Threatened miscarriage: evaluation and management
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《英国医生杂志》
1 Department of Obstetrics and Gynaecology, University Hospital of Ioannina, 45500 Ioannina, Greece, 2 Delvinaki Health Centre, Delvinaki, Ioannina, Greece
Correspondence to: A Sotiriadis asotir@cc.uoi.gr
Introduction
Doctors often prescribe bed rest and progesterone for women with symptoms of threatened miscarriage, but evidence is sparse and of low level (table 2).
Table 2 Pregnancy outcome in studies with various therapeutic regimens
Bed rest
In one study, 1228 out of 1279 (96%) general practitioners prescribed bed rest for heavy bleeding in early pregnancy, although only an eighth of them felt it was mandatory, and only one third felt it could affect outcome.3 Only one randomised controlled trial considers the impact of bed rest on the course of threatened miscarriage22; 61 women with viable pregnancies at less than eight gestational weeks and vaginal bleeding were randomly allocated into either injections of hCG, injections of placebo, or bed rest. The abortion rates in the three groups were 30%, 48%, and 75%—significant differences between hCG and bed rest groups but not between hCG and placebo groups or between placebo and bed rest groups. Although hCG performed significantly better than bed rest in this study, the lack of profound benefit over placebo, the concern about potential development of ovarian hyperstimulation syndrome, and the fact that threatened miscarriage may be the result of various conditions, irrelevant to luteal function, prevented further testing and application of hCG treatment in general obstetric practice.
In a retrospective study of 226 women who were hospitalised for reasons related to their pregnancy and previous threatened miscarriage, 16% of 146 women who were bed resting eventually miscarried, compared with a fifth of women who did not follow this option (not significant; P = 0.41).23 In contrast, a recent observational cohort study of 230 women with threatened miscarriage who were recommended bed rest showed that women who adhered to this suggestion had a miscarriage rate of 9.9%, compared with 23.3% of women who continued their usual activities (P = 0.03).24 The duration of vaginal bleeding, haematoma size and gestational age at diagnosis did not influence miscarriage rate. Although there is no definite evidence that bed rest can affect the course of pregnancy, abstinence from active environment for a couple of days may help women feel safer,w10 thus providing emotional relief.
Progesterone
Progesterone is prescribed in 13-40% of women with threatened miscarriage, according to published series.3 w2 Progesterone is the main product of the corpus luteum, and giving progestogen is expected to support a potentially deficient corpus luteum gravidarum and induce relaxation of a cramping uterus. The evidence on progesterone is of low quality. Recently, a meta-analysis assessed the impact of progesterone supplementation on miscarriage rate in various clinical settings25; however, it did not provide a separate analysis for progesterone in threatened miscarriage. Four published papers in the meta-analysis were assessing this relationship,w11-w14 one of them including three different regimens of progestogen,w11 and those data were reanalysed. Having miscarriage as outcome, random effects risk ratio was 1.10 (95% confidence interval 0.92 to 1.31) for progestogens group. In the only studies that provided sonographic evidence of fetal heart activity at presentation, the relative risk for miscarriage was 1.09 (90% confidence interval 0.90 to 1.33) for the progestogen group.w14 Thus, given the poor quality of the data, progesterone does not seem to improve outcome in women with threatened miscarriage. However, local application of a progestogen was found to subjectively decrease uterine cramping more rapidly than bed rest alone in one small study.w15
Other regimens
Buphenine hydrochloride (a vasodilator that is also used as a uterine muscle relaxant) was better than placebo in a randomised controlled trial. But the method of randomisation in this trial was unclear, and no other studies consider tocolysis in early threatened miscarriage.w16
Apart from its effectiveness, the extent of active support is generally questionable in cases of threatened miscarriage, since most pregnancies resulting in early fetal loss are chromosomally abnormal.w17
