three miscarriages before the first ultrasound examination and one extrauterine pregnancy, so the study population comprised 37 subjects (17 receiving aspirin and 20 placebo).

In the aspirin group, one top-quality embryo was transferred in eight (47.1%) subjects and two embryos in nine (52.9%) subjects. In the placebo group, nine (45.0%) patients received one top-quality embryo and 11 (55.0%) received two embryos. Eight (47.1%) patients underwent IVF and nine (52.9%) patients ICSI treatment in the aspirin group and the corresponding numbers were nine (45.0%) and 11 (55.0%) in the placebo group, respectively. In the aspirin group there was one first-trimester miscarriage (between 6 and 10 weeks' gestation), and one patient discontinued the study medication owing to early pregnancy bleeding. These patients were included in the final data analysis. Thirty-five subjects—of whom 15 received aspirin and 20 placebo—underwent the complete ultrasonographic protocol. There were four dichorionic–diamniotic twin pregnancies in the aspirin group and three similar twin pregnancies in the placebo group. A flow chart for the study is shown in Figure 1.

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Figure 1. Flow chart for the study. ET, embryo transfer.

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At 6 and 10 weeks' gestation ultrasound examination (Acuson Sequoia 512, Mountain View, CA, USA) was performed transvaginally using an 8-MHz transducer (EV-8C4), and at 13 and 18 weeks' gestation examination was performed transabdominally using an 8-MHz convex transducer by a single observer (M. H.) (measurements at each gestational age were taken up to 6 days after the precise date given).

Gestational age was determined by the day of embryo transfer. Normal fetal growth and development were confirmed during each ultrasonographic examination. At 13 weeks' gestation nuchal translucency (NT) thickness was measured and at 18 weeks' gestation a detailed fetal anatomic examination was performed.

Image-directed pulsed and color Doppler were used to obtain blood velocity waveforms from both proximal UtAs in every examination. In addition, at 6 and 10 weeks' gestation the subplacental arcuate arteries were identified and their blood velocity waveforms were obtained and PI values calculated. Early diastolic notching of the UtAs was noted.

At 10, 13 and 18 weeks' gestation umbilical artery (UA) blood flow velocity waveforms were obtained near the abdominal insertion of the umbilical cord. PI and mean velocity (Vmean = fetal heart rate × time-velocity integral) of the UAs were calculated. Fetal heart rate was measured from UA blood velocity waveforms.

The acoustic output of the system was displayed by mechanical and thermal indices, which were kept < 1.011. The insonation angle was minimized (< 30°) in every measurement and the high-pass filter was set at its minimum.

Sample size was calculated by Stata Statistics/Data Analysis 8.0 (Stata Corporation, College Station, TX, USA). To detect a decrease in UtA PI from 1.59, 10 to 1.0 at 18 weeks' gestation in favor of the aspirin group with α = 0.05 and power over 80%, we would need 16 subjects in each group. Statistical comparisons of the quantitative and categorical data between the groups were done with two-tailed t-test and Pearson's Chi-square test as intention-to-treat analysis. Comparison of the measured parameters within the groups between multiple study points was performed by one-way ANOVA for repeated measurements, and P < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Perinatal and neonatal data are shown in Table 1. Male infertility was more common (P < 0.05) in the placebo group (45%) compared to in the aspirin group (12%). No statistically significant differences were found in pregnancy complications such as the rate of pregnancy induced hypertension, IUGR and pre-eclampsia between the groups. The neonatal outcome data were comparable between the groups (Table 1). Every fetus had a normal NT measurement and all the newborns were healthy at the time of discharge from the hospital.

Table 1. Perinatal and neonatal data of the study groups
VariableAspirin group (n = 17)*Placebo group (n = 20)P
  • Data are shown as mean ± SD, median (range) or n (%).

  • *

    17 women with 20 fetuses.

  • 20 women with 23 fetuses.

  • One woman miscarried between 6 and 10 weeks after the first ultrasound examination. BMI, body mass index; GA, gestational age; IUGR, intrauterine growth restriction; NS, not significant; PIH, pregnancy-induced hypertension.

