Hum. Reprod. Advance Access originally published online on February 24, 2006
Human Reproduction 2006 21(7):1907-1911; doi:10.1093/humrep/del054
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
First-trimester bleeding and pregnancy outcome in singletons after assisted reproduction
Infertility Centre, University Hospital Gent, Gent, Belgium
1 To whom correspondence should be addressed at: University Hospital, De Pintelaan 185, B-9000 Gent, Belgium. E-mail: petra.desutter{at}ugent.be
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
BACKGROUND: First-trimester bleeding is frequent in assisted reproductive technique (ART) pregnancies. It is unknown whether first-trimester bleeding, if not ending in a spontaneous abortion, negatively influences further pregnancy outcome in ART in singletons. METHODS: Data were obtained from our ART database (1993–2002), with 1432 singleton ongoing pregnancies being included in this study. The outcome measures—second-trimester and third-trimester bleeding, preterm contraction rates, pregnancy duration, birthweight, Caesarean section rates, intrauterine growth retardation (IUGR), preterm prelabour rupture of membranes (P-PROM), neonatal intensive care unit (NICU) admission and perinatal mortality—were compared in the groups with and without first-trimester bleeding. RESULTS: Significantly more singleton pregnancies resulted from a vanishing twin in the group with first-trimester bleeding (8.7%) than in the controls (4.0%). A correlation was found between the incidence of first-trimester bleeding and the number of embryos transferred. First-trimester bleeding led to increased second-trimester [odds ratio (OR) = 4.56; confidence interval (CI) = 2.76–7.56] and third-trimester bleeding rates (OR = 2.85; CI = 1.42–5.73), P-PROM (OR = 2.44; CI = 1.38–4.31), preterm contractions (OR = 2.27; CI = 1.48–3.47) and NICU admissions (OR = 1.75; CI = 1.21–2.54). First-trimester bleeding increased the risk for preterm birth (OR = 1.64; CI = 1.05–2.55) and extreme preterm birth (OR = 3.05; CI = 1.12–8.31). CONCLUSIONS: First-trimester bleeding in an ongoing singleton pregnancy following ART increases the risk for pregnancy complications. The association between first-trimester bleeding, the number of embryos transferred and adverse pregnancy outcome provides a further argument in favour of single-embryo transfer.
Key words: ART/first-trimester bleeding/IVF/perinatal outcome/pregnancy
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
Infertility therapy has moved from an aetiological and often empirical method of treatment to a more successful technical approach, where assisted reproductive technique (ART) is used to bypass possible problems and enhance conception rates. If intrauterine insemination is unsuccessful or impossible, IVF without or with ICSI is now the treatment of choice. However, several studies have shown a poorer perinatal outcome after ART than after spontaneous conceptions, even for singletons (Rufat et al., 1994
; Gissler et al., 1995; Bergh et al., 1999; Koudstaal et al., 2000; Koivurova et al., 2002; Schieve et al., 2002, 2004; Kozinsky et al., 2003; Helmerhorst et al., 2004; Jackson et al., 2004). In some studies, the incidence of miscarriage, ectopic pregnancy and bleeding seems to be increased after ART (Craft and Al-Shawaf, 1991; Dhont et al., 1999; Hofmann et al., 2000; Pezeshki et al., 2000). It may well be that this worse outcome is the result of the infertility itself and patient characteristics rather than the treatment method per se (De Sutter et al., 2005). This is also substantiated by the inverse correlation between time-to-pregnancy and pregnancy outcome, even in spontaneous pregnancies (Basso and Baird, 2003; Axmon and Hagmar, 2005).
