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Dydrogesterone in threatened abortion: Pregnancy outcome
Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425
Dydrogesterone in threatened abortion: Pregnancy outcome M.H. Omar ∗ , M.K. Mashita, P.S. Lim, M.A. Jamil Department of Obstetrics and Gynaecology, University Kebangsaan, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia
Abstract Objective: To determine whether therapy with dydrogesterone in threatened abortion during the first trimester of pregnancy will improve pregnancy outcome. Design: Prospective open study. Subjects: Pregnant women presenting to the obstetric and gynaecology clinic admitting center with vaginal bleeding before 13 weeks gestation were evaluated for entry into the study. Women were excluded if they had a history of recurrent miscarriage. Method: Eligible subjects were randomized to receive either dydrogesterone 40 mg stat dose followed by 10 mg twice a day for one week or conservative therapy. Results: One hundred and 54 women were recruited. There was no statistically significant differences between the two groups with regard to pre-treatment status. The continuing pregnancy success rate was significantly (p = 0.037) higher in women treated with dydrogesterone (95.9%) compared with women who received conservative treatment (86.3%). The odds ratio of the success rate between dydrogesterone treatment and non-treatment was 3.773 (95% confidence interval: 1.009–14.108). Conclusion: Corpus luteal support with dydrogesterone has been shown to reduce the incidence of pregnancy loss in threatened abortion during the first trimester in women without a history of recurrent abortion. © 2005 Elsevier Ltd. All rights reserved. Keywords: Dydrogesterone; Threatened abortion; Pregnancy; Luteal support
1. Introduction Threatened abortion is associated with bleeding and/or uterine cramping while the cervix is closed. This stage of abortion may progress to spontaneous incomplete or complete abortion. While this event may be considered a part of the quality control process in human reproduction, it is important to know the possible etiologies and when therapy might prevent pregnancy loss. No one disputes the crucial role that progesterone plays in the maintenance of pregnancy [1]. Whether this is via the inhibition of oxytocin-induced myometrial activity [1,2] or through inhibition of prostaglandin excitation [3,4] is less clear. Studies have proven that progestogen treatment of miscarriage in early pregnancy is no more effective than placebo. Even so, progestogens have been prescribed for over 30 years ∗
Corresponding author. Fax: +603 91738946. E-mail address: [email protected] (M.H. Omar).
0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.08.013
by clinicians world-wide in the belief that they reduce the risk of pregnancy failure, in particular first trimester miscarriage. However, there is a lack of firm evidence from prospective controlled trials that any type of hormonal ‘deficiency’ is the cause of spontaneous abortion, so the value of giving progesterone [5] remains to be proven. In an attempt to derive an accurate assessment of the value of progestogens, a number of meta-analysis reviews have been undertaken. In 1989, Goldstein et al. [6] published a meta-analysis of randomized controlled trials of ‘progestational agents in pregnancy’, and concluded that progesterone and its analogues are ineffective in the maintenance of pregnancy. Keirse [7] conducted another more restricted meta-analysis involving the use of a single progestogenic agent, i.e.17 ␣-hydroxyprogesterone acetate. He concluded that there is no evidence from controlled trials to justify the clinical use of any progestational agent to prevent miscarriage. The difficulty in arriving at a consensus view concerning the usefulness of progestogens to prevent miscarriage does
M.H. Omar et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425
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not result from paucity of experimentation, but from several confounding variables, such as: 1. Progestogens encompass a wide range of synthetic progesterone-like hormones. 2. Different entry criteria, different doses and different routes of administration. 3. Most of the published (and unpublished) work was undertaken before it was possible to confirm a viable pregnancy using ultrasound and endocrinological assays. As a result, it is possible that progestogens do actually confer some protection from miscarriage, but it has not been revealed by these studies and reviews. 4. None of the studies demonstrated abnormal low-level serum progesterone before recruitment. 5. Most of the studies were too small to rule out or reveal a clinically important benefit. In the current study, we used dydrogesterone (Duphaston), a retro progesterone with a very good oral bioavailability. It is structurally and pharmacologically very similar to natural progesterone, has selective progestational activity in humans, and is a non-luteolysis and non-thermogenic agent. The objective of the study was to determine whether dydrogesterone therapy for threatened abortion in the first trimester will improve pregnancy outcome and, specifically, to evaluate the effectiveness of dydrogesterone in allowing the pregnancy to continue successfully beyond 20 weeks gestation.
