This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leonhardt, A.
Right arrow Articles by Seyberth, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leonhardt, A.
Right arrow Articles by Seyberth, H. W.
Related Collections
Right arrow Therapeutics & Toxicology
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

PEDIATRICS Vol. 111 No. 1 January 2003, pp. e77-e81

ELECTRONIC ARTICLE

Low-Dose Aspirin in Pregnancy: Maternal and Neonatal Aspirin Concentrations and Neonatal Prostanoid Formation

Andreas Leonhardt, MD*, Stefanie Bernert, MD*, Bernhard Watzer*, Gabriele Schmitz-Ziegler, MD{ddagger} and Hannsjörg W. Seyberth, MD*

* Departments of Pediatrics
{ddagger} Obstetrics and Gynecology, Philipp’s University, Marburg, Germany

-->
   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. To evaluate maternal and neonatal plasma concentrations of acetylsalicylic acid and salicylic acid and the neonatal endogenous prostanoid formation during low-dose aspirin prophylaxis (LDA; 100 mg daily) in pregnant women.

Methods. Concentrations of acetylsalicylic acid and salicylic acid in maternal plasma after at least 4 weeks of LDA (n = 14) and in umbilical cord plasma of newborns after maternal LDA (n = 7) were determined by gas chromatography–mass spectrometry. Platelet and renal formation of thromboxane A2 and the formation of prostaglandin E2 and prostacyclin were evaluated in vivo by quantification of index metabolites in plasma and urine by gas chromatography–mass spectrometry in neonates after maternal LDA (n = 14) and in a control group.

Results. In the pregnant women, acetylsalicylic acid and salicylic acid concentrations rapidly increased after ingestion of LDA. Acetylsalicylic acid was completely eliminated within 4 hours, whereas salicylic acid was detected with low concentrations at 18 and 21 hours after dosing. In the neonates, acetylsalicylic acid was not detected. Salicylic acid was detected in 1 infant only. Platelet thromboxane A2 formation in the newborn infants was significantly suppressed but recovered within 2 to 3 days after discontinuation of LDA. Renal thromboxane A2 formation and the formation of prostaglandin E2 and prostacyclin were not affected by LDA.

Conclusion. In pregnant women who are treated with LDA, acetylsalicylic acid is not completely inactivated in the portal circulation but reaches the uteroplacental circulation and exerts antiplatelet effects in the fetus and newborn.

Key Words: low-dose aspirin • prostanoids • newborn infant • mass spectrometry

Abbreviations: LDA, low-dose aspirin • Tx, thromboxane • PG, prostaglandin • GC-MS, gas chromatography-mass spectrometry


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Treatment of pregnant women with low-dose aspirin (LDA) for prevention of preeclampsia has been investigated extensively during the past years. Routine administration of LDA is not justified in women identified by clinical and historical risk factors.1,2 LDA, however, may be beneficial in small subgroups of high-risk women or if treatment is started very early or at a higher dose.3–7 In addition to its use in preeclampsia, LDA is under investigation for the prevention of other pregnancy complications.8,9

The main effect of LDA is inhibition of platelet thromboxane (Tx) A2 formation by irreversible acetylation of platelet cyclooxygenase.10 The formation of prostaglandins (PGs) and prostacyclin is only marginally affected.11 Acetylsalicylic acid crosses the placenta.12 The ingestion of aspirin in antiinflammatory doses by pregnant women has been associated with an increased risk of fetal and neonatal hemorrhage.13,14 So far, plasma levels of acetylsalicylic acid have not been measured in newborns after maternal LDA. Only a few investigations have addressed the effect of LDA on the fetal and neonatal formation of platelet TxA2. Both impaired15–18 and unimpaired19,20 formation of platelet TxA2 has been demonstrated. Most of these investigations15–18,20 measured the capacity of platelets to form TxA2 ex vivo, which is greater than the actual in vivo formation,21 whereas the neonatal endogenous formation of Tx, PGs, and prostacyclin after maternal LDA has not been evaluated.

