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ORIGINAL RESEARCH |
From the 1Early Pregnancy Unit, Elizabeth Garrett Anderson Hospital, Academic Department of Obstetrics and Gynaecology, University College London Hospital, London, United Kingdom.
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ABSTRACT |
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METHODS: A prospective cohort study was performed on 214 women presenting with bleeding in the first trimester and 214 asymptomatic age-matched controls. Main outcome measures included gestational age and weight at delivery and incidence of adverse pregnancy outcome.
RESULTS: The first-trimester miscarriage rate, after confirmation of viability in the threatened miscarriage group, was 9.3%. Compared with controls, women presenting with threatened miscarriage were more likely to deliver prematurely, 5.6% compared with 11.9%, respectively, (relative risk 2.29, 95% confidence interval 1.4–4.6), and this was most likely to be between 34 and 37 weeks. They were also more likely to have preterm prelabor rupture of membranes, 1.9% compared with 7%, respectively, (relative risk 3.72, 95% confidence interval 1.2–11.2). Overall, there was no difference in mean birth weight and in the incidence of other obstetric complications between the 2 groups; however, women in the threatened miscarriage group were more likely to deliver neonates between 1,501 g and 2,000 g (P = .04).
CONCLUSION: Women with threatened miscarriage in the first trimester are at increased risk of premature delivery, and this risk factor should be taken into consideration when deciding upon antenatal surveillance and management of their pregnancies.
LEVEL OF EVIDENCE: II-0
Preterm delivery, defined as delivery before 37 weeks of gestation, occurs with an incidence of 7–11% and is the leading cause of death of normal newborns.5 Preterm premature rupture of membranes (PPROM) occurs in up to 40% of preterm deliveries.6 The incidence of preterm labor has remained largely unchanged despite advances in obstetric care and the antenatal diagnosis and management of fetal abnormality and pregnancy complications such as preeclampsia and fetal growth restriction. Identification of women at risk remains the only strategy for reducing the incidence of premature delivery.
In this study we have examined cases of threatened miscarriage from early in the first trimester and followed them up prospectively until the end of pregnancy. Participants with significant vaginal bleeding in the first trimester were recruited, and ultrasound scan findings along with the presence or absence of intrauterine bleeding were recorded. We have examined the outcomes of these pregnancies and looked in detail at the pattern of preterm labor and PPROM in these cases to investigate prospectively the relationship between first-trimester threatened miscarriage and adverse pregnancy outcome.
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MATERIALS AND METHODS |
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The control group consisted of age-matched women who booked for antenatal care in the hospital during the same time period. They were identified consecutively, matched for maternal age, from the obstetric ultrasound database as having attended for routine first-trimester screening. Control cases were excluded if they had attended the Early Pregnancy Unit with threatened miscarriage in the first trimester or if they gave any history of first-trimester bleeding. Other exclusion criteria were the same as for those with threatened miscarriage.
The overall incidence of adverse pregnancy outcome after threatened miscarriage in our previous pilot study3 was 17.1% compared with 7.6% in the control group (relative risk [RR] 2.22). The sample size required for the prospective study was calculated at a 5% level of significance with 80% power, using the proportions 0.171 and 0.076. The sample size required to detect a difference was 376, 188 women in the threatened miscarriage group and 188 controls.
We followed up all women from both groups prospectively from their first appointment until delivery. Outcome data were obtained from the hospital notes and confirmed by telephone follow-up where necessary. Pregnancy outcome data collected included gestation at delivery, birth weight, and the incidence of adverse pregnancy outcomes. Demographic data examined included maternal age, gestation at recruitment, previous obstetric history, and smoking habits. First-trimester miscarriage was defined as miscarriage before 14 completed weeks of gestation; late miscarriage was defined as pregnancy loss from 14 to 22 weeks and 6 days gestation. Preterm labor was defined as delivery between 23 and 36 + 6 weeks of gestation, and PPROM was defined as rupture of the fetal membranes before 37 weeks of gestation before the onset of labor. Adverse pregnancy outcomes were classified into groups and included preeclampsia, defined as an arterial blood pressure of 140 mmHg systolic and 90 mmHg diastolic or above on 2 or more occasions 24 hours apart after 20 weeks gestation and with persistent proteinuria. Fetal growth restriction was defined as a documented fall-off in growth velocity on ultrasound scan, with or without abnormal uterine artery Doppler measures. The weight centiles for both cases and controls were calculated using maternal age, weight, ethnicity, gestation at delivery, and the sex of the neonate, using a centile calculator available online from the Perinatal Institute for Maternal and Child Health (www.gestation.net/centiles/). Other adverse outcomes recorded included placental abruption, congenital abnormalities, placenta previa, and neonatal complications requiring admission to the neonatal unit or treatment of the newborn infant.