until the bleeding stopped. They were also recommended bed rest and received folic acid. The control group comprised patients who were managed conservatively with bed rest and folic acid only. The patients were also advised to avoid sexual intercourse. The subjects were followed up until 20 weeks gestation. Relevant data were collected from each case file regarding maternal age, race, estimated gestational age at entry, parity and medication history. Other information included the severity of symptoms and ultrasound findings. Treatment was considered successful if the women carried the pregnancy beyond 20 weeks gestation. 2.3. Statistical analyses All data obtained was analyzed using the Chi-square test. The test was considered significant if the p-value was <0.05. For the purpose of this study, the following definitions were used [8]: 1. Miscarriage: this was defined as spontaneous loss of an intrauterine pregnancy at ≤ 20 weeks gestation, calculated from the first day of the last menstrual period. 2. Recurrent miscarriage: this was defined as three or more consecutive miscarriages. 3. Continuing pregnancy: this was defined as an intrauterine pregnancy that had advanced beyond 20 weeks gestation.
2. Methods 2.1. Design
3. Results
This prospective open study was conducted between 1 March 2002 and 28 February 2004.
During the 2 year study period, a total of 678 women presented with bleeding within the first 20 weeks of gestation. Of these, 205 were diagnosed at the first visit as having threatened abortion at less than 13 weeks gestation and were without a history of recurrent abortion. Therefore, the actual prevalence of threatened abortion in the first trimester was only 30.2%. After reviewing the notes of these 205 cases, only 194 showed foetal viability with the correct size for the dates confirmed by ultrasound according to the inclusion criteria. However, 40 (20.6%) of these patients defaulted during follow-up. Thus, 154 patients (74 in the dydrogesterone group and 80 in the control group) were eligible for comparison. The majority of the patients were young (<30 years old) (Fig. 1); only 32 patients (20.7%) were ≥35 years old. The majority were in their first or second pregnancy (66.8%) and most presented around the eighth gestational week. There were no significant differences between the groups with respect to mean maternal age, gravida and gestational age (Table 1). Even though Malays formed the largest group, the numbers of patients from the three different races were equally distributed in both groups with no statistically significant differences between them (p = 0.842).
2.2. Patient sample The registration records of all pregnant women who presented to the Obstetric and Gynecology Admitting Center (OGAC) with vaginal bleeding before 20 weeks gestation were evaluated. Patients were included if they had the following criteria: 1. 2. 3. 4. 5. 6. 7.
Mild or moderate vaginal bleeding No history of loss of conception material Absence of systemic illness or fever Normal size and shape gestation sac at 5 weeks Presence of yolk sac at 5–6 weeks Presence of fetal heart at 7 weeks Gestational age less than 13 weeks Patients were excluded from the study if they had:
1. Empty sac of more than 26 mm 2. History of recurrent miscarriage The treatment group comprised patients who received dydrogesterone 40 mg stat, followed by 10 mg twice a day
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3.1. Vaginal bleeding Sixty-six patients (42.9%) presented with vaginal bleeding, out of whom 29 (43.9%) were from the dydrogesterone group and 37 (56.1%) were from the control group. The successful pregnancy outcome at 20 weeks in the dydrogesterone group was 93.1% compared with 83.8% in the control group; this difference was not statistically significant. 3.2. Vaginal spotting Eighty-eight patients (57.1%) presented with per vaginal spotting, out of whom 45 (51.1%) were in the dydrogesterone group and 43 (48.9%) were in the control group. The successful pregnancy outcome at 20 weeks was 97.8% in the dydrogesterone group compared with 88.4% in the control group; this difference was not statistically significant.
Fig. 1. Age distribution amongst the patients (n = 154). Table 1 Baseline characteristics Dydrogesterone (n = 74)
Control (n = 80)
p-value
Race (n) Malay Chinese Indian Others
42 25 5 2
49 22 7 2
0.842
Mean age (years) Mean gravida (n) Mean gestation (weeks)
30 2.5 8.4
29 2.4 8.5
0.225 0.880 0.896
3.3. Foetal heart activity
Of the 154 patients enrolled, 14 had a miscarriage (3 in the dydrogesterone group and 11 in the control group); this difference between the groups was statistically significant (p = 0.037) (Table 2). All 14 patients required evacuation. The odds ratio indicated a preference for dydrogesterone treatment, although the 95% confidence interval (CI) was very wide. The baseline characteristics and ultrasound findings in relation to success rate are summarised in Table 3.