Maternal age (years)30.4 ± 3.431.4 ± 3.8NS
BMI (kg/m2)23.2 ± 3.4625.6 ± 4.90NS
Etiology of infertility
 Endometriosis5 (29)5 (25)NS
 Tubal2 (12)1 (5)NS
 Hormonal4 (24)1 (5)NS
 Male2 (12)9 (45)0.046
 Unexplained4 (24)4 (20)NS
Pregnancy history
 Patients with previous3 (18)6 (30)NS
  pregnancy   
 Live birth3 (18)5 (25)NS
Pregnancy complications
 PIH3 (18)5 (25)NS
 Pre-eclampsia3 (18)2 (10)NS
  Mild2 (12)2 
  Severe1 (6)0 
 Prematurity3 (18)1 (5)NS
 IUGR1 (6)1 (5)NS
Vaginal bleeding during pregnancy1 (6)2 (10)NS
GA at delivery (weeks)38.2 (2.6)39.1 (2.8)NS
Mode of delivery
 Vaginal9 (56)15 (75)NS
 Cesarean section7 (44)5 (25)NS
Birth weight (g)3010 ± 6203360 ± 742NS
Apgar score at 5 min9 (7–10)9 (6–10)NS
Umbilical artery pH7.23 ± 0.0707.23 ± 0.08NS
Blood loss during delivery (mL)730 ± 589532 ± 635NS

At 6 weeks' gestation arcuate artery PI was lower (P = 0.02) in the aspirin group compared to the placebo group, while UtA PIs did not differ significantly between the groups (Table 2, Figure 2). UtA PIs decreased with advancing gestation in both groups. However, at 18 weeks' gestation the PIs of the right and left UtAs were lower in the aspirin group compared to the placebo group (P < 0.05) (Table 2, Figure 3). Bilateral early diastolic notching in the UtAs was noted in all cases at 6 weeks' gestation. At 10, 13 and 18 weeks' gestation, bilateral notching was noted in 11 (73%), 7 (47%) and 2 (13%) cases, respectively, in the aspirin group and in 16 (80%), 9 (45%) and 8 (40%) cases, respectively, in the placebo group. At 18 weeks' gestation, bilateral notching tended to be more common in the placebo group than in the aspirin group (P = 0.06) (Table 2).

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Figure 2. Arcuate artery pulsatility index at 6 and 10 weeks' gestation (mean ± SD). ○, Aspirin group; ●, Placebo group; *P < 0.05 compared to placebo group.

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thumbnail image

Figure 3. Right (a) and left (b) uterine artery pulsatility index at 6, 10, 13 and 18 weeks' gestation (mean ± SD). ○, Aspirin group; ●, Placebo group; *P < 0.05 compared to placebo group.

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Table 2. Hemodynamic data of the study groups
Variable6 weeks' gestation10 weeks' gestation13 weeks' gestation18 weeks' gestation
Aspirin group (n = 17)Placebo group (n = 20)PAspirin group (n = 15)Placebo group (n = 20)PAspirin group (n = 15)Placebo group (n = 20)PAspirin group (n = 15)Placebo group (n = 20)P
  1. Data are given as mean ± SD. NS, not significant; PI, pulsatility index; Vmean, mean velocity.

Arcuate artery PI1.71 ± 0.452.34 ± 0.610.021.51 ± 0.892.06 ± 0.94NS 
Uterine artery PI
 Right2.60 ± 0.522.32 ± 0.60NS1.76 ± 0.741.74 ± 0.67NS1.09 ± 0.431.17 ± 0.57NS0.79 ± 0.371.14 ± 0.430.026
 Left2.59 ± 0.632.35 ± 0.73NS1.88 ± 0.682.06 ± 0.59NS1.39 ± 0.481.33 ± 0.77NS0.87 ± 0.351.20 ± 0.500.044
Notch (%)
 Bilateral17 ± 10020 ± 100NS11 ± 7316 ± 80NS7 ± 479 ± 45NS2 ± 138 ± 40NS
 Unilateral 3 ± 204 ± 20NS5 ± 336 ± 30NS5 ± 336 ± 30NS
Umbilical artery
 PI 2.87 ± 0.313.03 ± 0.25NS1.99 ± 0.241.87 ± 0.30NS1.42 ± 0.241.37 ± 0.23NS
 Vmean (cm/s) 5.76 ± 1.715.63 ± 1.46NS10.89 ± 3.5210.81 ± 2.39NS17.02 ± 3.3816.41 ± 3.07NS