The present study was designed to determine maternal and neonatal plasma levels of acetylsalicylic acid and salicylic acid during LDA treatment in women at risk for pregnancy-induced hypertension. In the neonates, the inhibition and recovery of platelet TxA2 formation, the renal TxA2 formation, and the formation of prostacyclin and PGE2 were evaluated in vivo.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Control Subjects
Pregnant women and their newborn infants were included in the study when the women had been treated with 100 mg of aspirin daily for prevention of preeclampsia. The women started LDA prophylaxis at 14 to 33 (median: 20) gestational weeks. Because of anesthesiological concerns, LDA was discontinued before the expected parturition to preserve the possibility of performing an epidural anesthesia, which was considered to be otherwise associated with an increased risk of hemorrhage. Therefore, the number of days from discontinuation of LDA to delivery differed between the newborns. This procedure enabled us to evaluate the relationship between alterations in neonatal prostanoid formation and the number of days without LDA. Because 21% of women in LDA trials are noncompliers,22 urinary excretion of 2,3-dinor-TxB2, reflecting platelet TxA2 formation,23 was measured while the women were still treated with LDA and was compared with the urinary excretion of 2,3-dinor-TxB2 in healthy pregnant women matched for gestational age (±10 days). Only newborn infants of mothers with complete inhibition of 2,3-dinor-TxB2 excretion were evaluated further. In the pregnant women, plasma concentrations of acetylsalicylic acid and salicylic acid were measured after at least 4 weeks of LDA treatment. In a subgroup of newborns, concentrations of acetylsalicylic acid, salicylic acid, and 11-dehydro-TxB2, which reflects the in vivo formation of platelet TxA2,23 were determined in umbilical cord blood. In all newborns, urinary excretion of index metabolites of platelet (2,3-dinor-TxB2) and renal (TxB2) TxA2 formation23 and the formation of PGE2 (PGE2 and 7{alpha}-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid)24 and prostacyclin (6-keto-PGF1{alpha} and 2,3-dinor-6-keto-PGF1{alpha})25 were measured during the first days of life. Plasma 11-dehydro-TxB2 and urinary prostanoid metabolites were also measured in healthy, age-matched (±2 days) term infants who were born after an uneventful pregnancy. The concept of assessing the in vivo formation of TxA2, PGE2, and prostacyclin by measuring index metabolites in plasma or urine has been evaluated in adults23–25 and does therefore not necessarily apply to newborns. Newborns, however, generate the same metabolites that reflect the in vivo generation of the respective primary prostanoids in adults.26 Consequently, index metabolites have been used successfully to investigate the generation of TxA2 by neonatal platelets15,16,18,19 and to clarify the role of prostanoids in various diseases of newborns.27–32 The local ethics committee for clinical studies approved the study protocol. Informed consent was obtained from all mothers.

Sample Collection
Umbilical cord blood was collected with a large-bore cannula into ice-cold tubes containing indomethacin in a 3.8% sodium citrate solution immediately after clamping of the umbilical cord. The sample was immediately centrifuged at 4°C and 1000 g. The plasma was frozen at -80°C. Urine was collected over a period of 24 hours in the women. In the newborns, urine was collected in a urine bag for infants over a period of 3 to 13 (median: 10) hours. The urine bag was connected to a container in a refrigerator. During the collection period, the urine was kept at 4°C. After the collection period, the volume was determined and an aliquot was stored at -80°C until analysis.

