| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From The Academic Department of Obstetrics and Gynecology, Royal Free and University College London Medical School, London, United Kingdom.
Address reprint requests to: Eric Jauniaux, MD, PhD, Academic Department of Obstetrics and Gynecology, University College London Medical School, 86-96 Chenies Mews, London WC1E 6HX, UK; E-mail: e.jauniaux{at}ucl.ac.uk.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-fetoprotein (MSAFP) levels and pregnancy outcome; and to study the significance of ultrasound evidence of an intrauterine hematoma on pregnancy outcome in these patients. METHODS: A retrospective, case–control study was performed on 144 women presenting with bleeding in the first trimester and 144 age-matched control subjects who attended for routine dating scans during the same time scale. The presence or absence of an intrauterine hematoma, MSAFP, and pregnancy outcomes were recorded.
RESULTS: The incidence of adverse pregnancy outcome was significantly (P = .02) higher in women with a history of first-trimester threatened miscarriage than in the control group. The relative risk (RR) of an adverse pregnancy outcome for the study group was 2.22 (95% confidence interval [CI] 1.12, 4.39) compared with the control group. The RR of delivering a baby of less than 1000 g was 4.43 (95% CI 0.5, 39.2) in women with first-trimester threatened miscarriage. This was independent of the presence of an intrauterine hematoma. The RR of MSAFP being raised to more than 2.5 multiples of the median (MoM) in the study group was 6.25 (95% CI 0.77, 50.6). There was no difference between women with threatened miscarriage who had or did not have ultrasound evidence of an intrauterine hematoma.
CONCLUSION: Threatened miscarriage in the first trimester is associated with an increased incidence of adverse pregnancy outcome, independently of the presence of an intra-uterine hematoma. Higher MSAFP in threatened miscarriage suggests a direct placental injury even in the absence of a hematoma.
Threatened miscarriage, defined as vaginal bleeding before 24 weeks’ gestation, is a common complication affecting 15–20% of viable pregnancies.1 Women presenting with pain and bleeding in early pregnancy are typically offered ultrasound assessment to confirm whether there is a viable intrauterine pregnancy. Many sonographers also report the presence or absence of intrauterine hematoma, partly to offer an explanation for the maternal symptoms but also as a prognostic sign for the future outcome of the pregnancy.
The resolution of intrauterine hematoma and the prognostic relevance of this ultrasound finding are poorly understood. The presence of hematoma has been associated with a 4–33% rate of miscarriage depending on the gestational age at which the complication is described.2 In pregnancies that continue, early bleeding is associated with increased maternal serum -fetoprotein (MSAFP) levels and is recognized as a cause of inaccurate risk assessment in biochemical screening for neural tube and chromosomal abnormalities.3 High MSAFP levels (greater than 2.5 multiples of the median [MoM]) are associated with a number of pregnancy complications, including fetal growth restriction (FGR), pregnancy-induced hypertension, and preterm labor, as well as with a higher prevalence of intrauterine and neonatal death.4
Threatened miscarriage and intrauterine hematoma have been shown to be associated with an increased incidence of preterm labor and low birth weight,5 but an association with complications such as premature rupture of membranes (PROM), FGR, and pregnancy-induced hypertension has not been confirmed.2,5,6
Recently, attention has been given to the role of reactive oxygen species in obstetrics, in particular to their role in preeclampsia7 and preterm prelabor rupture of membranes,8 and the possibility of prevention with the use of dietary supplementation to prevent these complications of pregnancy. A role for reactive oxygen species in the pathogenesis of early pregnancy loss is only recently becoming apparent9; however, the association between threatened miscarriage and later pregnancy complications could in part be explained by an increase in reactive oxygen species and chronic damage to the fetal membranes with subsequent impaired placentation.
This study examines the effect of threatened miscarriage before 12 completed weeks of gestation on second-trimester MSAFP and pregnancy outcome. The cohort is subdivided into women who were noted to have ultrasound evidence of intrauterine hematoma at presentation and those who did not to examine the significance of this finding.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Data on the ultrasound findings at the time of presentation together with ultrasound findings at 11–14 weeks’ and 20 weeks’ gestation (routinely scheduled appointments within our department) were obtained from the ultrasound department’s computerized database. These were matched with the results of maternal serum biochemistry and data regarding the outcome of pregnancy from the hospital’s maternity services database. Further outcome information was collected by reviewing the patients’ medical records.