The results were similar in a subgroup analysis in which we excluded all the twin pregnancies. Arcuate artery PI at 6 weeks' gestation was lower (P = 0.02) in the aspirin group (1.85 ± 0.33) compared to the placebo group (2.34 ± 0.28). In the aspirin group, right (0.79 ± 0.30) and left (0.78 ± 0.42) UtA PIs were lower (P < 0.03) at 18 weeks' gestation than in the placebo group (1.19 ± 0.46 and 1.18 ± 0.45, respectively). At 18 weeks' gestation, the incidence of bilateral UtA notching was 2/11 (18%) in the aspirin group and 8/17 (47%) in the placebo group (P = 0.11).

UA PI decreased and Vmean increased significantly with advancing gestation, but they did not differ significantly between the groups (Table 2, Figure 4).

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Figure 4. Umbilical artery pulsatility index (a) and mean velocity (Vmean) (b) at 10, 13 and 18 weeks' gestation (mean ± SD). ○, Aspirin group; ●, Placebo group.

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There were five cases of pre-eclampsia (13.5%), three (one singleton, two twin pregnancies) in the aspirin group and two (one singleton and one twin pregnancy) in the placebo group (Table 1). All of them showed normal UtA PI without bilateral notching at 18 weeks' gestation.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This randomized, placebo-controlled, double-blind study revealed that 100 mg aspirin daily, started concomitantly with gonadotropin stimulation for unselected IVF/ICSI subjects, was related to significantly lower uteroplacental vascular impedance in early and mid gestation compared to the placebo group. Umbilicoplacental circulation was not affected by low-dose aspirin therapy.

In the present study, we found that in the low-dose aspirin group arcuate artery PI at 6 weeks' gestation and UtA PI at 18 weeks' gestation were significantly lower compared to the placebo group. Increased UtA vascular impedance at 20–24 weeks' gestation reflects abnormal trophoblastic implantation and remodeling of the spiral arteries, thus increasing the risk for developing severe pre-eclampsia or IUGR later in pregnancy9, 10. In pregnancies complicated by pre-eclampsia or IUGR, placental histology shows a superficial invasion of trophoblastic tissue, which is thought to lead to insufficient remodeling of the spiral arteries and abnormal development of placental vasculature. In the late first trimester and during the second trimester the spiral arteries are normally transformed to slack and unocclusive sacs, but in pre-eclampsia they maintain their vasoconstrictive properties12. In addition, in pre-eclampsia production of thromboxane, which induces platelet aggregation and constriction of vascular smooth muscle, is excessive13. Low-dose aspirin irreversibly inhibits cyclo-oxygenase activity leading to decreased synthesis of thromboxane1, 2, thus at least to some extent correcting the imbalance between thromboxane and prostacyclin production. The results of the present study may reflect more successful trophoblastic invasion with improved remodeling of spiral arteries in subjects treated with aspirin compared to the placebo group. The incidence of bilateral UtA notching at 18 weeks' gestation tended to be lower in the aspirin group compared to the placebo group. We propose that low-dose aspirin when started prior to pregnancy may improve uteroplacental circulation.

