Miwa Miyazaki, Yoshimitsu Kuwabara. and Toshiyuki Takeshita. Abstract. Introduction

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1 doi: /jog J. Obstet. Gynaecol. Res. Vol. 44, J. No. Obstet. 1: 87 92, Gynaecol. January Res Influence of perinatal low-dose acetylsalicylic acid therapy on fetal hemodynamics evaluated by determining the acceleration-time/ejection-time ratio in the ductus arteriosus Miwa Miyazaki, Yoshimitsu Kuwabara and Toshiyuki Takeshita Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan Abstract Aim: Acceleration-time/ejection-time ratio (At/Et ratio) of Doppler waveform is an established hemodynamic parameters that reflect proximal stenosis. Using this parameter, we evaluated whether perinatal low-dose acetylsalicylic acid (ASA) therapy could alter hemodynamics in the ductus arteriosus. Methods: Pulse Doppler measurements of the fetal ductus arteriosus were performed longitudinally from 20 to 37 gestational weeks in 106 healthy pregnant women (controls) and 65 pregnant women taking daily low-dose ASA (80 or 100 mg/day) because of a history of recurrent pregnancy loss. The At/Et ratio, pulsatility index (PI), and peak systolic velocity were evaluated and statistically analyzed. Results: The At/Et ratio significantly increased with gestational age in both the ASA group (r = 0.54) and the control group (r = 0.35), while the PI did not. Median peak systolic velocities also increased with gestational age in both the ASA group (r = 0.39) and the control group (r =0.31).Nosignificant differences in At/Et ratio, PI, or peak systolic velocity were observed between the ASA group and the control group. Conclusion: Administration of low-dose ASA during pregnancy did not appear to alter hemodynamics in the fetal ductus arteriosus. Key words: acceleration time, Doppler waveform, ductus arteriosus, low-dose acetylsalicylic acid therapy. Introduction Acetylsalicylic acid (ASA) is the most widely prescribed agent in the world and is a pivotal antiplatelet agent used for secondary prevention of coronary artery disease and cerebrovascular disease. 1 ASA is also prescribed to women with high-risk pregnancies, in an attempt to prevent or delay the onset of pregnancy-induced hypertension (PIH) and/or fetal growth restriction. Numerous trials have shown limited but positive results, with a 10% reduction in pre-eclampsia and a 20% reduction in risk for fetal growth restriction in pregnant women taking daily low-dose ASA. 2,3 More recently, ASA has been administered widely to improve pregnancy outcomes in patients with a history of miscarriage and to improve the success of in vitro fertilization. Although the pathophysiological mechanisms are not fully understood, thrombus formation in the intravillous space is thought to be associated with pregnancy loss. Therefore, antithrombotic therapy for patients with thrombophilia is reasonable, and indeed a large systematic review demonstrated that combined ASA and heparin treatment confers some benefit to a subset of women with recurrent pregnancy loss due to anti-phospholipid syndrome. 4 6 As with other non-steroidal anti-inflammatory drugs, ASA is known to inhibit the synthesis of prostaglandin, which is the most important mediator of vasodilation Received: March Accepted: July Correspondence: Dr Yoshimitsu Kuwabara, Department of Obstetrics and Gynecology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo , Japan. kuwa@nms.ac.jp These two authors contributed equally to this work Japan Society of Obstetrics and Gynecology 87 1

2 M. Miyazaki et al. in the ductus arteriosus during fetal life, especially in the third trimester. Therefore, even with low-dose administration, daily fetal exposure to ASA raises concerns regarding the potential risk of premature closure of the ductus arteriosus. Despite the increasing frequency with which ASA is prescribed during pregnancy, no clear answer has been provided on this issue. Thus, this study was performed to evaluate whether ductal blood flow is altered during pregnancy with routine exposure to low-dose ASA. To evaluate constriction of the ductus arteriosus, we assessed Doppler waveform parameters from the ductus arteriosus, including the accelerationtime/ejection-time ratio (At/Et ratio), which is an established hemodynamic parameter that reflects substantial upstream stenosis. 7 Methods All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All human subjects provided written informed consent with guarantees of confidentiality. Study population In this cross-sectional study, pulsed Doppler measurements of the blood flow in the fetal ductus arteriosus were taken longitudinally from 20 to 37 gestational weeks in 106 healthy pregnant women (control group; 185 total measurements) and from 20 to 35 gestational weeks in 65 pregnant women taking low-dose ASA, either 100 mg/day (Bayer; Leverkusen, Germany) or 81 mg/day (Eisai; Tokyo, Japan), because of a history of recurrent pregnancy loss (ASA group; 170 total measurements). Gestational age (GA) was determined by ultrasound in the first trimester, confirmation of the last menstrual period by a second-trimester ultrasound, or