However, ART pregnancies seem to be at risk for another complication, which is first-trimester bleeding. In spontaneous pregnancies, this occurs in about 20% of pregnancies (Everett, 1997), but after ART, the incidence is increased (29% in Goldman et al., 1988; 31% in Dantas et al., 1996; 36.2% in Hofmann et al., 2000; 31.2% in Pezeshki et al., 2000). It has been shown that first-trimester bleeding is correlated with an increased risk for miscarriage both in spontaneous (50% in Everett, 1997) and in IVF pregnancies (25% in Goldman et al., 1988; 44% in Dantas et al., 1996; 28.2% in Hofmann et al., 2000; 30.8% in Pezeshki et al., 2000). In ongoing spontaneous pregnancies complicated by first-trimester bleeding, lower birthweights have been found, but a direct relationship could not be demonstrated (Strobino and Pantel-Silverman, 1989). Little is known on the outcome of ongoing pregnancies after ART when first-trimester bleeding has occurred. The aim of this study was to investigate whether this first-trimester complication influences the further course and the outcome of the pregnancy after ART if it does not end in a spontaneous abortion.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
Patient treatment
The database of the Gent University Hospital Infertility Centre was used for this study. All patients undergoing IVF or ICSI between 1993 and 2002 and having obtained an ongoing pregnancy (beyond 12 weeks of amenorrhoea) were included. The standard ovarian stimulation protocol made use of cycle synchronization with a standard contraceptive pill for 2–6 weeks. In more than 90% of the patients, a short GnRH agonist protocol was used, consisting of 0.1 mg of triptorelin (Decapeptyl, Ipsen, France), injected subcutaneously from day 5 onwards after discontinuation of the oral contraceptive. This was followed by HMG (either Humegon, Organon, The Netherlands or Menopur, Ferring, Germany) or rFSH (either Gonal-F, Serono, Switzerland or Puregon, Organon, The Netherlands) from day 7 onwards. The starting dose in a first cycle was 150 or 225 IU, but this dose was adjusted after 7 days, according to the individual response of the patient. The follicular phase was monitored by means of transvaginal ultrasound scanning of the ovaries and serum estradiol measurements [the latter especially in poor responders and in patients at risk for the ovarian hyperstimulation syndrome (OHSS)].
In about 10% of our patients, a long GnRH agonist protocol was used. Triptorelin (Decapeptyl) 3.75 mg i.m. was administered when the patient had been taking her contraceptive pill for at least 2 weeks. Another 2 weeks after triptorelin administration, she could stop the pill and start 1 week later with the gonadotrophin injections. Monitoring was similar to the monitoring in patients treated with the short protocol.
hCG (Pregnyl, Organon, The Netherlands) 5000 IU or 10 000 IU was administered when half of all mature follicles had reached a mean diameter of at least 20 mm, measured in two planes. Thirty-four hours after hCG injection, oocytes were retrieved by transvaginal ultrasound-guided follicular puncture under general anaesthesia using propofol or lately under local anaesthesia. IVF and ICSI were performed as described elsewhere (Laverge et al., 2001). All embryos were transferred on day 2 or day 3. No major changes in techniques or culture conditions were introduced during the study period.
In 1997, we started transferring one embryo in good prognosis cases, especially in patients aged less than 37 years, in first or second treatment cycles and when at least one excellent or good-quality embryo was present (De Sutter et al., 2003). In other cases, two embryos were transferred.
The luteal phase was supported by either progesterone i.m. injections 50 mg daily or intravaginally 3x 200 mg (Utrogestan, Piette Laboratories, Drogenbos, Belgium) or three injections of 1500 IU hCG (Pregnyl).
Pregnancy detection
Pregnancy was diagnosed by the detection of a positive serum hCG at least 14 days after insemination or embryo transfer, followed by a rise in hCG levels. All patients received a transvaginal ultrasound scan between 6 and 7 weeks to differentiate between biochemical and clinical (presence of an intrauterine fetal sac) pregnancies and to diagnose ectopic implantations. All pregnancies were further monitored by transvaginal ultrasound until 12 weeks amenorrhoea. Only singleton pregnancies were included. Pregnancy duration was calculated exactly from the date of oocyte retrieval.
Pregnancy outcome parameters
Pregnancy outcome parameters analysed were first-, second- and third-trimester bleeding, duration of pregnancy, birthweight, incidence of preterm contractions, perinatal mortality rates, Caesarean section rates, stay in neonatal intensive care unit (NICU), Apgar score and intrauterine growth retardation (IUGR). Vaginal bleeding was scored as ‘none’, ‘little’, ‘moderate’ or ‘a lot’, but for the purpose of this study and because of the subjective nature of this scoring, the three latter groups were taken together. A preterm delivery was defined as a delivery at a pregnancy duration of less than 37 completed weeks, a very preterm delivery at less than 32 completed weeks, low birthweight as less than 2500 g, very low birth rate as less than 1500 g. IUGR was defined as a birthweight below the tenth percentile for the pregnancy duration, using the charts by Usher and McLean (1969). Perinatal mortality rates included stillbirths with a birthweight of >500 g and neonatal deaths during the first post-natal week.