In the present study medication was started concomitantly with gonadotropin stimulation. Many previous large studies have failed to show any beneficial effects of aspirin on the incidence of pre-eclampsia and IUGR. However, in these studies the low-dose aspirin therapy was started in subjects with increased UtA impedance at 14–16 weeks' gestation or later3–7. Some small studies have shown that low-dose aspirin treatment may be beneficial when started at 12–16 weeks' gestation in high-risk populations to prevent pre-eclampsia14, 15. A recently published meta-analysis showed a 10% reduction in the incidence of pre-eclampsia in a population treated with aspirin, but no significant effect on the prevention of IUGR16. The lack of reduction in the incidence of pre-eclampsia and IUGR may be due to the fact that the low-dose aspirin therapy was started too late, when the primary pathophysiological insult leading to clinical manifestation of pre-eclampsia had already occurred. Our results suggest that aspirin therapy at a dose of 100 mg per day, when started early enough, may have beneficial effects on placental angiogenesis, trophoblastic invasion and formation of the uteroplacental circulation.

In this study population, the total incidence of pre-eclampsia classified according to ACOG criteria17 was higher (13.5%) compared to the normal population (3–7%), which is in agreement with previous findings in IVF/ICSI pregnancies18. In the aspirin group, there was one severe case of pre-eclampsia (singleton) and two mild cases (twins) and in the placebo group there were two mild cases (one singelton, one twin). None of these cases was early-onset pre-eclampsia (delivery at < 34 weeks) with IUGR. The UtA PI was within normal limits in every pre-eclamptic case and none of them had bilateral UtA notching at 18 weeks' gestation. This demonstrates that pre-eclampsia may develop even in the presence of normal uteroplacental circulation in mid gestation.

UA Vmean, which reflects UA volume blood flow, increased and vascular impedance decreased significantly in both groups with advancing gestation. No significant differences were found in any neonatal outcome variable. This suggests that low-dose aspirin does not have significant effects on the umbilicoplacental circulation. Furthermore, bleeding complications during pregnancy or delivery did not differ between the groups, which is in accordance with previous large studies4, 5, 17, 19. Li et al. found, in their interview-conducted population-based cohort study, that non-steroidal anti-inflammatory drugs during conception or early pregnancy can increase the risk of miscarriage20. In the present study the rate of miscarriage was not significantly different between the groups.

Aspirin in doses of 80–160 mg daily in healthy volunteers21 and 0.5–2.0 mg/kg daily in hypertensive pregnant women22 has been shown to increase the prostacyclin : thromboxane ratio. Viinikka et al. noted that aspirin at a dose of 50 mg/day inhibited more than 90% of platelet thromboxane production, and significantly decreased the urinary excretion of thromboxane metabolites, but did not decrease the urinary excretion of prostaglandin metabolites23. Thus, the dose of 100 mg daily used in the present study is sufficient to demonstrate the possible beneficial effects of aspirin on the prostacyclin : thromboxane ratio.

Ultrasound, especially color and pulsed Doppler, is known to cause thermal and mechanical effects on biological tissues. To maximize the diagnostic benefit of ultrasound and minimize adverse effects, exposure time in this study was kept as low as possible and thermal and mechanical indices were monitored during examination and were kept < 1.011. Examinations were recorded on videotapes and all the analyses were done off-line. The recommendations of the World Federation for Ultrasound in Medicine and Biology24 were followed as well as the ethical guidelines for ultrasound in human fetuses in the first trimester25.

The limitation of this study is small sample size, especially in the aspirin group. However, this sample size was sufficient to show statistically significant differences in uteroplacental hemodynamic parameters between the groups. In addition, no systematic placental histological examination was performed. Based on the present study we cannot conclude whether low-dose aspirin decreases the incidence of pre-eclampsia, delays the onset of pre-eclampsia or improves other pregnancy outcome parameters in IVF/ICSI pregnancies when the medication is started prior to pregnancy. At this moment, there is not enough evidence to recommend the routine use of low-dose aspirin therapy in these patients, and further studies are needed.

In conclusion, the results of this randomized, placebo-controlled, double-blind study showed that low-dose aspirin reduced uteroplacental vascular impedance in early and mid pregnancy in unselected IVF and ICSI subjects when medication was started concomitantly with controlled ovarian hyperstimulation. This may reflect improved trophoblastic invasion and remodeling of the spiral arteries. Aspirin does not seem to affect umbilicoplacental circulation during the first half of pregnancy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was supported by the University of Oulu, Bayer AG, The Academy of Finland and the Sigrid Juselius Foundation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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