in vitro fertilization or artificial insemination dating. ASA administration was started before pregnancy and completed at 35 weeks and 6 days of gestation. Exclusion criteria included multiple gestations, fetal growth < 1.5 standard deviations (SD) or >1.5 SD for gestational age, known chromosomal/structural abnormalities, pre-existing maternal medical conditions (e.g., diabetes, renal disease, or hypertensive disorders), uterine contractions, ruptured membranes, oligohydramnios (defined as a sonographic amniotic fluid index < 5cmor a maximum vertical pocket < 2 cm), and active infection. Healthy pregnant women were randomly chosen from outpatients who visited our hospital. Doppler assessment Using a 3.2-MHz curvilinear transducer (Voluson E8, GE Healthcare, USA), routine ultrasound examinations were performed for fetal anatomy and biometry. In each case, the ultrasound examination also confirmed fetal well-being, GA, amniotic fluid volume, and estimated fetal bodyweight. Pulsed Doppler measurements of the fetal ductus arteriosus were performed longitudinally at random from 20 to 37 gestational weeks. All analyses of flow velocity waveforms were obtained during fetal apnea and the absence of gross body movements. All measurements were performed by a single provider who knew whether the patient was taking ASA. Women were placed in a semi-recumbent position, and a systematic examination of the fetal heart was performed to exclude major structural heart defects. An axial plane through the fetal thorax was used to obtain a 4-chamber view of the heart. Doppler flow waveforms of the ductus arteriosus were taken in semi-horizontal images of the fetal upper thorax by placing the cursor close to the inlet portion to the descending aorta (Fig. 1a). During measurement, the angle of insonation was maintained at <60. Two consecutive ductus arteriosus waveforms with corresponding measurements were acquired for each fetus and these measurements were averaged. Parameters of Doppler flow waveforms, including the pulsatility index (PI), At, Et, and peak systolic velocity, were measured from the ductus arteriosus waveform. The PI was calculated as follows: (peak systolic velocity end diastolic velocity)/time-averaged mean velocity. At refers to the time interval from the beginning of the systolic upstroke to the achievement of peak systolic velocity. Et refers to the time interval from the beginning to the end of the ventricular systole (Fig. 1b). Data analyses Pulsed Doppler measurements of the fetal ductus arteriosus were performed longitudinally from 20 to 37 gestational weeks, and cross-sectional data were analyzed separately. All results are expressed as the median ± quartiles. The relations between various parameters (PI, A/E ratio, peak systolic velocity) and gestational age were tested and expressed using the Pearson product moment correlation coefficient. Group medians (ASA vs control) were compared using the Mann Whitney U-test for independent data. P-values < 0.05 were considered statistically significant Japan Society of Obstetrics and Gynecology

3 Influenceof oflow-dose low-dose ASA ASA on on fetal fetal circulation Influence Figure 1 (a) Doppler flow waveforms of the ductus arteriosus were measured in semi-horizontal images of a fetal upper thorax by placing the cursor close to the inlet portion of the descending aorta, as shown in the circle. (b) The acceleration time (At) refers to the time interval from the beginning of the systolic upstroke to the achievement of peak velocity. The ejection time (Et) refers to the time interval from the beginning to the end of ventricular systole. Results The characteristics of the subjects are shown in Table 1. No significant difference was observed in mean patient age. Because heparin does not cross the placenta, heparin administration is thought not to affect potential changes in fetal circulation caused by ASA. To obtain a sufficient number of measurements, we categorized patients who were administered ASA alone and patients administered ASA plus heparin as the ASA-administered group (single-agent ASA, 87 measurements from 32 patients; combination of low-dose ASA and heparin, 83 measurements from 33 patients). From 20 to 35 gestational weeks, the ductal PI showed no significant change with gestational age between the ASA and control groups (Fig. 2a). However, the At/Et ratio significantly increased with gestational age in both the ASA group (r = 0.54) and the control group (r = 0.35; Fig. 2b). Peak systolic velocities also increased with gestational age in both the ASA group (r = 0.39) and the control group (r = 0.31; Fig. 2c). No significant differences were observed in the median At/Et ratio, median PI, or median peak systolic velocity through the ductus arteriosus blood flow between the ASA group and the control group (Table 2). Discussion Premature closure of the ductus arteriosus, which can occur naturally, is a rare event and is reported to occur in 1 in 1000 to 1 in term deliveries.8 On the other hand, some reports have provided evidence that intrauterine ductus arteriosus constriction is associated with