Statistics
Because none of the analysed parameters were normally distributed, non-parametric tests (mainly the Mann–Whitney U-test) were used for continuous variables. For dichotomous variables,, chi-square and Fisher’s exact test were used. Odds ratios (ORs) were calculated together with their 95% confidence intervals (95% CIs). The level of statistical significance was set at P = 0.05. For the analysis, SPSS (version 11.0, Chicago) was used.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
In our centre, 8366 ART cycles were performed from 1993 until 2002, of which 2635 resulted in a positive pregnancy test (31.5%). Of these, 2450 were clinical pregnancies (not biochemical or ectopic). From all clinical pregnancies, 772 presented with first-trimester bleeding (31.5%), and ultimately 436 miscarried (17.8% of all clinical pregnancies and 56.5% of patients with first-trimester bleeding). From the remaining 2014 ongoing pregnancies, 582 (28.9%) were multiple and 1432 (71.1%) singleton pregnancies, including vanishing twins. These pregnancies represented 1280 women and were further used in this study.
Of these 1432 pregnancies, 253 (17.7%) had presented with first-trimester bleeding, and 1179 had had no bleeding (82.3%). Mean age was not different between both groups (32 ± 4.2 years in the study versus 32 ± 3.9 years in the control group), as was parity (71.8% primiparous women in the control versus 73.5% in the study group). The percentage of IVF and ICSI treatments was not different between the groups (75% ICSI in the control versus 72% in the study group). The proportion of recognized vanishing twins (two fetal sacs at first ultrasound scans with only one vital fetus at 12 weeks) was significantly higher in the study group (22/253 or 8.7%) than in the controls (47/1179 or 4.0%) (OR = 2.29; CI = 1.36–3.86). Correspondingly, the mean number of transferred embryos was slightly (but significantly) higher in the study (2.39 ± 0.85) than in the control group (2.18 ± 0.79) (P = 0.0007), and the incidence of first-trimester bleeding proportionally increased with the number of embryos transferred (Table I).
|
Table I further summarizes the pregnancy outcome parameters in both groups. Significantly more second- and third-trimester bleeding was found in the study group, as well as preterm prelabour rupture of membranes (P-PROM), preterm and very preterm birth and very low birthweight. Mean pregnancy duration and birthweight were also lower in the group with first-trimester bleeding than in controls. No differences were found for IUGR, intrauterine death, Caesarean section rates, Apgar scores or perinatal mortality rates.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
First-trimester bleeding is often a sign of threatening abortion and as such worrisome for both patient and doctor (Broen et al., 2004
). If on ultrasound a vital fetus is observed and there is a blood collection or clot around the fetal sac, it seems worthwhile to advise the patient to take bed rest, but in fact, there is no evidence that whatever precaution or treatment is beneficial. Neither progesterone (Oates-Whitehead et al., 2003) nor hCG injections (Qureshi et al., 2005) have demonstrated to be beneficial in improving pregnancy outcome. Most of these pregnancies will go on and lead to the delivery of a healthy child. However, several older studies have shown that first-trimester bleeding is correlated with preterm birth (Batzofin et al., 1984; Strobino and Pantel-Silverman, 1989; Williams et al., 1991; Sipilä et al., 1992). In a recent population-based study, Weiss et al. (2004) have demonstrated that first-trimester vaginal bleeding is an independent risk factor for adverse obstetric outcome that is directly proportional to the amount of bleeding. In cases of threatening abortion, bleeding mostly originates from the placenta, and in this large collaborative study, it has been demonstrated that the worse outcome of these pregnancies results from ‘placenta-related’ complications. Patients who reported light bleeding showed an increased risk for pre-eclampsia, preterm delivery, placental abruption and Caesarean delivery. Patients who reported heavy vaginal bleeding were at risk for IUGR, preterm delivery, P-PROM, placental abruption and Caesarean delivery.