The control group included 144 consecutive asymptomatic women attending the routine obstetric ultrasound department for a dating scan at 11–14 weeks’ gestation. The controls were selected from the ultrasound department database, using "routine dating scan" as the search word and were scanned over the same time scale as the subjects. They were matched with study cases for maternal age and parity. Multiple pregnancies were excluded from analysis, as were women who had previously attended the early pregnancy unit in the index pregnancy or those who reported bleeding earlier in pregnancy. Women referred from other hospitals for nuchal translucency scans were also excluded.
Pregnancies were dated on the basis of maternal history unless the initial ultrasound findings (measurement of crown-rump length) showed a disparity in excess of 7 days. An intrauterine hematoma was defined as a crescent-shaped, echo-free area between the chorionic membrane and the myometrium. An adverse pregnancy outcome was defined as any serious complication of pregnancy resulting in hospital attendance or admission, requiring treatment or delivery, or resulting in admission to the neonatal unit or treatment of the newborn infant. These adverse outcomes were classified into groups including pregnancy-induced hypertension, defined as arterial blood pressure of at least 140 mm Hg systolic and 90 mm Hg diastolic on two occasions 24 hours apart after 20 weeks of pregnancy; FGR, defined as birth weight less than the 10th percentile; placental abruption; PROM; and preterm labor.
The maternal age distribution and AFP values of the two groups were compared using the Mann–Whitney rank-sum test. Relative frequencies of adverse pregnancy outcome in the study and control groups were compared using the Fisher exact test. Results were considered significant when P < .05. Relative risks (RRs) and confidence intervals (CIs) for poor pregnancy outcome were also established. Statistical analysis was performed with The Statistics Package, Confidence Interval Analysis (CIA 1.1, 1991, Martin Gardener, BMJ Publications, London, United Kingdom).
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. The median maternal ages were 31 (17–41) and 32 (16–40) years in the study and control groups, respectively, and there was no significant difference in the age distribution of these groups (Mann–Whitney rank-sum test, P = .68). Also, 50.7% women in the study group were multigravid compared with 56% in the control group. The median gestational age at the time of the first ultrasound examination was 8 weeks and 5 days (range 4–14 weeks) in the study group and 11 weeks and 5 days (range 5–16 weeks) in the control group. Within 4 weeks of presentation, 15 women in the study group and one woman in the control group opted to terminate the pregnancy for psychosocial reasons and were excluded from the final analysis.
|
Ten (7.8%) women in the study group miscarried before 14 weeks’ gestation. The adverse pregnancy outcomes affecting the remainder of the study and control groups are shown in Table 2. The prevalence of adverse pregnancy outcome was significantly higher in women with a history of first-trimester threatened miscarriage than in the control subjects (P = .02). The RR of an adverse pregnancy outcome for women in the study group was 2.22 (95% CI 1.12, 4.39) compared with the control group. Although there was no significant difference in the incidence of pregnancy-induced hypertension or FGR between the two groups, the RR of delivering a baby less than 1000 g was 4.43 (95% CI 0.50, 39.2) in women with first-trimester threatened miscarriage. There was also a nonsignificant increase in the incidence of preterm labor in the study group (RR 3.05; 95% CI 0.99, 9.34).
|
.
|
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Approximately 3% of pregnant women will have a MSAFP of 2.5 MoM or higher in the second trimester of pregnancy.4 In two thirds, the etiology will be established as either being a structural fetal abnormality, for example, a neural tube defect, an abdominal wall defect, obstruction of the gastrointestinal tract, or a placental abnormality such as a chorioangioma. Unexplained elevated MSAFP is present in about 1% of the obstetric population, and the elevated MSAFP has been associated with most placental vascular pathologies where a breakdown of the fetomaternal placental barrier occurs,4 allowing greater transfer of AFP into maternal serum and thus giving rise to abnormally elevated levels. Furthermore, women with elevated MSAFP have a higher incidence of positive Kleihauer–Betke stains,10 confirming that elevated MSAFP values are secondary to feto-maternal hemorrhage. This can certainly explain the increased risk of MSAFP greater than 2.5 MoM in women presenting with threatened miscarriage during the first trimester. However, it must be emphasized that within this group of women there was no difference in the incidence of high MSAFP between those with and those without a hematoma. It must also be noted that in our population, the median gestational age for women to present with a threatened miscarriage was 8 weeks, and no women had a serum screening before 15 weeks’ gestation. The actual half-life of AFP in the blood circulation is around 4–5 days,11,12 suggesting that bleeding in early pregnancy is associated with chronic damage to the villous barrier.