the use of prostaglandin inhibitors; the same is true for ASA. One study reported higher salicylate levels and the absence of right-to-left shunting in infants with persistent pulmonary hypertension born from mothers administered ASA during pregnancy.9 Another study reported the odds of developing persistent pulmonary hypertension with in utero ASA exposure to be 8.09 (95% confidence interval, ).10 However, it should be noted that the doses of ASA were not specified in these studies, and would likely have differed from the daily Table 1 Patient characteristics Age (years) Number of patients Number of measurements Gestational age at examination (weeks) Category Healthy pregnant women Pregnant women taking ASA alone Pregnant women taking a combination of ASA and heparin 34.6 ± ± ± Control group ASA group Values are expressed as the mean ± standard deviation. ASA, acetylsalicylic acid Japan Japan Society Societyof ofobstetrics Obstetricsand andgynecology Gynecology 89 3

4 M. Miyazaki et al. Figure 2 Individual values of the (a) pulsatility index, (b) peak systolic velocity, and (c) acceleration-time/ejection-time (At/Et) ratio in the ductus arteriosus obtained from the acetylsalicylic acid (ASA) and control groups. Linear approximations and the squares of the coefficients are shown. Table 2 Doppler values for the ductus arteriosus in the ASA and control groups at the indicated gestational weeks Gestational week ASA n Control n P Pulsatility index ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS Peak systolic velocity ( ) ( NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS At/Et ratio ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS ( ) ( ) NS Values are expressed as median and quartiles. Group medians were analyzed by the Mann Whitney U-test for independent data. P-values < 0.05 were considered statistically significant. ASA, acetylsalicylic acid; NS, not significant Japan Society of Obstetrics and Gynecology

5 Influence of low-dose ASA on fetal circulation low-dose exposure given during pregnancy. In several randomized trials conducted to study the effects of daily low-dose ASA versus a placebo, no increase in fetal death or neonatal mortality was observed, 2,11 indicating that the effect of low-dose ASA administration on the hemodynamics of the ductus arteriosus is negligible or non-existent. Although accumulating epidemiological evidence supports the safety of low-dose ASA therapy as described above, no studies have provided a rigorous evaluation of the ductus arteriosus by studying fetal blood flow dynamics. Previously, a randomized control study showed no significant differences in PI values between a low-dose ASA group and a placebo group. 12 Because the PI is influenced by both inflow and peripheral resistance, only a very tight stenosis can cause the PI to change sufficiently to be diagnostic of inadequate inflow. 13 Therefore, assessment of the PI alone provides insufficient data to conclude that daily low-dose ASA administration during pregnancy does not alter the hemodynamics in the ductus arteriosus. Herein, we have demonstrated gestational-agespecific values of fetal hemodynamic parameters, including At/Et ratios calculated from blood flow waveforms of the fetus ductus arteriosus, which were derived from a prospective cross-sectional study of 355 total measurements targeting pregnant women with or without administration of low-dose ASA (control group: 185; ASA group: 170) from 20 to 37 weeks of gestation. The Doppler velocity waveforms of the ductus arteriosus were characterized by high systolic velocities (peak systolic velocities) and low diastolic velocities. As reported in a previous study, 14,15 peak systolic velocities increased with advancing gestational age, and the values were comparable to those from past studies. The PI from Doppler velocity waveforms of the ductus arteriosus have been reported to be independent of gestational age. In this study, the mean PI was 2.29 (SD, 0.38), which is in accordance with the published longitudinal studies of Doppler velocity waveforms of the ductus arteriosus, in which mean PI of 2.47 (SD, 0.3) and 2.46 (SD, 0.26) were calculated. 15,16 Our results are comparable to previous values of published hemodynamic parameters, indicating that the measurements in this study were obtained correctly and are reproducible. In this study, we evaluated the At/Et ratio of Doppler velocity waveforms of the ductus arteriosus by collecting cross-sectional data during pregnancy, which has not previously been reported. Stenosis of an artery causes a pressure drop in the immediate post-stenotic lesion, which weakens the pulse in the downstream arterial network, characterized by pulsus tardus (pulse wave slow to rise). This phenomenon is observed as a prolonged acceleration time in a Doppler ultrasound; therefore, the acceleration time is regarded as a hemodynamic parameter that can reflect substantial upstream stenosis. 17 Evaluating the At/Et ratio can help minimize the influence of the heart rate on individual parameters. 