Rh prophylaxis
Vaginal bleeding in early pregnancy raises the question of whether to give anti-D immunoglobulin in Rh D negative women. Unfortunately, there are no conclusive data on this topic, and all evidence comes from expert or panel opinions (level C). According to the guidelines of the Royal College of Obstetricians and Gynecologists and the American College of Obstetricians and Gynaecologists, although Rh D alloimmunisation attributable to first trimester threatened miscarriage is rare, giving anti-D globulin should be considered for non-sensitised Rh D negative women with a threatened miscarriage after 12 weeks of pregnancy, or in cases of heavy or repeated bleeding or where there is associated abdominal pain, particularly as gestation approaches 12 weeks.w18 w19 In contrast, anti-D Ig is not considered necessary in women with threatened miscarriage with a viable fetus and cessation of bleeding before 12 weeks' gestation.w19
Additional educational resources
Websites for doctors
www.update-software.com/Cochrane—The home page of Cochrane Library, where registered users can reach a large number of meta-analyses of therapeutic interventions in obstetrics
www.rcog.org.uk/mainpages.asp?SectionID=5—The good practice page of the Royal College of Obstetricians and Gynaecologists has many evidence based clinical guidelines of obstetric interest, including that on Rhesus prophylaxis
www.earlypregnancy.com—Page of the Special Interest Group Early Pregnancy of ESHRE including useful links and updated scientific information on early pregnancy
Websites for patients
http://health.allrefer.com/health/abortion-threatened.html—Gives information on several health issues; an introduction to threatened miscarriage and miscarriage
www.emedicine.com/med/topic3308.htm—Gives useful information on threatened miscarriage and miscarriage; suitable for doctors and patients
Conclusions
Makrydimas G, Sebire NJ, Lolis D, Vlassis N, Nicolaides KH. Fetal loss following ultrasound diagnosis of a live fetus at 6-10 weeks of gestation. Ultrasound Obstet Gynecol 2003;22: 368-72.
Johns J, Hyett J, Jauniaux E. Obstetric outcome after threatened miscarriage with and without a hematoma on ultrasound. Obstet Gynecol 2003;102: 483-7.
Everett C, Ashurst H, Chalmers I. Reported management of threatened miscarriage by general practitioners in Wessex. BMJ 1987;295: 583-6.
Falco P, Milano V, Pilu G, David C, Grisolia G, Rizzo N, Bovicelli L. Sonography of pregnancies with first-trimester bleeding and a viable embryo: a study of prognostic indicators by logistic regression analysis. Ultrasound Obstet Gynecol 1996;7: 165-9.
Falco P, Zagonari S, Gabrielli S, Bevini M, Pilu G, Bovicelli L. Sonography of pregnancies with first-trimester bleeding and a small intrauterine gestational sac without a demonstrable embryo. Ultrasound Obstet Gynecol 2003;21: 62-5.
Tongsong T, Wanapirak C, Srisomboon J, Sirichotiyakul S, Polsrisuthikul T, Pongsatha S. Transvaginal ultrasound in threatened abortions with empty gestational sacs. Int J Gynaecol Obstet 1994;46: 297-301.
Tongsong T, Srisomboon J, Wanapirak C, Sirichotiyakul S, Pongsatha S, Polsrisuthikul T. Pregnancy outcome of threatened abortion with demonstrable fetal cardiac activity: a cohort study. J Obstet Gynaecol 1995;21: 331-5.
Tannirandorn Y, Sangsawang S, Manotaya S, Uerpairojkit B, Samritpradit P, Charoenvidhya D. Fetal loss in threatened abortion after embryonic/fetal heart activity. Int J Gynaecol Obstet 2003;81: 263-6.
Everett CB, Preece E. Women with bleeding in the first 20 weeks of pregnancy: value of general practice ultrasound in detecting fetal heart movement. Br J Gen Pract 1996;46: 7-9.
La Marca A, Morgante G, De Leo V. Human chorionic gonadotrophin, thyroid function, and immunological indices in threatened abortion. Obstet Gynecol 1998;92: 206-11.
al-Sebai MA, Diver M, Hipkin LJ. The role of a single free beta-human chorionic gonadotrophin measurement in the diagnosis of early pregnancy failure and the prognosis of fetal viability. Hum Reprod 1996;11: 881-8.
Reljic M. The significance of crown-rump length measurement for predicting adverse pregnancy outcome of threatened abortion. Ultrasound Obstet Gynecol 2001;17: 510-2.
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.