Analytical Methods
The methods for quantification of prostanoids in urine and plasma by gas chromatography–mass spectrometry (GC-MS) have been previously developed in our laboratory and have been described elsewhere.33,34 Quantification of acetylsalicylic acid and salicylic acid was accomplished as follows. Deuterated salicylic acid was prepared by a bromine-deuterium exchange reaction.35 The obtained [3,5-2H2]salicylic acid was converted by an acetylating reaction with [2H6]acetic anhydride and [2H2]SO4 to the corresponding [2H5]acetylsalicylic acid. The deuterated standards contain 2.4% (salicylic acid) and 0.9% (acetylsalicylic acid) nondeuterated material. Standard solutions of [3,5-2H2]salicylic acid and [2H5]acetylsalicylic acid in ethanol were stored at -80°C. Plasma (500 µL) was spiked with 500 ng of [2H2]salicylic acid and 500 ng of [2H5]acetylsalicylic acid. A total of 1.5 mL of 0.06 M sodium phosphate buffer, 1.5 mL of 0.05 M tetrabutyl-ammonium hydrogensulfate (phase-transfer catalyst), 10 µL of pentafluorobenzyl bromide (reagent), and 2 mL of dichloromethane as extracting solvent were added. Under vigorous stirring for 10 minutes, the mixture was allowed to form the pentafluorobenzyl derivatives of salicylic acid and acetylsalicylic acid. After centrifugation, the organic phase was evaporated to dryness under nitrogen. The residue was resuspended in 1 mL of hexane, and 1 mL of water was added. After mixing for 30 seconds and centrifugation with 1000 x g for 5 minutes, the hexane phase was taken and dried under a gentle stream of dry nitrogen. The sample was dissolved in 20 µL of ethyl acetate. One microliter of this solution was injected into the GC-MS/MS system. GC-MS/MS analysis was conducted on a Finnigan MAT TSQ45 GC-MS (Finnigan MAT, Bremen, Germany). GC separation was performed on a fused silica capillary column (DB-5; 20 m x 0.25 mm internal diameter, film thickness 0.25 µm; J&W, Carlo Erba, Hofheim, Germany) in splitless mode at an inlet pressure of 100 kPa. The GC oven temperature program was as follows: the initial temperature of 100°C was held for 2 minutes then increased at 25°C/min to 280°C and at 10°C/min to 310°C. This temperature was held for 2 minutes. Mass spectrometer conditions were as follows: GC injector temperature 250°C, interface temperature 290°C, methane chemical ionization gas pressure 50 Pa, electron energy 70 eV, emission current 0.2 mA, conversion dynode 3 kV, and electron multiplier 2000 V. Collision cell pressure was 0.2 Pa, and collision energy was 12 eV. The most intense ions in the upper mass region were [M+H]+ (salicylic acid, m/z 319 and 2H2-salicylic acid, m/z 321), [M+H-(CH2 = C = O)]+ (acetylsalicylic acid, m/z 319), and [M+H-(C2H2 = C = O)]+ (2H5-acetylsalicylic acid, m/z 322). These ions were chosen as parent ions for collisionally activated decomposition. In the collisionally activated decomposition spectra of all derivatives, only 3 daughter ions of the parent ion ([P]+) could be observed: [P-H2O]+, [P-PFBOH]+, and PFB+. Of these, the most intense ion ([PFB]+) was used for quantification in the selective reaction monitoring mode. Because of the relatively high amount of undeuterated material in the deuterated internal standards, the detection limit was 30 ng/mL for both acetylsalicylic acid and salicylic acid. The assay was validated in the concentration range of 30 to 500 ng/mL. Acetylsalicylic acid was stable in plasma samples kept 1 hour at room temperature. During sample preparation, no shift from acetylsalicylic acid to salicylic acid was observed. The intra-assay accuracy was less than ±10% bias from the nominal concentration. The interassay precisions (day-to-day variability) were <15% (coefficient of variation) for acetylsalicylic acid and salicylic acid.

Statistical Analysis
Continuous data were assessed for normal distribution with normal plots and the Shapiro-Francia W test.36 Nonparametric statistical methods were used because not all variables were normally distributed. Data were expressed as the median (25th, 75th percentiles) unless otherwise stated. The primary study parameters were urinary excretion of 2,3-dinor-TxB2 and plasma concentrations of 11-dehydro-TxB2 in the newborns. Urinary excretion of TxB2 and of PGE2 and prostacyclin index metabolites were secondary study parameters analyzed exploratively. Comparisons of the medians of 2 groups were performed by the Mann-Whitney U test. The relationship between continuous variables was analyzed by Spearman rank correlation. P < .05 was considered significant. All analyses were performed with use of StatView software 5.0 (SAS Institute Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Fourteen newborn infants and their mothers were included in the study. The infants were born at 36 to 42 (median: 40) gestational weeks. Birth weight was 3455 g (3280 g; 3720 g). All infants were healthy. In particular, no hemorrhage or clinical signs of impaired platelet function were observed. Intracranial hemorrhage was excluded by cerebral ultrasound.