The majority (61%) of the patients (n = 94) had demonstrable viability of the pregnancy at the time of presentation as shown by the presence of foetal heart activity. The successful pregnancy outcome at 20 weeks in the dydrogesterone group was 97.8% compared with 91.8% in the control group; this difference was not statistically significant for the presence of foetal heart activity alone. 3.4. Presence of yolk sac In the presence of yolk sacs (n = 77), only 2 miscarriages occurred, both of which were in the control group. The successful pregnancy outcome at 20 weeks in the dydrogesterone group was therefore 100% compared with 95.1% in the control group; this difference was not statistically significant.
Table 2 Effect of dydrogesterone or control treatment on the continuing pregnancy rate Continuing pregnancy
Dydrogesterone (n = 74) Control (n = 80)
Yes
No
71 (95.9%) 69 (86.3%)
3 (4.1%) 11 (13.8%)
p-value
Odds ratio
95% CI
0.037
3.773
1.009–14.108
CI: confidence interval. Table 3 Presenting symptoms and ultrasound findings in relation to success rate: total group (dydrogesterone/control groups)
Vaginal bleeding Vaginal spotting Foetal heart activity Presence of yolk sac Regular IUGS Foetal heart activity + presence of yolk sac IUGS: intrauterine gestational sac.
Success (n)
Miscarriage (n)
%
p-value (dydrogesterone versus control)
66 (29/37) 88 (45/43) 65 (31/34) 48 (23/25) 12 (7/5) 29 (13/16)
8 (2/6) 6 (1/5) 4 (1/3) 1 (0/1) 5 (2/3) 1 (0/1)
12.1 (6.9/16.2) 6.8 (2.2/11.6) 6.2 (3.2/8.8) 2.1 (0/4) 41.7 (28.6/60) 3.4 (0/6.3)
0.250 0.106 0.615 1.000 0.558 1.000
424
M.H. Omar et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425
3.5. Regular intrauterine gestational sac The highest proportion of miscarriages occurred in the group with only a regular gestational sac at the time of presentation. This might be due to the fact that the presence of a regular gestational sac at the time of presentation was not absolutely representative of a viable pregnancy, but rather of an early missed miscarriage or a blighted ovum, both of which are difficult to exclude.
4. Discussion Vaginal bleeding complicates 20% of diagnosed pregnancies [9]. About 15% of all clinically recognized pregnancies end in spontaneous miscarriage [10] and 75% of the losses occur in the first eight weeks of gestation. However, after a viable foetus has been detected with ultrasound in the tenth week of an uncomplicated pregnancy, the reported loss is only 2–6% [11,12]. In threatened miscarriage with a viable foetus, only 12% will end in miscarriage [13]. In this study, the prevalence of miscarriage in pregnancies with a viable foetus at five weeks gestation was 7.1%. In almost 60% of cases, the cause of foetal loss is related to a chromosomal disorder of the conceptus [14]. For most other cases, the causes are unknown, but some may be related to endocrine disorders. Laboratory studies have suggested that progesterone plays an important role in the maintenance of pregnancy, but clinical studies have not shown any beneficial effects of progestogens in early pregnancy [15,16], perhaps because of the limited role of this hormonal disorder in the aetiology of early miscarriage. Furthermore, there is no reliable method for selecting patients who might benefit from hormonal treatment. Although the precise role of progesterone is still debatable, further support for its therapeutic possibilities comes from the hormonal profile of women who experience recurrent miscarriage without any obvious non-hormonal aetiology. In addition, luteal phase defect has been shown to occur more frequently among women with recurrent miscarriage [17]. Because of this evidence, it is not unreasonable to suppose that treatment in very early pregnancy might have an effect on the risk of pregnancy failure. It is not surprising that progestogens have indeed been prescribed by many clinicians with just such aims in mind and a large number of trials, controlled and otherwise, have been undertaken to discover whether or not the supposed benefits were real. In this study, dydrogesterone was used and the aim was to see whether it improves pregnancy outcome in the treatment of threatened abortion in early pregnancy. The result of this study showed progestogens, administered to women with threatened miscarriage in the first trimester but without a history of recurrent miscarriage, to be beneficial in the maintenance of pregnancy beyond 20 weeks gestation. The pregnancy success rate, in terms of viable pregnancies at 20 weeks, was 95.9% in the women