Pedersen JF, Mantoni M. Prevalence and significance of subchorionic hemorrhage in threatened abortion: a sonographic study. Am J Roentgenol 1990;154: 535-7.
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.
Nagy S, Bush M, Stone J, Lapinski RH, Gardo S. Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy. Obstet Gynecol 2003;102: 94-100.
al-Sebai MA, Kingsland CR, Diver M, Hipkin L, McFadyen IR. The role of a single progesterone measurement in the diagnosis of early pregnancy failure and the prognosis of fetal viability. Br J Obstet Gynaecol 1995;102: 364-9.
Florio P, Luisi S, D'Antona D, Severi FM, Rago G, Petraglia F. Maternal serum inhibin A levels may predict pregnancy outcome in women with threatened abortion. Fertil Steril 2004;81: 468-70.
Schmidt T, Rein DT, Foth D, Eibach HW, Kurbacher CM, Mallmann P, et al. Prognostic value of repeated serum CA 125 measurements in first trimester pregnancy. Eur J Obstet Gynecol Reprod Biol 2001;97: 168-73.
Fiegler P, Katz M, Kaminski K, Rudol G. Clinical value of a single serum CA-125 level in women with symptoms of imminent abortion during the first trimester of pregnancy. J Reprod Med 2003;48: 982-8.
Ruge S, Pedersen JF, Sorensen S, Lange AP. Can pregnancy-associated plasma protein A (PAPP-A) predict the outcome of pregnancy in women with threatened abortion and confirmed fetal viability? Acta Obstet Gynecol Scand 1990;69: 589-95.
Harrison RF. A comparative study of human chorionic gonadotropin, placebo, and bed rest for women with early threatened abortion. Int J Fertil Menopausal Stud 1993;38: 160-5.
Giobbe M, Fazzio M, Boni T. . Minerva Ginecol 2001;53: 337-40.
Ben-Haroush A, Yogev Y, Mashiach R, Meizner I. Pregnancy outcome of threatened abortion with subchorionic hematoma: possible benefit of bed-rest? Isr Med Assoc J 2003;5: 422-4.
Oates-Whitehead RM, Haas DM, Carrier JAK. Progestogen for preventing miscarriage. In: Cochrane Library. Chichester: Wiley, 2003. (Issue 4.)(Alexandros Sotiriadis, re)
Correspondence to: A Sotiriadis asotir@cc.uoi.gr
Introduction
Doctors often prescribe bed rest and progesterone for women with symptoms of threatened miscarriage, but evidence is sparse and of low level (table 2).
Table 2 Pregnancy outcome in studies with various therapeutic regimens
Bed rest
In one study, 1228 out of 1279 (96%) general practitioners prescribed bed rest for heavy bleeding in early pregnancy, although only an eighth of them felt it was mandatory, and only one third felt it could affect outcome.3 Only one randomised controlled trial considers the impact of bed rest on the course of threatened miscarriage22; 61 women with viable pregnancies at less than eight gestational weeks and vaginal bleeding were randomly allocated into either injections of hCG, injections of placebo, or bed rest. The abortion rates in the three groups were 30%, 48%, and 75%—significant differences between hCG and bed rest groups but not between hCG and placebo groups or between placebo and bed rest groups. Although hCG performed significantly better than bed rest in this study, the lack of profound benefit over placebo, the concern about potential development of ovarian hyperstimulation syndrome, and the fact that threatened miscarriage may be the result of various conditions, irrelevant to luteal function, prevented further testing and application of hCG treatment in general obstetric practice.
In a retrospective study of 226 women who were hospitalised for reasons related to their pregnancy and previous threatened miscarriage, 16% of 146 women who were bed resting eventually miscarried, compared with a fifth of women who did not follow this option (not significant; P = 0.41).23 In contrast, a recent observational cohort study of 230 women with threatened miscarriage who were recommended bed rest showed that women who adhered to this suggestion had a miscarriage rate of 9.9%, compared with 23.3% of women who continued their usual activities (P = 0.03).24 The duration of vaginal bleeding, haematoma size and gestational age at diagnosis did not influence miscarriage rate. Although there is no definite evidence that bed rest can affect the course of pregnancy, abstinence from active environment for a couple of days may help women feel safer,w10 thus providing emotional relief.