Ultrasound data collected included gestation from the crown–rump length (CRL) and the presence or absence of an intrauterine hematoma, defined as a crescent-shaped echo-free area between the chorionic membrane and the myometrium.7 The presence of an intrauterine hematoma, its location, and its volume was recorded on each subject and the maximal hematoma volume in milliliters calculated for each. Hematoma volume was calculated using the formula: length x width x depth x 0.5 = volume (in milliliters).8 In pregnancies where a hematoma was identified, the subjects underwent repeat scans on a weekly to fortnightly basis until resolution of the hematoma. Pregnancies were dated from the last menstrual period (LMP) and confirmed on ultrasonography using the CRL. Pregnancies were redated if there was a discrepancy between the two of greater than 7 days. All scans on women in the threatened miscarriage group were performed by the same operator using an Acuson 128/XP (Acuson Corporation, Mountain View, CA) with a 7-MHz transvaginal probe.
All studies on women presenting with threatened miscarriage were reviewed by The Joint University College London and University College London Hospital Committees on the Ethics of Human Research. Statistical analysis was performed using SPSS 12.0.1 for Windows (SPSS Inc., Chicago, IL) and Statgraphics Plus 5.1 (StatPoint, Inc., Herndon, VA). Pregnancy outcomes were compared using the McNemar 
2 test, and gestational ages and birth weights were compared using paired t tests).
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RESULTS |
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The overall first-trimester miscarriage rate for the study group, after a viable pregnancy was diagnosed on ultrasonography was 9.3%. Women in the control group were recruited later in the first trimester than the cases (8 weeks compared with 11 weeks), and there were no first-trimester miscarriages in the control group. Once first-trimester miscarriages and terminations of pregnancy were excluded, the live birth rate over 23 weeks in the threatened miscarriage group was significantly lower than controls, 95% compared with 99.5%, respectively (P = .004).
Mean birth weight is dependent on gestation, ethnicity, maternal weight, height, and sex of the baby. The weight centiles for both cases and controls were calculated using the above variables, using a centile calculator available online from the Perinatal Institute for Maternal and Child Health, and no differences were found between the 2 groups. There was also no difference in the overall mean birth weight between the 2 groups (P = .078), but women in the threatened miscarriage group were more likely to deliver babies between 1,501 g and 2,000 g (P = .04). This difference seemed to be related to premature delivery, because a comparison of birth weights by gestation showed no difference between the groups, the median birth weights were the same, and the incidence of documented fetal growth restriction between the 2 groups was also nonsignificant (P = .1).
Women in the threatened miscarriage group had a significantly increased risk of preterm labor compared with the control group (Table 2). In the study group, 11.9% women delivered prematurely compared with 5.6% in the control group (P = .018, RR 2.29, 95% confidence interval [CI] 1.4–4.6). Cumulative delivery rates for gestation (Fig. 1) found that these women were more likely to deliver between 34 and 37 weeks of gestation (Table 3). The incidence of preterm premature rupture of membranes was also significantly increased (Table 2), with a relative risk of 3.72 (P = .01, 95% CI 1.2–11.2). In the study group, 7% women had PPROM compared with 1.9% in the control group. If midtrimester membrane rupture is also taken into account, the risk increases further to a RR of 4.2 (P = .006, 95% CI 1.4–12.3). Subgroup analysis confirmed that the risk of PPROM was increased after threatened miscarriage in primigravidas (P = .019, RR 5.1, 95% CI 1.15–22.5), but in multigravidas and for preterm labor, the findings did not reach statistical significance (Table 2). The incidence of midtrimester loss was increased, but this finding was not significant (P = .068, RR 6.9, 95% CI 0.86–56). When smokers were compared with nonsmokers, within the threatened miscarriage group, there were no differences in the incidence of preterm labor or PPROM.