Plasma Concentration of Acetylsalicylic Acid and Salicylic Acid
In the pregnant women, plasma concentrations of acetylsalicylic acid and salicylic acid increased rapidly after ingestion of LDA (Fig 1). The highest plasma levels of acetylsalicylic acid (4210 ng/mL) and salicylic acid (7928 ng/mL) were measured after 30 and 75 minutes, respectively. Four hours after ingestion of LDA, acetylsalicylic acid was no longer detectable. Plasma concentrations of salicylic acid were 59 and 64 ng/mL after 18 and 21 hours, respectively. Plasma concentrations of acetylsalicylic acid and salicylic acid were measured in umbilical cord blood in a subgroup of 7 newborns. The infants’ mothers had discontinued LDA 1 to 13 days (median: 3 days) before delivery. Acetylsalicylic acid was not detected in any of the samples. Salicylic acid (39 ng/mL) was detected in 1 infant. This infants’ mother had discontinued LDA 1 day before delivery.



View larger version (17K):
[in this window]
[in a new window]
  		Fig 1. Plasma concentrations of acetylsalicylic acid and salicylic acid in pregnant women after at least 4 weeks of prophylaxis with LDA (100 mg/d).

 
Formation of Platelet TxA2 in Pregnant Women During LDA
In all women, platelet TxA2 formation was evaluated by measuring the urinary excretion of 2,3-dinor-TxB2 1 to 18 days (median: 6 days) before parturition and while the women were still taking LDA. Urinary excretion of 2,3-dinor-TxB2 was lower in the pregnant women who had been treated with LDA as compared with healthy, untreated pregnant women (3.8 ng/h/1.73 m2 [2.4 ng/h/1.73 m2; 5.4 ng/h/1.73 m2] vs 26.8 ng/h/1.73 m2 [23.2 ng/h/1.73 m2; 31.6 ng/h/1.73 m2]; P < .0001). Urinary excretion rates of 2,3-dinor-TxB2 of the 2 groups did not overlap (range: 2.0–7.1 and 11.1–53.3 ng/h/1.73 m2 in the LDA and control groups, respectively). This indicates complete inhibition of platelet TxA2 formation at the time of the investigation.

Formation of Prostanoids in the Newborn Infants
Plasma concentrations of 11-dehydro-TxB2 were measured in umbilical cord blood of a subgroup of 7 newborns. The infants’ mothers had discontinued LDA 1 to 13 days (median: 3 days) before delivery. Plasma 11-dehydro-TxB2 correlated with the days without LDA (r2 = 0.88, r = 0.94, P = .02; Fig 2) and was lower in the newborns after maternal LDA prophylaxis than in the control subjects (20.1 pg/mL [7.7 pg/mL; 42.6 pg/mL] versus 70.7 [42.4 pg/mL; 117.0 pg/mL]; P = .01; Fig 2). Urinary excretion of prostanoid metabolites was measured in all newborns. At the time of the investigation, the infants were 1 to 10 days old (median: 2 days) and the infants’ mothers had discontinued LDA 1 to 17 days before (median: 5.5 days). Urinary 2,3-dinor-TxB2 (platelet TxA2 formation) was lower in the newborns after maternal LDA than in the control subjects (14.4 ng/h/1.73 m2 [10.1 ng/h/1.73 m2; 19.6 ng/h/1.73 m2] vs 21.4 ng/h/1.73 m2 [17.8 ng/h/1.73 m2; 32.7 ng/h/1.73 m2]; P = .02). 2,3-Dinor-TxB2 was weakly correlated with the days without LDA (r = 0.52, P = .06). Urinary TxB2 excretion (mainly renal TxA2 formation) was not different between the 2 groups (3.7 ng/h/1.73 m2 [1.5 ng/h/1.73 m2; 6.0 ng/h/1.73 m2] vs 4.6 ng/h/1.73 m2 [2.8 ng/h/1.73 m2; 8.6 ng/h/1.73 m2]; P = .34). Neither the urinary excretion of PGE2 and 7{alpha}-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid (formation of PGE2) nor the urinary excretion of 6-keto-PGF1{alpha} and 2,3-dinor-6-keto-PGF1{alpha} (formation of prostacyclin) was affected by maternal LDA prophylaxis (data not shown).