Progesterone
Progesterone is prescribed in 13-40% of women with threatened miscarriage, according to published series.3 w2 Progesterone is the main product of the corpus luteum, and giving progestogen is expected to support a potentially deficient corpus luteum gravidarum and induce relaxation of a cramping uterus. The evidence on progesterone is of low quality. Recently, a meta-analysis assessed the impact of progesterone supplementation on miscarriage rate in various clinical settings25; however, it did not provide a separate analysis for progesterone in threatened miscarriage. Four published papers in the meta-analysis were assessing this relationship,w11-w14 one of them including three different regimens of progestogen,w11 and those data were reanalysed. Having miscarriage as outcome, random effects risk ratio was 1.10 (95% confidence interval 0.92 to 1.31) for progestogens group. In the only studies that provided sonographic evidence of fetal heart activity at presentation, the relative risk for miscarriage was 1.09 (90% confidence interval 0.90 to 1.33) for the progestogen group.w14 Thus, given the poor quality of the data, progesterone does not seem to improve outcome in women with threatened miscarriage. However, local application of a progestogen was found to subjectively decrease uterine cramping more rapidly than bed rest alone in one small study.w15
Other regimens
Buphenine hydrochloride (a vasodilator that is also used as a uterine muscle relaxant) was better than placebo in a randomised controlled trial. But the method of randomisation in this trial was unclear, and no other studies consider tocolysis in early threatened miscarriage.w16
Apart from its effectiveness, the extent of active support is generally questionable in cases of threatened miscarriage, since most pregnancies resulting in early fetal loss are chromosomally abnormal.w17
Rh prophylaxis
Vaginal bleeding in early pregnancy raises the question of whether to give anti-D immunoglobulin in Rh D negative women. Unfortunately, there are no conclusive data on this topic, and all evidence comes from expert or panel opinions (level C). According to the guidelines of the Royal College of Obstetricians and Gynecologists and the American College of Obstetricians and Gynaecologists, although Rh D alloimmunisation attributable to first trimester threatened miscarriage is rare, giving anti-D globulin should be considered for non-sensitised Rh D negative women with a threatened miscarriage after 12 weeks of pregnancy, or in cases of heavy or repeated bleeding or where there is associated abdominal pain, particularly as gestation approaches 12 weeks.w18 w19 In contrast, anti-D Ig is not considered necessary in women with threatened miscarriage with a viable fetus and cessation of bleeding before 12 weeks' gestation.w19
Additional educational resources
Websites for doctors
www.update-software.com/Cochrane—The home page of Cochrane Library, where registered users can reach a large number of meta-analyses of therapeutic interventions in obstetrics
www.rcog.org.uk/mainpages.asp?SectionID=5—The good practice page of the Royal College of Obstetricians and Gynaecologists has many evidence based clinical guidelines of obstetric interest, including that on Rhesus prophylaxis
www.earlypregnancy.com—Page of the Special Interest Group Early Pregnancy of ESHRE including useful links and updated scientific information on early pregnancy
Websites for patients
http://health.allrefer.com/health/abortion-threatened.html—Gives information on several health issues; an introduction to threatened miscarriage and miscarriage
www.emedicine.com/med/topic3308.htm—Gives useful information on threatened miscarriage and miscarriage; suitable for doctors and patients
Conclusions
Makrydimas G, Sebire NJ, Lolis D, Vlassis N, Nicolaides KH. Fetal loss following ultrasound diagnosis of a live fetus at 6-10 weeks of gestation. Ultrasound Obstet Gynecol 2003;22: 368-72.
Johns J, Hyett J, Jauniaux E. Obstetric outcome after threatened miscarriage with and without a hematoma on ultrasound. Obstet Gynecol 2003;102: 483-7.
Everett C, Ashurst H, Chalmers I. Reported management of threatened miscarriage by general practitioners in Wessex. BMJ 1987;295: 583-6.
Falco P, Milano V, Pilu G, David C, Grisolia G, Rizzo N, Bovicelli L. Sonography of pregnancies with first-trimester bleeding and a viable embryo: a study of prognostic indicators by logistic regression analysis. Ultrasound Obstet Gynecol 1996;7: 165-9.