who were treated with dydrogesterone and 86.3% in women who was treated conservatively; this difference was statistically significant (p = 0.037). In this study, almost equal numbers of patients achieved continuity of pregnancy following presentation with either vaginal bleeding (93.1% in the dydrogesterone group and 83.8% in the control group) or spotting (97.8% in the dydrogesterone group and 88.4% in the control group). Chung et al. [18] have shown that clinical assessment of threatened miscarriage is unreliable in most cases and should be superseded by an ultra-sonography assessment. A history of having passed a tissue mass, the presence of products of conception in the vagina and an open cervix were the only signs or symptoms associated with greater than a 90% chance that the pregnancy was non-viable. Patients with these signs or symptoms were excluded from this study. All patients in this study had the viability of their foetuses confirmed by ultrasound. With ultrasound, a correct diagnosis of the in-utero situation was reported to be made on admission in 93% of cases and this increased further after one week to 99% of cases [19]. In another study, a single examination with ultrasound alone provided a correct prognosis of the pregnancy in 78% of cases with threatened abortion [20]. Hormonal measurement is a complementary method that may confirm or refute the un-favorable prognosis. In addition, hormonal measurement may provide some insight as to the subsequent evolution of the threatened pregnancy, even in the presence of normal ultrasounds. In conclusion, treatment of first trimester threatened abortion (without a history of recurrent miscarriage) with dydrogesterone appeared to be efficacious in improving the chances of the pregnancy advancing beyond 20 weeks gestation. However, the study is not very powerful as the sample size was not sufficiently large and the 95% CI of the odds ratio was too wide. Further large randomized trials are needed to establish the role of dydrogesterone and to evaluate the impact of hormonal levels in first trimester threatened miscarriage. References [1] F. Fuch, A.R. Fuch, Induction and inhibition of labour in the rabbit, Acta Endocrinol. 26 (1958) 615–624. [2] A.L. Csapo, M.O. Pulkien, B. Ruttner, J.P. Sauvage, W.G. Wiest, The significance of the human corpus luteum in pregnancy maintenance, Am. J. Obstet. Gynecol. 112 (1972) 1061–1067. [3] A.L. Csapo, M.R. Henzi, H.L. Kaihola, Suppression of uterine activity and abortion by inhibition of prostaglandin synthesis, Prostaglandins 7 (1974) 39–47. [4] A.L. Csapo, Effects of progesterone, prostaglandin F and its analogue ICI 81008 on the excitability and threshold of the uterus, Am. J. Obstet. Gynecol. 124 (1976) 367–378. [5] A.J. Wilcox, C.R. Weinberg, R.E. Wehman, E.G. Armstrong, R.E. Canfield, B.C. Nisula, Measuring early pregnancy loss: laboratory and field methods, Fertil. Steril. 44 (1985) 366–374. [6] P. Goldstein, J. Berrier, S. Rosen, H.S. Sacks, T.C. Chalmers, A meta-analysis of randomized control trials of progestational agents in pregnancy, Br. J. Obstet. Gynecol. 96 (1989) 265–274.
M.H. Omar et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425 [7] M.J.N.C. Keirse, Progestogen administration in pregnancy may prevent preterm delivery, Br. J. Obstet. Gynecol. 97 (1990) 149–158. [8] S. Daya, Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials, Br. J. Obstet. Gynecol. 96 (1989) 275–280. [9] B.A. Strobino, J. Pantel-Silverman, First trimester vaginal bleeding and the loss of chromosomally normal and abnormal conceptions, Am. J. Obstet. Gynecol. 157 (1987) 1150–1154. [10] G.M. Stirrat, Recurrent abortion-a review (Commentary), Br. J. Obstet. Gynecol. 90 (1983) 881–883. [11] B. Gustavii, Chorionic biopsy and miscarriage in first trimester, Lancet I (1984) 562. [12] F.R. McFadyen, Missed abortion and later spontaneous abortion in pregnancies clinically normal at 7–12 weeks, Eur. J. Obstet. Gynecol. Reprod. Biol. 20 (1985) 381–384. [13] L.M. Hill, D. Guzick, J. Fries, J. Hixson, Fetal loss rate after ultrasonically documented cardiac activity between 6 and 14 weeks menstrual age, J. Clin. Ultrasound 19 (1990) 221–223. [14] J.G. Lauritsen, Etiology of spontaneous abortion, Acta Obstet. Gynecol. Scand. 52 (Suppl.) (1976) 24–29.