View larger version (17K):
[in this window]
[in a new window]
  		Fig 2. Concentration of 11-dehydro-TxB2 reflecting in vivo platelet thromboxane A2 formation in umbilical cord blood of newborns after maternal LDA prophylaxis. The infants’ mothers had discontinued LDA 1 to 13 days before delivery. 11-dehydro-TxB2 correlated with the days without LDA aspirin (r2 = 0.88, r = 0.94, P = .02; top) and was lower in the newborns after maternal LDA than in the control subjects (P = .01; bottom). The broken line in the top panel indicates the fifth percentile of the control group.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found an inhibition of platelet TxA2 formation in neonates of pregnant women who had been treated with 100 mg of aspirin daily. Both acetylsalicylic acid and salicylic acid were detected in the plasma of the pregnant women in considerable amounts. At birth, plasma acetylsalicylic acid was below the detection limit in all newborns, and salicylic acid was detected in a very low concentration in 1 infant only.

Plasma concentrations of acetylsalicylic acid and salicylic acid measured in the present investigation largely agree with published pharmacokinetic data of both compounds in healthy adults10,37 and in pregnant women after a single aspirin dose.38 It has been assumed that during LDA prophylaxis in pregnant women only very little acetylsalicylic acid reaches the uteroplacental circulation and may subsequently be transported across the placenta into the fetal compartment because acetylsalicylic acid is almost completely inactivated in the portal circulation.20 The results of the present investigation, however, definitely indicate that the fetus is exposed to acetylsalicylic acid and salicylic acid during LDA prophylaxis in pregnancy.

Ex vivo studies indicate that acetylsalicylic acid readily crosses the placenta.12 The placental transfer of salicylic acid has been demonstrated in vivo.39,40 After chronic ingestion of acetylsalicylic acid in antiinflammatory doses, plasma concentrations of salicylic acid are higher in the newborn infants than in the mothers because the protein binding of salicylic acid is considerably higher in neonatal than in maternal plasma.39,40 Newborn infants mainly eliminate salicylic acid by conversion to the glycine and glucuronic acid conjugates.40 The capacity of these pathways is very low, and elimination of salicylic acid by newborn infants is, therefore, much slower than in adults with a half-life of approximately 4 to 11 hours.40 Against this background, salicylic acid might accumulate in the fetus and might therefore be detectable in the neonate. In the newborns studied, however, salicylic acid was detected with a very low concentration in umbilical cord blood in only 1 infant, whose mother had ingested the last aspirin dose 1 day before delivery. This suggests that the concentration of salicylic acid in the fetus is actually very low during maternal LDA. On the basis of a neonatal to maternal plasma salicylic acid concentration ratio of 1.639 and a maternal trough level of salicylic acid of approximately 50 ng/mL as suggested by the present study, an estimate of the resulting fetal plasma concentration of salicylic acid is <100 ng/mL.

Although acetylsalicylic acid concentrations were high in the pregnant women, the drug was not detected in any of the newborn infants studied 24 hours or more after the last maternal LDA. The concentrations of acetylsalicylic acid in the systemic and uteroplacental circulation of pregnant women, however, obviously result in substantial amounts of acetylsalicylic acid that cross the placenta and exert antiplatelet activity in the fetus. This assumption is confirmed by the analysis of the endogenous prostanoid formation in the newborn infants, which demonstrates the typical pattern of prostanoid formation during LDA treatment. The formation of platelet TxA2 is selectively inhibited, whereas the renal TxA2 formation and the formation of PGE2 and prostacyclin are not affected. The inhibition of platelet TxA2 formation cannot be ascribed to the placental transfer of salicylic acid, because even the administration of high doses of salicylic acid (1200 mg daily) has no effect on platelet TxA2 formation.41 Benigni et al15 demonstrated that treating pregnant women with 60 mg of aspirin daily resulted in a 63% reduction of the ex vivo capacity of neonatal platelets to release TxA2 in umbilical cord blood. Valcamonico et al18 and Regan et al16 obtained similar results. The ex vivo capacity of platelet TxA2 formation, however, is considerably greater than the actual in vivo biosynthetic rate.21 We therefore measured the plasma 11-dehydro-TxB2 concentration and the urinary 2,3-dinor-TxB2 excretion. Both compounds reflect the in vivo formation of platelet TxA2.21,23 Thus, maternal LDA inhibits the actual in vivo formation of TxA2 in the fetus and neonate.