Yang et al. (2005) found that older women were at increased risk for vaginal bleeding during pregnancy and also found a relation with passive smoking exposure. Especially at risk were women with prior preterm birth, multiple prior spontaneous or induced abortions but not women with a single prior spontaneous or induced abortion. Nothing much is known about infertility or assisted reproduction in this regard. Previously, four studies have been performed on the subject of first-trimester bleeding in ART pregnancies. All four (Goldman et al., 1988; Dantas et al., 1996; Hofmann et al., 2000; Pezeshki et al., 2000) have shown that first-trimester bleeding after ART increases the risk for spontaneous abortion [according to Pezeshki et al. (2000) especially in younger women]. Also from our data, it seems that first-trimester bleeding is frequent in ART pregnancies (31.5%) and associated with a high risk for spontaneous abortion (56.5%). So far, no data have been published on the further outcome of these pregnancies.
This study shows strengths and weaknesses. Its strength is that it uses prospectively recorded data during first-trimester visits in our centre. In this way, confounding bias such as recall is avoided. Also, a larger number of pregnancies have been studied than in previous studies on first-trimester bleeding in ART pregnancies. A possible weakness is the subjective character of the symptom ‘vaginal bleeding’, but because it was in every case asked for at each visit, no cases of bleeding are thought to have been missed. Because of the subjective character of the estimation of the amount of blood loss, the scoring in ‘light’, ‘moderate’ and ‘a lot’ was not used in the data analysis. Because pregnancy follow-up did not take place in our centre in most cases, another weakness of this study could be underreporting of obstetrical complications, such as second- and third-trimester bleeding, hypertension and pre-eclampsia. For this reason, we tried to use mainly hard output parameters such as mortality, pregnancy duration and birthweight. Also, smoking habits of all women were not recorded.
From our data, it seems that first-trimester bleeding in ongoing ART pregnancies is not related to maternal age, parity or the fact whether IVF or ICSI was performed, because both the study and the control group were comparable in these respects. The exact cause of first-trimester bleeding is not clear, but the fact that first-trimester is more prevalent in ART than in spontaneous pregnancies could point to differences in the implantation process after ART. Also, early vanishing twins (many being unrecognized) following double-embryo transfer could be an explanation for the increased incidence of first-trimester bleeding in ART pregnancies. It is interesting to note that there is a linear correlation between the incidence of first-trimester bleeding and the number of embryos transferred. This is very suggestive of a vanishing twin effect. It has been shown that 10% of all singleton pregnancies after IVF result from a vanishing twin pregnancy (Pinborg et al., 2005). In our study, this percentage was somewhat lower (overall 4.8%, the same percentage as we previously reported in Tummers et al., 2003), but it is striking that this rate was double in patients with first-trimester bleeding (8.7%) as compared with controls (4.0%). The fact that significantly more embryos were transferred in the first-trimester bleeding group than in controls may point to the fact that in part of the patients, this bleeding is associated with both recognized and unrecognized vanishing twins. Further study is needed to investigate whether first-trimester bleeding and the corresponding adverse pregnancy outcome is also found in pregnancies resulting from single-embryo transfer. Indeed, data are accumulating that pregnancy outcome of ART singletons is more favourable when they occur following single- than double-embryo transfer (De Sutter et al., 2003; De Neubourg et al., 2005; Pinborg et al., 2005).
Our data show that first-trimester bleeding correlates with an increased rate of preterm and very preterm birth and consequently a lower birthweight (with a mean of 115 g). IUGR was not more frequent in the study group than in the control group. Both preterm premature rupture of membranes and an increased rate of preterm contractions could be the cause of the observed increased preterm birth rate. Besides the hypothesis of Weiss et al. (2004), who have postulated that first-trimester bleeding is indicative of chronic placental impairment, it could also be that retroplacental hematomas lead to increased uterine contractility and ultimately to preterm contractions and birth.
In conclusion, first-trimester bleeding does not necessarily lead to spontaneous abortion, a fact that should reassure patients. On the other hand, first-trimester bleeding clearly is associated with an impaired pregnancy outcome, and as an independent risk factor for obstetrical and perinatal problems (Weiss et al., 2004), it should be taken into account in studies analysing pregnancy outcome after ART. The fact that the incidence of first-trimester bleeding increases with the number of embryos transferred is another argument to move to single-embryo transfer.
|
Acknowledgements |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
The first author is the holder of a fundamental clinical research mandate by the Flemish foundation of scientific research (FWO-Vlaanderen).