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[15] J.W. Goldzieher, Double-blind trial of a progestin in habitual abortion, JAMA 188 (1964) 651–654. [16] G. Tognoni, E. Ferrario, M. Inzalaco, P.G. Crosignani, Progestagens in threatened abortion, Lancet ii (1980) 1242–1243. [17] T.C. Li, S.H. Ding, B. Anstie, E. Tuckerman, K. Wood, S. Laird, Use of human menopausal gonadotropins in the management of endometrial defects associated with recurrent miscarriage: prelimary report, Fertil. Steril. 75 (2) (2001) 434–437. [18] T.K. Chung, D.S. Sahotz, T.K. Lau, J.M. Mongelli, J.A. Spencer, C.J. Haines, Threatened abortion: prediction of viability based on signs and symptoms, Aust. N. Z. J. Obstet. Gynecol. 39 (1999) 443– 447. [19] B.C. Eriksen, S.H. Eik-Nes, Prognostic value of ultrasound, hCG and progesterone in threatened abortion, J. Clin. Ultrasound 14 (1986) 3–9. [20] R. Dessaive, R. de Hertogh, K. Thomas, Correlation between hormonal levels and ultrasound in patients with threatened abortion, Gynecol. Obstet. Invest. 14 (1982) 65–78.
Dydrogesterone in threatened abortion: Pregnancy outcome M.H. Omar ∗ , M.K. Mashita, P.S. Lim, M.A. Jamil Department of Obstetrics and Gynaecology, University Kebangsaan, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia
Abstract Objective: To determine whether therapy with dydrogesterone in threatened abortion during the first trimester of pregnancy will improve pregnancy outcome. Design: Prospective open study. Subjects: Pregnant women presenting to the obstetric and gynaecology clinic admitting center with vaginal bleeding before 13 weeks gestation were evaluated for entry into the study. Women were excluded if they had a history of recurrent miscarriage. Method: Eligible subjects were randomized to receive either dydrogesterone 40 mg stat dose followed by 10 mg twice a day for one week or conservative therapy. Results: One hundred and 54 women were recruited. There was no statistically significant differences between the two groups with regard to pre-treatment status. The continuing pregnancy success rate was significantly (p = 0.037) higher in women treated with dydrogesterone (95.9%) compared with women who received conservative treatment (86.3%). The odds ratio of the success rate between dydrogesterone treatment and non-treatment was 3.773 (95% confidence interval: 1.009–14.108). Conclusion: Corpus luteal support with dydrogesterone has been shown to reduce the incidence of pregnancy loss in threatened abortion during the first trimester in women without a history of recurrent abortion. © 2005 Elsevier Ltd. All rights reserved. Keywords: Dydrogesterone; Threatened abortion; Pregnancy; Luteal support
1. Introduction Threatened abortion is associated with bleeding and/or uterine cramping while the cervix is closed. This stage of abortion may progress to spontaneous incomplete or complete abortion. While this event may be considered a part of the quality control process in human reproduction, it is important to know the possible etiologies and when therapy might prevent pregnancy loss. No one disputes the crucial role that progesterone plays in the maintenance of pregnancy [1]. Whether this is via the inhibition of oxytocin-induced myometrial activity [1,2] or through inhibition of prostaglandin excitation [3,4] is less clear. Studies have proven that progestogen treatment of miscarriage in early pregnancy is no more effective than placebo. Even so, progestogens have been prescribed for over 30 years ∗
Corresponding author. Fax: +603 91738946. E-mail address: [email protected] (M.H. Omar).
0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.08.013
by clinicians world-wide in the belief that they reduce the risk of pregnancy failure, in particular first trimester miscarriage. However, there is a lack of firm evidence from prospective controlled trials that any type of hormonal ‘deficiency’ is the cause of spontaneous abortion, so the value of giving progesterone [5] remains to be proven. In an attempt to derive an accurate assessment of the value of progestogens, a number of meta-analysis reviews have been undertaken. In 1989, Goldstein et al. [6] published a meta-analysis of randomized controlled trials of ‘progestational agents in pregnancy’, and concluded that progesterone and its analogues are ineffective in the maintenance of pregnancy. Keirse [7] conducted another more restricted meta-analysis involving the use of a single progestogenic agent, i.e.17 ␣-hydroxyprogesterone acetate. He concluded that there is no evidence from controlled trials to justify the clinical use of any progestational agent to prevent miscarriage. The difficulty in arriving at a consensus view concerning the usefulness of progestogens to prevent miscarriage does
M.H. Omar et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425
422
not result from paucity of experimentation, but from several confounding variables, such as: 1. Progestogens encompass a wide range of synthetic progesterone-like hormones. 2. Different entry criteria, different doses and different routes of administration. 3. Most of the published (and unpublished) work was undertaken before it was possible to confirm a viable pregnancy using ultrasound and endocrinological assays. As a result, it is possible that progestogens do actually confer some protection from miscarriage, but it has not been revealed by these studies and reviews. 4. None of the studies demonstrated abnormal low-level serum progesterone before recruitment. 5. Most of the studies were too small to rule out or reveal a clinically important benefit. In the current study, we used dydrogesterone (Duphaston), a retro progesterone with a very good oral bioavailability. It is structurally and pharmacologically very similar to natural progesterone, has selective progestational activity in humans, and is a non-luteolysis and non-thermogenic agent. The objective of the study was to determine whether dydrogesterone therapy for threatened abortion in the first trimester will improve pregnancy outcome and, specifically, to evaluate the effectiveness of dydrogesterone in allowing the pregnancy to continue successfully beyond 20 weeks gestation.