First-trimester threatened miscarriage with a subchorionic hematoma on ultrasound has been associated with a higher incidence of miscarriage,13–18 premature labor,13,14,18 stillbirth,13 and placenta abruption.13 The incidence of these complications increases when the bleeding occurs during the second trimester.18 A meta-analysis19 has confirmed an association between vaginal bleeding and adverse pregnancy outcome, but has also identified discrepancies in the reported risks of vaginal bleeding and magnitudes of association between bleeding and adverse outcome, observed across studies. These discrepancies were attributed to inconsistent definitions of subchorionic hematoma, size of study groups, and patient selection, as most authors selected women with vaginal bleeding and a hematoma on ultrasound. Although the present study does not support the concept that women presenting with a hematoma are more at risk of adverse pregnancy outcome than those without, many authors have previously reported an association between the size of the hematoma and subsequent complications.6,17 This association remains controversial for women presenting with threatened miscarriage during the first trimester.2,16
Subchorionic bleeding could affect pregnancy outcome in several ways. Theoretically, a large hematoma could be a threat to the continuance of the pregnancy by a direct pressure-volume effect. This may well be dependent upon the site of the hematoma,20 its distance from the site of the placenta, and the volume of the hematoma.6 Because of the retrospective nature of our study, we could not assess these parameters, but it is likely that a large hematoma involving the definitive placenta may lead to a full miscarriage within days or a few weeks after the first bleed. Our data suggest that beyond the immediate risk of a miscarriage, there is no difference in women presenting during the first trimester with vaginal bleeding with or without a hematoma on ultrasound and that it is the bleeding itself, which appears to affect the development of the pregnancy.
Bleeding in the first trimester with or without the presence of a hematoma may be associated with a chronic inflammatory reaction in the decidua resulting in persistent myometrial activity and expulsion of the pregnancy.21 It is known that in about two thirds of early pregnancy failures, there is defective placentation, which is mainly characterized by a thinner and fragmented trophoblast shell and reduced cytotrophoblast invasion of the lumen at the tips of the spiral arteries.22 There is also evidence that later pregnancy complications such as preeclampsia, preterm labor,23 and most recently PROM24 are associated with impaired placentation and failure of physiologic invasion of the spiral arteries.25 In normal pregnancy, there is a burst of oxidative stress as the maternal circulation is established, which may serve a physiologic role in stimulating placental differentiation and regulate cell function.26 Along with the rise in oxygen tension, there is a parallel rise in the expression of antioxidant enzymes within the placental tissues.27 A delicate balance is, therefore, achieved between the production of free radicals and protective antioxidant activity. A change in the equilibrium, resulting in an increase in free radical formation, such as a premature influx of oxygenated blood with hematoma formation, the presence of substances that form free radicals, or a reduction in local antioxidant levels may well result in an impairment in placentation and subsequent pregnancy complications, from miscarriage at one end of the spectrum and PROM and preeclampsia at the other. There is already mounting evidence of a role for free radical damage in PROM and preeclampsia; however, its role in miscarriage is only recently emerging.9 The excessive entry of maternal blood inside the membranes if located near the placenta may have a direct mechanical effect on the villous tissue and an indirect oxidative stress effect, which contributes to cellular dysfunction or damage.
|
Footnotes |
|---|
Received January 14, 2003. Received in revised form April 4, 2003. Accepted April 17, 2003.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Pearlstone M, Baxi L. Subchorionic haematoma: A review. Obstet Gynecol Surv 1993;48:65–8.[Medline]
3. Cuckle H, Van Oudgaarden ED, Mason G, Holding S. Taking account of vaginal bleeding in screening for Down’s syndrome. Br J Obstet Gynaecol 1994;101: 948–53.[Medline]
4. Pahal GS, Jauniaux E. Maternal serum biochemical screening for pregnancy complications other than aneuploidy. Curr Opin Obstet Gynecol 1997;9:379–86.[Medline]
5. Baztofin JH, Fielding WL, Friedman EA. Effect of vaginal bleeding in early pregnancy outcome. Obstet Gynecol 1984;63:515–8.
6. Mantoni M, Fog Pedersen J. Intrauterine haematoma—An ultrasonic study of threatened abortion. Br J Obstet Gynaecol 1981;88:47–51.[Medline]
7. Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk. Lancet 1999;354:810–6.[Medline]
8. Plessinger MA, Woods JR, Miller R. Pretreatment of human amnion-chorion with vitamins C and E prevents hypochlorous acid-induced damage. Am J Obstet Gynecol 2000;183:979–85.[Medline]
9. Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblastic oxidative stress in relation to temporal and regional difference in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 2003;162:115–25.