7 Longitudinal evaluation of the At/Et ratio revealed that it increased with advancing gestational age, similar to the peak systolic velocity. Based on a comparison of the At/Et ratio between the control and ASA groups, matched for gestational age, administration of low-dose ASA should not cause constriction of the ductus arteriosus, which supports epidemiological evidence of the safety of low-dose ASA therapy. Further investigation, including assessment of the At/Et ratio in fetuses with premature closure of the ductus arteriosus, is necessary to establish criteria to define the pathophysiology with this parameter. On the other hand, measurement of the ductus arteriosus waveforms in late pregnancy is often difficult due to the skeleton of the fetus, fetal position, and relative reduction of amniotic fluid volume. This issue might be the hurdle in clinical application, and it is necessary to verify the reproducibility and the inter-examiner reliability of measured values carefully. Because PIH mostly becomes overt in late pregnancy, it is reasonable to maintain low-dose ASA administration until the third trimester to improve an imbalance of arachidonic acid and prostacyclin, which is one aspect of the pathophysiology of this disease. Furthermore, the perinatal risks associated with thrombotic diathesis represented by anti-phospholipid syndrome include not only early pregnancy miscarriage, but also other adverse perinatal events, such as fetal death after mid-term, fetal growth restriction, and PIH. 18 In this regard, it might also be reasonable to continue anti-thrombotic treatment until the third trimester of pregnancy. Based on a largescale epidemiological study of over women from randomized trials of low-dose ASA versus a placebo, low-dose ASA does not cause adverse perinatal outcomes, such as low birthweight, perinatal mortality, or neonatal cerebral hemorrhage. 2,11 Taken together with our results demonstrating that low-dose ASA administration did not influence ductal hemodynamics, continuation of anti-thrombotic therapy with low-dose ASA in patients with perinatal risks can be considered until the third trimester. In conclusion, based on evaluation of the At/Et ratio from Doppler velocity waveforms of the ductus arteriosus, administration of low-dose ASA appears not to alter fetal hemodynamics. Thus, it is not necessary 2017 Japan Society of Obstetrics and Gynecology 91 5

6 M. Miyazaki et al. to stop ASA administration in light of pre-term closure of the ductus arteriosus if the continuation of low-dose ASA therapy is considered beneficial in terms of the perinatal outcome. Disclosure The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. References 1. Fisher M, Knappertz V. The dose of aspirin for the prevention of cardiovascular and cerebrovascular events. Curr Med Res Opin 2006; 22: Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: A metaanalysis of individual patient data. Lancet 2007; 369: Xu TT, Zhou F, Deng CY, Huang GQ, Li JK, Wang XD. Lowdose aspirin for preventing preeclampsia and its complications: A meta-analysis. JClinHypertens2015; 17: Lim W, Crowther MA, Eikelboom JW. Management of antiphospholipid antibody syndrome: A systematic review. JAMA 2006; 295: Mak A, Cheung MW, Cheak AA, Ho RC. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: A meta-analysis of randomized controlled trials and meta-regression. Rheumatology 2010; 49: Laskin CA, Spitzer KA, Clark CA et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: Results from the randomized, controlled HepASA Trial. J Rheumatol 2009; 36: Kitabatake A, Inoue M, Asao M et al. Noninvasive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 1983; 68: Kohler HG. Premature closure of the ductus arteriosus (P.C.D. A.): A possible cause of intrauterine circulatory failure. Early Hum Dev 1978; 2: Perkin RM, Levin DL, Clark R. Serum salicylate levels and right-to-left ductus shunts in newborn infants with persistent pulmonary hypertension. J Pediatr 1980; 96: Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001; 107: Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: Systematic review. BMJ 2001; 322: Grab D, Paulus WE, Erdmann M et al. Effects of low-dose aspirin on uterine and fetal blood flow during pregnancy: Results of a randomized, placebo-controlled, double-blind trial. Ultrasound Obstet Gynecol 2000; 15: Evans DH, Barrie WW, Asher MJ, Bentley S, Bell PR. The relationship between ultrasonic pulsatility index and proximal arterial stenosis in a canine model. Circ Res 1980; 46: Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography. Circulation 1987; 75: Mielke G, Benda N. Blood flow velocity waveforms of the fetal pulmonary artery and the ductus arteriosus: Reference ranges from 13 weeks to term. Ultrasound Obstet Gynecol 2000; 15: Tulzer G, Gudmundsson S, Sharkey AM, Wood DC, Cohen AW, Huhta JC. Doppler echocardiography of fetal ductus arteriosus constriction versus increased right ventricular output. JAmCollCardiol1991; 18: Kotval PS. Doppler waveform parvus and tardus. A sign of proximal flow obstruction. JUltrasoundMed1989; 8: Kupferminc MJ. Thrombophilia and pregnancy. Reprod Biol Endocrinol 2003; 14: Japan Society of Obstetrics and Gynecology