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgements References |
|---|
Axmon A and Hagmar L. (2005) Time to pregnancy and pregnancy outcome. Fertil Steril 84:966–974.[CrossRef][Web of Science][Medline]
Basso O and Baird DD. (2003) Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 18:2478–2484.
Batzofin JH, Fielding WL, Friedman EA. (1984) Effect of vaginal bleeding in early pregnancy on outcome. Obstet Gynecol 63:515–518.[Medline]
Bergh T, Ericson A, Hillensjo T, Nygren KG, Wennerholm UB. (1999) Deliveries and children born after in-vitro feritilisation in Sweden 1982–95. Lancet 354:1579–1585 A retrospective cohort study.[CrossRef][Web of Science][Medline]
Broen AN, Moum T, Bodker AS, Ekebeg O. (2004) Psychological impact on women of miscarriage versus induced abortion: a 2 year follow-up study. Psychosom Med 66:265–271.
Craft I and Al-Shawaf T. (1991) Outcome and complications of assisted reproduction. Curr Opin Obstet Gynecol 3:668–673.[Web of Science][Medline]
Dantas ZN, Singh AP, Karachalios P, Asch RH, Balmaceda JP, Stone SC. (1996) Vaginal bleeding and early pregnancy outcome in an infertile population. J Assist Reprod Genet 13:212–215.[CrossRef][Medline]
De Neubourg D, Mangelschots K, Van Royen E, Steylemans A, Vercruyssen M, Elseviers M, Gerris J. (2005) The obstetrical and neonatal outcome of babies born after single embryo transfer in IVF/ICSI does not compare unfavorably to spontaneous conceived babies. Abstract Book of the 21st Annual Meeting of ESHRE (OUP, Oxford, UK)i56 abstract nr O-151.
De Sutter P, Van der Elst J, Coetsier T, Dhont M. (2003) Single embryo transfer and multiple pregnancy rate reduction in IVF/ICSI: a 5-year appraisal. Reprod Biomed Online 6:464–469.[Medline]
De Sutter P, Veldeman L, Kok P, Szymczak N, Van der Elst J, Dhont M. (2005) Comparison of outcome of pregnancy after intra-uterine insemination (IUI) and IVF. Hum Reprod 20:1642–1646.
Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. (1999) Perinatal outcome of pregnancies after assisted reproduction: a case-control study. Am J Obstet Gynecol 181:688–695.[CrossRef][Web of Science][Medline]
Everett C. (1997) Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. BMJ 315:32–34.
Gissler M, Silverio MM, Hemminki E. (1995) In-vitro fertilization pregnancies and perinatal health in Finland 1991–1993. Hum Reprod 10:1856–1861.
Goldman JA, Ashkenazi J, Ben-David M, Feldberg D, Dicker D, Voliovitz I. (1988) First trimester bleeding in clinical IVF pregnancies. Hum Reprod 3:807–809.
Helmerhorst F, Perquin D, Donker D, Keirse M. (2004) Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 328:261–264.
Hofmann G, Gundrun C, Drake L, Bertsche A. (2000) Frequency and effect of vaginal bleeding on pregnancy outcome during the first 3 weeks after positive B-hCG test results following IVF-ET. Fertil Steril 74:609–610.[Medline]
Jackson R, Gibson K, Wu I, Croughan M. (2004) Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 103:551–562.
Koivurova S, Hartikainen AL, Karinen L, Gissler M, Hemminki E, Martikainen H, Tuomivaara L, Järvelin MJ. (2002) The course of pregnancy and delivery and the use of maternal healthcare services after standard IVF in Northern Finland 1990–1995. Hum Reprod 17:2897–2903.
Koudstaal J, Braat D, Bruinse H, Naaktgeboren N, Vermeiden J, Visser G. (2000) Obstetric outcome of singleton pregnancies after IVF: a matched control study in four Dutch university hospitals. Hum Reprod 15:1819–1825.