Plasma 11-dehydro-TxB2 was clearly lower in the newborns after maternal LDA than in the control subjects. The difference between the 2 groups was less pronounced with respect to urinary 2,3-dinor-TxB2 excretion. The different inhibition of platelet TxA2 formation as assessed by plasma 11-dehydro-TxB2 and urinary 2,3-dinor-TxB2 is probably attributable to the shorter period of time that elapsed since the last ingestion of aspirin by the mothers in the newborns with analysis of plasma 11-dehydro-TxB2 (median: 3 days) as compared with the newborns with analysis of urinary 2,3-dinor-TxB2 (median: 5.5 days). The correlation between plasma 11-dehydro-TxB2 in umbilical cord blood and the days without LDA indicates rapid recovery of platelet TxA2 formation. Already 2 to 3 days after the infants’ mothers had ingested the last aspirin dose, plasma 11-dehydro-TxB2 in the newborns exceeded the fifth percentile of plasma 11-dehydro-TxB2 in the control subjects (Fig 2). Valcamonico et al18 and Benigni et al15 demonstrated recovery of the ex vivo capacity to form platelet TxA2 in neonates after LDA within 4 and 5 days. These findings are consistent with the idea that inhibition of platelet TxA2 formation by aspirin is attributable to irreversible acetylation of platelet cyclooxygenase and will recover with the production of unaffected platelets. The results also indicate that during LDA and until 2 to 3 days after the last aspirin dose, platelet function may be impaired in the fetus and newborn infant.

Inhibition of platelet TxA2 formation in the fetus and neonate as observed in the present study may be clinically relevant. Ingestion of aspirin in analgesic or antiinflammatory doses a few days before delivery is associated with bleeding complications in the newborn infant.13,14 In contrast, major hemorrhage was not observed in the large number of infants who were born after LDA prophylaxis in pregnancy.1,42,43 In adults, inhibition of the capacity to form TxA2 must be virtually complete (>95%) before Tx-dependent platelet activation is influenced in vivo.44,45 Neither the previously published studies15,16,18 nor the findings of the present study support the assumption of complete inhibition of fetal or neonatal platelet TxA2 formation by LDA in pregnancy when aspirin doses up to 100 mg daily are used. It has been suggested that a higher aspirin dose might possibly be more effective in the prevention of preeclampsia.4,46,47 Considering, however, the inhibition of platelet TxA2 formation already present in the neonates after 100 mg of aspirin daily and the dose-dependent decline of platelet TxA2 formation when aspirin doses of 20 to 325 mg/d are ingested,11 increasing the aspirin dose will result in a more pronounced inhibition of platelet TxA2 formation, which may be associated with an increased risk of fetal and neonatal hemorrhage.


   ACKNOWLEDGMENTS
 
This study was supported in part by grants from Stiftung P.E. Kempkes and Bayer AG (Leverkusen, Germany).

We thank H. Schweer for the quantification of prostanoids in plasma and urine, D. Haas for documentation of clinical data, and A. Stöppler for reviewing the manuscript.


   FOOTNOTES
 
Received for publication May 21, 2002; Accepted Sep 13, 2002.

Reprint requests to (A.L.) Department of Pediatrics, Deutschhausstr 12, D-35037 Marburg, Germany. E-mail: andreas.leonhardt{at}mailer.uni-marburg.de