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The gestation at presentation with vaginal bleeding and an intrauterine hematoma were compared between the groups. Pregnancies that ended in a first-trimester miscarriage presented at a significantly earlier gestation than those that continued on to a preterm or term birth (P = .004 and P = .003, respectively). When gestation at maximal hematoma volumes for each pregnancy were compared, those that ended with first-trimester miscarriage reached maximal volume significantly earlier than term births (P = .001). Pregnancies ending in preterm birth reached maximal hematoma volume significantly later than term births (P < .001). Intrauterine hematoma volumes were divided into 5 groups: 1 mL or less, 1–5 mL, 5–10 mL, 10–50 mL and more than 50 mL. There were no significant differences between the groups in terms of the live birth, preterm labor, PPROM, or late miscarriage rates.
The incidence of preeclampsia was similar between the cases and controls (P = .47), as was abruption (P = .22) and placenta previa (P = .1). There were no significant differences in the number of congenital abnormalities between the groups.
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DISCUSSION |
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Although the mean birth weight in the threatened miscarriage group was lower than in the controls, it did not reach statistical significance. This lack of a significant difference between cases and controls may be explained by the fact that the preterm deliveries occurred mainly between 34 and 36 weeks of gestation. The women in the threatened miscarriage group were more likely to deliver babies between 1,500 g and 2,000 g; however, births at earlier gestations and therefore at lower weights were few in this population. Birth at these gestations is considered to carry significantly lower risk of neonatal mortality and morbidity than earlier gestations. Babies born at this gestation rarely require neonatal intensive care, but they still carry an increased risk of neonatal and infant mortality and morbidity compared with babies born after 37 weeks. A large study10 examining the effect of birth weight on developmental delay estimated that the risk of delay is directly related to weight at birth. The additional health care costs for the care of these infants, both in the neonatal period and in the first year of life are also significantly higher than their term counterparts,12,13 and it has been estimated that births between 34 and 37 weeks gestation contribute an excess cost of almost $50 million per annum in the United States.13
Several studies have reported an association between first-trimester bleeding and abnormal pregnancy outcome, including preterm deliveries,3,4,7,14,15 fetal growth restriction,4,7,14,15 and low birth weight,4,7,14,15 but the majority of these reports, are retrospective, are uncontrolled, or rely on patient recall recruiting later in the pregnancy. The largest study was conducted by Weiss et al4 and concluded that first-trimester bleeding was an independent risk factor for adverse obstetric outcome. The investigators recruited women at 10–14 weeks and divided women into subsets based on whether there was a history of bleeding in the 4 weeks before enrollment. The spontaneous pregnancy loss rates before 24 weeks in both the cases and controls were extremely low in their study and may be explained by the later recruitment of the cases, when many of the early miscarriages will have already occurred. In the current prospective study we have been able to identify women early in pregnancy and follow them from the time of the first bleeding episode until completion of their pregnancy. We have confirmed the findings of our previous study3 and in addition confirm the literature suggesting that the mechanism of preterm labor in many of these cases is PPROM. The literature on early pregnancy loss rates after threatened miscarriage is variable. In the present study, where the mean gestation at presentation was 8 weeks, the early loss rate was 9.3%, which is similar to that reported before 8 weeks of gestation.16 Studies conducted later in the first trimester have reported considerably lower loss rates, particularly after 10 weeks of gestation.1,4,17
The data presented suggest that bleeding between the chorionic membrane and the uterine wall can result in a spectrum of effects on pregnancy development and outcome. At one end, direct pressure and disruption of the placental bed results in miscarriage. At the other end of the spectrum is PPROM, where there is minimal or no disruption to uteroplacental development but a chronic inflammatory reaction within the decidua and placental membranes, with weakening and eventual rupture of the membranes.