Kozinsky Z, Zadori J, Orvos H, Katona M, Pal A, Kovacs L. (2003) Obstetric and neonatal risk of pregnancies after assisted reproductive technology: a matched control study. Acta Obstet Gynecol Scand 82:850–856.[CrossRef][Web of Science][Medline]
Laverge H, De Sutter P, Van der Elst J, Dhont M. (2001) A prospective, randomized study comparing day 2 and day 3 embryo transfer in human IVF. Hum Reprod 16:476–480.
Oates-Whitehead RM, Haas DM, Carrier JAK. (2003) Progestogen for preventing miscarriage [Cochrane review]. The Cochrane Library (Wiley, Chichester, UK) Issue 4.
Pezeshki K, Feldman J, Stein DE, Lobel SM, Grazi RV. (2000) Bleeding and spontaneous abortion after therapy for infertility. Fertil Steril 74:504–508.[CrossRef][Web of Science][Medline]
Pinborg A, Lidegaard O, la Cour Freiesleben N, Andersen AN. (2005) Consequences of vanishing twins in IVF/ICSI pregnancies. Hum Reprod 20:2821–2829.
Qureshi NS, Edi-Osagie EC, Ogbo V, Ray S, Hopkins RE. (2005) First trimester threatened miscarriage treatment with human chorionic gonadotrophins: a randomised controlled trial. BJOG 112:1536–1541.[Medline]
Rufat P, Olivennes F, De Mouzon J, Dehan M, Frydman R. (1994) Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989). Fertil Steril 61:324–330.[Web of Science][Medline]
Schieve L, Meikle S, Ferre C, Peterson H, Jeng G, Wilcox L. (2002) Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 346:731–737.
Schieve L, Rasmussen S, Buck G, Schendel D, Reynolds M, Wright V. (2004) Are children born after assisted reproductive technology at increased risk for adverse health outcomes? Obstet Gynecol 103:1154–1163.[CrossRef][Web of Science][Medline]
Sipilä P, Hartikainen-Sorri AL, Oja H, Von Wendt L. (1992) Perinatal outcome of pregnancies complicated by vaginal bleeding. Br J Obstet Gynaecol 99:959–963.[Web of Science][Medline]
Strobino B and Pantel-Silverman J. (1989) Gestational vaginal bleeding and pregnancy outcome. Am J Epidemiol 129:806–815.
Tummers P, De Sutter P, Dhont M. (2003) Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 18:1720–1723.
Usher R and McLean F. (1969) Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 74:901–910.[CrossRef][Web of Science][Medline]
Weiss JL, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, Hankins GD, Berkowitz RL, Gross SJ, Dugoff L, et al. (2004) Threatened miscarriage: a risk factor for poor pregnancy outcome, a population based screening study. Am J Obstet Gynecol 190:745–750.[CrossRef][Web of Science][Medline]
Williams M, Mittendorf R, Lieberman E, Monson R. (1991) Adverse infant outcomes associated with first-trimester vaginal bleeding. Obstet Gynecol 78:14–18.[Medline]
Yang J, Savitz DA, Dole N, Hartmann KE, Herring AH, Olshan AF, Thorp JM Jr. (2005) Predictors of vaginal bleeding during the first two trimesters of pregnancy. Paediatr Perinat Epidemiol 19:276–283.[Medline]
Submitted on January 3, 2006; resubmitted on January 26, 2006; accepted on January 30, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R.H.F. van Oppenraaij, E. Jauniaux, O.B. Christiansen, J.A. Horcajadas, R.G. Farquharson, N. Exalto, and on behalf of the ESHRE Special Interest Group for Predicting adverse obstetric outcome after early pregnancy events and complications: a review Hum. Reprod. Update, July 1, 2009; 15(4): 409 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.C. Gjerris, A. Loft, A. Pinborg, M. Christiansen, and A. Tabor The effect of a 'vanishing twin' on biochemical and ultrasound first trimester screening markers for Down's syndrome in pregnancies conceived by assisted reproductive technology Hum. Reprod., January 1, 2009; 24(1): 55 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pinborg, O. Lidegaard, N. la Cour Freiesleben, and A. N. Andersen Vanishing twins: a predictor of small-for-gestational age in IVF singletons Hum. Reprod., October 1, 2007; 22(10): 2707 - 2714. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||