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet.1994; 343 :619 –629[CrossRef][Web of Science][Medline]
  2. Barth W. Low-dose aspirin for preeclampsia: the unresolved question. N Engl J Med.1998; 338 :756 –757[Free Full Text]
  3. Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review. Br Med J.2001; 322 :329 –333[Abstract/Free Full Text]
  4. Dekker G, Sibai B. Primary, secondary, and tertiary prevention of pre-eclampsia. Lancet.2001; 357 :209 –215[CrossRef][Web of Science][Medline]
  5. Heyborne KD. Preeclampsia prevention: lessons from the low-dose aspirin therapy trials. Am J Obstet Gynecol.2000; 183 :523 –528[CrossRef][Web of Science][Medline]
  6. Coomarasamy A, Papaioannou S, Gee H, Khan KS. Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: a meta-analysis. Obstet Gynecol.2001; 98 :861 –866[CrossRef][Web of Science][Medline]
  7. Uzan S. Aspirin and prevention of vascular complications: there are still indications. Ultrasound Obstet Gynecol.2001; 15 :4 –6[CrossRef][Web of Science]
  8. Empson M, Lassere M, Craig JC, Scott JR. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol.2002; 99 :135 –144[CrossRef][Web of Science][Medline]
  9. Weckstein LN, Jacobson A, Galen D, Hampton K, Hammel J. Low-dose aspirin for oocyte donation recipients with a thin endometrium: prospective, randomized study. Fertil Steril.1997; 68 :927 –930[CrossRef][Web of Science][Medline]
  10. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest.2001; 119 :39S –63S[Free Full Text]
  11. FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest.1983; 71 :676 –688
  12. Jacobson RL, Brewer A, Eis A, Siddiqqi TA, Myatt L. Transfer of aspirin across the perfused human placental cotyledon. Am J Obstet Gynecol.1991; 165 :939 –944[Web of Science][Medline]
  13. Stuart MJ, Gross SJ, Elrad H, Graeber JE. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N Engl J Med.1982; 307 :909 –912[Abstract]
  14. Rumack CM, Guggenheim MA, Rumack BH, Peterson RG, Johnson ML, Braithwaite WR. Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol.1981; 58 :52S –56S
  15. Benigni A, Gregorini G, Frusca T, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med.1989; 321 :357 –362[Abstract]
  16. Regan CL, McAdam BF, McParland P, Boylan PC, FitzGerald GA, Fitzgerald DJ. Reduced fetal exposure to aspirin using a novel controlled-release preparation in normotensive and hypertensive pregnancies. Br J Obstet Gynaecol.1998; 105 :732 –738[Web of Science][Medline]
  17. Parker CR, Hauth JC, Goldenberg RL, Cooper RL, DuBard MB. Umbilical cord serum levels of thromboxane B2 in term infants of women who participated in a placebo-controlled trial of low-dose aspirin. J Matern Fetal Med.2000; 9 :209 –215[CrossRef][Medline]
  18. Valcamonico A, Foschini M, Soregaroli M, Tarantini M, Frusca T. Low dose aspirin in pregnancy: a clinical and biochemical study of effects on the newborn. J Perinat Med.1993; 21 :235 –240[Web of Science][Medline]
  19. Viinikka L, Hartikainen Sorri AL, Lumme R, Hiilesmaa V, Ylikorkala O. Low dose aspirin in hypertensive pregnant women: effect on pregnancy outcome and prostacyclin-thromboxane balance in mother and newborn. Br J Obstet Gynaecol.1993; 100 :809 –815[Web of Science][Medline]
  20. Louden KA, Broughton Pipkin F, Heptinstall S, et al. Neonatal platelet reactivity and serum thromboxane B2 production in whole blood: the effect of maternal low dose aspirin. Br J Obstet Gynaecol.1994; 101 :203 –208[Web of Science][Medline]
  21. FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation.1983; 67 :1174 –1177[Free Full Text]
  22. Hauth JC, Goldenberg RL, Parker CR Jr, Copper RL, Cutter GR. Maternal serum thromboxane B2 reduction versus pregnancy outcome in a low-dose aspirin trial. Am J Obstet Gynecol.1995; 173 :578 –584[CrossRef][Web of Science][Medline]
  23. FitzGerald GA, Healy C, Daugherty J. Thromboxane A2 biosynthesis in human disease. Fed Proc.1987; 46 :154 –158[Web of Science][Medline]
  24. Hamberg M, Samuelsson B. On the metabolism of prostaglandins E1 and E2 in man. J Biol Chem.1971; 246 :6713 –6721[Abstract/Free Full Text]
  25. Rosenkranz B, Fischer C, Weimer KE, Frolich JC. Metabolism of prostacyclin and 6-keto-prostaglandin F1 alpha in man. J Biol Chem.1980; 255 :10194 –10198[Abstract/Free Full Text]
  26. Leonhardt A, Busch C, Schweer H, Seyberth HW. Reference intervals and developmental changes of urinary prostanoid excretion in healthy newborns, infants and children. Acta Paediatr Scand.1992; 81 :191 –196[CrossRef]