Falco P, Zagonari S, Gabrielli S, Bevini M, Pilu G, Bovicelli L. Sonography of pregnancies with first-trimester bleeding and a small intrauterine gestational sac without a demonstrable embryo. Ultrasound Obstet Gynecol 2003;21: 62-5.
Tongsong T, Wanapirak C, Srisomboon J, Sirichotiyakul S, Polsrisuthikul T, Pongsatha S. Transvaginal ultrasound in threatened abortions with empty gestational sacs. Int J Gynaecol Obstet 1994;46: 297-301.
Tongsong T, Srisomboon J, Wanapirak C, Sirichotiyakul S, Pongsatha S, Polsrisuthikul T. Pregnancy outcome of threatened abortion with demonstrable fetal cardiac activity: a cohort study. J Obstet Gynaecol 1995;21: 331-5.
Tannirandorn Y, Sangsawang S, Manotaya S, Uerpairojkit B, Samritpradit P, Charoenvidhya D. Fetal loss in threatened abortion after embryonic/fetal heart activity. Int J Gynaecol Obstet 2003;81: 263-6.
Everett CB, Preece E. Women with bleeding in the first 20 weeks of pregnancy: value of general practice ultrasound in detecting fetal heart movement. Br J Gen Pract 1996;46: 7-9.
La Marca A, Morgante G, De Leo V. Human chorionic gonadotrophin, thyroid function, and immunological indices in threatened abortion. Obstet Gynecol 1998;92: 206-11.
al-Sebai MA, Diver M, Hipkin LJ. The role of a single free beta-human chorionic gonadotrophin measurement in the diagnosis of early pregnancy failure and the prognosis of fetal viability. Hum Reprod 1996;11: 881-8.
Reljic M. The significance of crown-rump length measurement for predicting adverse pregnancy outcome of threatened abortion. Ultrasound Obstet Gynecol 2001;17: 510-2.
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.
Pedersen JF, Mantoni M. Prevalence and significance of subchorionic hemorrhage in threatened abortion: a sonographic study. Am J Roentgenol 1990;154: 535-7.
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.
Nagy S, Bush M, Stone J, Lapinski RH, Gardo S. Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy. Obstet Gynecol 2003;102: 94-100.
al-Sebai MA, Kingsland CR, Diver M, Hipkin L, McFadyen IR. The role of a single progesterone measurement in the diagnosis of early pregnancy failure and the prognosis of fetal viability. Br J Obstet Gynaecol 1995;102: 364-9.
Florio P, Luisi S, D'Antona D, Severi FM, Rago G, Petraglia F. Maternal serum inhibin A levels may predict pregnancy outcome in women with threatened abortion. Fertil Steril 2004;81: 468-70.
Schmidt T, Rein DT, Foth D, Eibach HW, Kurbacher CM, Mallmann P, et al. Prognostic value of repeated serum CA 125 measurements in first trimester pregnancy. Eur J Obstet Gynecol Reprod Biol 2001;97: 168-73.
Fiegler P, Katz M, Kaminski K, Rudol G. Clinical value of a single serum CA-125 level in women with symptoms of imminent abortion during the first trimester of pregnancy. J Reprod Med 2003;48: 982-8.
Ruge S, Pedersen JF, Sorensen S, Lange AP. Can pregnancy-associated plasma protein A (PAPP-A) predict the outcome of pregnancy in women with threatened abortion and confirmed fetal viability? Acta Obstet Gynecol Scand 1990;69: 589-95.
Harrison RF. A comparative study of human chorionic gonadotropin, placebo, and bed rest for women with early threatened abortion. Int J Fertil Menopausal Stud 1993;38: 160-5.
Giobbe M, Fazzio M, Boni T. . Minerva Ginecol 2001;53: 337-40.
Ben-Haroush A, Yogev Y, Mashiach R, Meizner I. Pregnancy outcome of threatened abortion with subchorionic hematoma: possible benefit of bed-rest? Isr Med Assoc J 2003;5: 422-4.
Oates-Whitehead RM, Haas DM, Carrier JAK. Progestogen for preventing miscarriage. In: Cochrane Library. Chichester: Wiley, 2003. (Issue 4.)(Alexandros Sotiriadis, re)