10. Hay DL, Barrie JU, Davison GB, Buttery BW, Horacek I, Pepperell RJ, et al. The relation between maternal serum alpha-fetoprotein levels and feto-maternal haemorrhage. Br J Obstet Gynaecol 1979;86:516–20.[Medline]
11. Han SJ, Yoo S, Choi SH, Hwang EH. Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors. Pediatr Surg Int 1997;12:599–602.[Medline]
12. Ohama K, Nagase H, Ogino K, Tsuchida K, Tanaka M, Kubo M, et al. Alpha-fetoprotein (AFP) levels in normal children. Eur J Pediatr Surg 1997;7:267–9.[Medline]
13. Ball RH, Ade CM, Schoenborn JA, Crane JP. The clinical significance of ultrasonographically detected subchorionic hemorrhages. Am J Obstet Gynecol 1996;174:996–1002.[Medline]
14. Tongsong T, Srisomboon J, Wanapirak C, Sirichotiyakul S, Pongsatha S, Polrisuthikul T. Pregnancy outcome of threatened abortion with demonstrable fetal cardiac activity: A cohort study. J Obstet Gynaecol 1995;21:331–5.
15. Dickey RP, Olar TT, Curole DN, Taylor SN, Matulich EM. Relationship of first trimester subchorionic bleeding detected by color Doppler ultrasound to subchorionic fluid, clinical bleeding and pregnancy outcome. Obstet Gynecol 1992;80:415–20.[Medline]
16. Borlum KG, Thomsen A, Clausen I, Eriksen G. Long-term prognosis of pregnancies in women with intrauterine hematomas. Obstet Gynecol 1989;74:231–3.
17. Bennett GL, Bromley B, Lieberman E, Benacerraf BR. Subchorionic haemorrhage in first trimester pregnancies: Prediction of pregnancy outcome with sonography. Radiology 1996;200:803–6.
18. Pedersen JF, Mantoni M. Large intrauterine haematomata in threatened miscarriage. Frequency and clinical consequences. Br J Obstet Gynaecol 1990;97:75–7.[Medline]
19. Ananth CV, Savitz DA. Vaginal bleeding and adverse reproductive outcomes: A meta-analysis. Paediatr Perinat Epidemiol 1994;8:62–78.[Medline]
20. Kurjak A, Schulman H, Zudenigo D, Kupesic S, Kos M, Goldenberg M. Subchorionic hematomas in early pregnancy: Clinical outcome and blood flow patterns. J Matern Fetal Med 1996;5:41–4.[Medline]
21. Strobino BA, Pantel-Silverman J. First trimester vaginal bleeding and the loss of chromosomally abnormal conceptions. Am J Obstet Gynecol 1987;157:1150–4.[Medline]
22. Hustin J, Jauniaux E, Schaaps JP. Histological study of the materno-embryonic interface in spontaneous abortion. Placenta 1990;11:477–86.[Medline]
23. Salafia CM, Lopez-Zeno JA, Sherer DM, Whittington SS, Minior VK, Vintzileos AM. Histologic evidence of old intrauterine bleeding is more frequent in prematurity. Am J Obstet Gynecol 1995;173:1065–70.[Medline]
24. Kim YM, Chaiworapongsa T, Gomez R, Bujold E, Yoon BH, Rotmensch S, et al. Failure of the physiologic transformation of the spiral arteries in the placental bed in preterm, premature rupture of membranes. Am J Obstet Gynecol 2002;187:1137–42.[Medline]
25. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response in pregnancies complicated by pre-eclampsia and by small for gestational age infants. Br J Obstet Gynaecol 1986;93:1049–59.[Medline]
26. Jauniaux E, Watson AL, Hempstock J, Bao Y-P, Skepper JN, Burton GJ. Onset of maternal arterial bloodflow and placental oxidative stress; a possible factor in human early pregnancy failure. Am J Pathol 2000;157:2111–22.
27. Watson AL, Palmer ME, Jauniaux ER, Burton GJ. Variations in expression of copper/zinc superoxide dismutase in villous trophoblast of the human placenta with gestational age. Placenta 1997;18:295–9.[Medline]
This article has been cited by other articles:
|
|
 |
|
  E. Jauniaux, L. Poston, and G. J. Burton Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution Hum. Reprod. Update, November 1, 2006; 12(6): 747 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Johns and E. Jauniaux Threatened miscarriage as a predictor of obstetric outcome. Obstet. Gynecol., April 1, 2006; 107(4): 845 - 850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Maso, G. D'Ottavio, F. De Seta, A. Sartore, M. Piccoli, and G. Mandruzzato First-Trimester Intrauterine Hematoma and Outcome of Pregnancy Obstet. Gynecol., February 1, 2005; 105(2): 339 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sotiriadis, S. Papatheodorou, and G. Makrydimas Threatened miscarriage: evaluation and management BMJ, July 17, 2004; 329(7458): 152 - 155. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