A possible mechanism for the eventual membrane rupture could involve increased free radical production within the placental membranes as a result of the first-trimester insult. Subchorionic bleeding will result in an increase in the amount of free iron available, catalyzing the generation of the extremely damaging hydroxyl radical and subsequent free radical damage to the membranes. There is good in vitro evidence for increased oxidative stress in PPROM, and vitamin C (a powerful antioxidant) has been shown to be involved in several biochemical processes in collagen synthesis and maintenance, which is vital to the strength of the placental membranes.18,19 Vitamin E (an essential lipid-soluble antioxidant) is concentrated in the syncytiotrophoblast brush border in early pregnancy20 and seems to play an active role in early pregnancy development.21
Identifying women who are at "high risk" for preterm labor is imprecise, and screening strategies have included screening for bacterial vaginosis and biophysical markers, such as cervical length and fetal fibronectin. Many of these strategies depend heavily on a past history of preterm birth22 or concentrate on correct diagnosis of women who already present with symptoms of preterm labor22 and therefore do not identify all women who are at risk.
Development of interventions, such as progesterone23 and antioxidant supplementation, clearly require further investigation; however, identification of women at risk would allow such interventions to be implemented from a much earlier gestation. The data presented in this paper are probably more important for their role in raising awareness among health care professionals and women alike that they may be at increased risk of preterm labor or PPROM. Increased antenatal surveillance, possibly with cervical length measurements or the use of fetal fibronectin tests, might identify women within this group who are at increased risk. This would result in a higher index of suspicion in women presenting with symptoms later in pregnancy, enabling prompt identification of these complications should they occur. Knowledge of this increased risk may also facilitate decision making regarding management, for example, timely administration of antibiotics and corticosteroids or decisions regarding mode, place, and timing of delivery, which will inevitably improve neonatal outcome.
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Footnotes |
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Funded by the Early Pregnancy Research Fund (University College London Hospital charity).
Corresponding author: Jemma Johns, Academic Department of Obstetrics and Gynaecology, University College London Medical School, 86-96 Chenies Mews, London WC1E 6HX, United Kingdom; e-mail: j.johns{at}ucl.ac.uk.
doi:10.1097/01.AOG.0000206186.91335.9a
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REFERENCES |
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2. Babb P. Birth statistics 1993. Popul Trends 1995;79:31–3.
3. Johns J, Hyett J, Jauniaux E. Obstetric outcome after threatened miscarriage with and without a hematoma on ultrasound. Obstet Gynecol 2003;102:483–7.
4. Weiss JL, Malone FD, Vidaver J, Ball RH, Nyberg DA, Comstock CH, et al. Threatened abortion: a risk factor for poor pregnancy outcome, a population-based screening study. Am J Obstet Gynecol 2004;190:745–50.[Medline]
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16. Bennett GL, Bromley B, Lieberman E, Benacerraf BR. Subchorionic hemorrhage in first-trimester pregnancies: prediction of pregnancy outcome with sonography. Radiology 1996;200:803–6.
17. Williams MA, Mittendorf R, Lieberman E, Monson RR. Adverse infant outcomes associated with first-trimester vaginal bleeding. Obstet Gynecol 1991;78:14–8.
18. Chojkier M, Houglum K, Solis-Herruzo J, Brenner DA. Stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts: a role for lipid peroxidation? J Biol Chem 1989;264:16957–62.
19. Plessinger MA, Woods JR Jr, Miller RK. Pretreatment of human amnion-chorion with vitamins C and E prevents hypochlorous acid-induced damage. Am J Obstet Gynecol 2000;183:979–85.[Medline]
20. Qanungo S, Mukherjea M. Ontogenic profile of some antioxidants and lipid peroxidation in human placental and fetal tissues. Mol Cell Biochem 2000;215:11–9.[Medline]
21. Jauniaux E, Cindrova-Davies T, Johns J, Dunster C, Hempstock J, Kelly FJ, et al. Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestational sac. J Clin Endocrinol Metab 2004;89:1452–8.
22. Iams JD. Prediction and early detection of preterm labor. Obstet Gynecol 2003;101:402–12.
23. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419–24.[Medline]
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