  27. Seyberth HW, Königer SJ, Rascher W, Kühl PG, Schweer H. Role of prostaglandins in hyperprostaglandin E syndrome and in selected renal tubular disorders. Pediatr Nephrol.1987; 1 :491 –497[CrossRef][Web of Science][Medline]
  28. Hoch B, Bernhard M. Central apnoea and endogenous prostaglandins in neonates. Acta Paediatr.2000; 89 :1364 –1368[CrossRef][Web of Science][Medline]
  29. Kuhl PG, Cotton RB, Schweer H, Seyberth HW. Endogenous formation of prostanoids in neonates with persistent pulmonary hypertension. Arch Dis Child.1989; 64 :949 –952[Abstract/Free Full Text]
  30. Kuhl PG, Schonig G, Schweer H, Seyberth HW. Increased renal biosynthesis of prostaglandin E2 and thromboxane B2 in human congenital obstructive uropathy. Pediatr Res.1990; 27 :103 –107[Web of Science][Medline]
  31. Stier C, Hess M, Watzer B, Schweer H, Seyberth HW, Leonhardt A. Prostanoid formation during feeding of a preterm formula with long-chain polyunsaturated fatty acids in healthy preterm infants during the first weeks of life. Pediatr Res.1997; 42 :509 –513[Web of Science][Medline]
  32. Seyberth HW, Müller H, Ulmer HE, Wille L. Urinary excretion rates of 6-keto-PGF1a in neonates recovering from respiratory distress with and without patent ductus arteriosus. Pediatr Res.1984; 18 :520 –524[Web of Science][Medline]
  33. Schweer H, Watzer B, Seyberth HW. Determination of seven prostanoids in 1 ml urine by gas chromatography-negative ion chemical ionization triple stage quadruple mass spectrometry. J Chromatogr.1994; B652 :221 –227
  34. Schweer H, Meese CO, Fürst O, Kühl PG, Seyberth HW. Tandem mass spectrometric determination of 11-dehydro-TxB2, an index metabolite of TxB2, in plasma and urine. Anal Biochem.1987; 164 :156 –163[CrossRef][Web of Science][Medline]
  35. Tashiro M, Nakayama K, Fukata G. Preparation of all the possible ring-deuterated benzoic acids by reductive dehalogenation of the corresponding halogenobenzoic acids with Raney alloys in an alkaline deuterium oxide solution. J Chem Soc (Perkin 1).1983; 10 :2315 –2318
  36. Altman DG. Practical Statistics for Medical Research. 1st ed. Boca Raton, FL: Chapman & Hall/CRC; 1991
  37. Benedek IH, Joshi AS, Pieniaszek HJ, King SY, Kornhauser DM. Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy young volunteers. J Clin Pharmacol.1995; 35 :1181 –1186[Abstract]
  38. Rymark P, Berntorp E, Nordsjo P, Liedholm H, Melander A, Gennser G. Low-dose aspirin to pregnant women: single dose pharmacokinetics and influence of short term treatment on bleeding time. J Perinat Med.1994; 22 :205 –211[Web of Science][Medline]
  39. Levy G, Procknal JA, Garrettson LK. Distribution of salicylate between neonatal and maternal serum at diffusion equilibrium. Clin Pharmacol Ther.1975; 18 :210 –214[Web of Science][Medline]
  40. Levy G, Garrettson LK. Kinetics of salicylate elimination by newborn infants of mothers who ingested aspirin before delivery. Pediatrics.1974; 53 :201 –210[Abstract/Free Full Text]
  41. Rosenkranz B, Fischer C, Meese CO, Frolich JC. Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man. Br J Clin Pharmacol.1986; 21 :309 –317[Web of Science][Medline]
  42. Italian Study Group of Aspirin in Pregnancy. Low-dose aspirin in prevention and treatment of intrauterine growth retardation and pregnancy-induced hypertension. Lancet.1993; 341 :396 –400[Web of Science][Medline]
  43. Sibai BM, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med.1993; 329 :1213 –1218[Abstract/Free Full Text]
  44. Reilly IA, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood.1987; 69 :180 –186[Abstract/Free Full Text]
  45. Di Minno G, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood.1983; 61 :1081 –1085[Abstract/Free Full Text]
  46. Pipkin FB, Crowther C, De Swiet M, et al. Where next for prophylaxis against pre-eclampsia? Br J Obstet Gynaecol.1996; 103 :603 –607[Web of Science][Medline]
  47. Wallenburg HC. Prevention of pre-eclampsia: status and perspectives 2000. Eur J Obstet Gynecol Reprod Biol.2001; 94 :13 –22[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leonhardt, A.
Right arrow Articles by Seyberth, H. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leonhardt, A.
Right arrow Articles by Seyberth, H. W.
Related Collections
Right arrow Therapeutics & Toxicology
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?