until the bleeding stopped. They were also recommended bed rest and received folic acid. The control group comprised patients who were managed conservatively with bed rest and folic acid only. The patients were also advised to avoid sexual intercourse. The subjects were followed up until 20 weeks gestation. Relevant data were collected from each case file regarding maternal age, race, estimated gestational age at entry, parity and medication history. Other information included the severity of symptoms and ultrasound findings. Treatment was considered successful if the women carried the pregnancy beyond 20 weeks gestation. 2.3. Statistical analyses All data obtained was analyzed using the Chi-square test. The test was considered significant if the p-value was <0.05. For the purpose of this study, the following definitions were used [8]: 1. Miscarriage: this was defined as spontaneous loss of an intrauterine pregnancy at ≤ 20 weeks gestation, calculated from the first day of the last menstrual period. 2. Recurrent miscarriage: this was defined as three or more consecutive miscarriages. 3. Continuing pregnancy: this was defined as an intrauterine pregnancy that had advanced beyond 20 weeks gestation.
2. Methods 2.1. Design
3. Results
This prospective open study was conducted between 1 March 2002 and 28 February 2004.
During the 2 year study period, a total of 678 women presented with bleeding within the first 20 weeks of gestation. Of these, 205 were diagnosed at the first visit as having threatened abortion at less than 13 weeks gestation and were without a history of recurrent abortion. Therefore, the actual prevalence of threatened abortion in the first trimester was only 30.2%. After reviewing the notes of these 205 cases, only 194 showed foetal viability with the correct size for the dates confirmed by ultrasound according to the inclusion criteria. However, 40 (20.6%) of these patients defaulted during follow-up. Thus, 154 patients (74 in the dydrogesterone group and 80 in the control group) were eligible for comparison. The majority of the patients were young (<30 years old) (Fig. 1); only 32 patients (20.7%) were ≥35 years old. The majority were in their first or second pregnancy (66.8%) and most presented around the eighth gestational week. There were no significant differences between the groups with respect to mean maternal age, gravida and gestational age (Table 1). Even though Malays formed the largest group, the numbers of patients from the three different races were equally distributed in both groups with no statistically significant differences between them (p = 0.842).
2.2. Patient sample The registration records of all pregnant women who presented to the Obstetric and Gynecology Admitting Center (OGAC) with vaginal bleeding before 20 weeks gestation were evaluated. Patients were included if they had the following criteria: 1. 2. 3. 4. 5. 6. 7.
Mild or moderate vaginal bleeding No history of loss of conception material Absence of systemic illness or fever Normal size and shape gestation sac at 5 weeks Presence of yolk sac at 5–6 weeks Presence of fetal heart at 7 weeks Gestational age less than 13 weeks Patients were excluded from the study if they had:
1. Empty sac of more than 26 mm 2. History of recurrent miscarriage The treatment group comprised patients who received dydrogesterone 40 mg stat, followed by 10 mg twice a day
M.H. Omar et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425
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3.1. Vaginal bleeding Sixty-six patients (42.9%) presented with vaginal bleeding, out of whom 29 (43.9%) were from the dydrogesterone group and 37 (56.1%) were from the control group. The successful pregnancy outcome at 20 weeks in the dydrogesterone group was 93.1% compared with 83.8% in the control group; this difference was not statistically significant. 3.2. Vaginal spotting Eighty-eight patients (57.1%) presented with per vaginal spotting, out of whom 45 (51.1%) were in the dydrogesterone group and 43 (48.9%) were in the control group. The successful pregnancy outcome at 20 weeks was 97.8% in the dydrogesterone group compared with 88.4% in the control group; this difference was not statistically significant.
Fig. 1. Age distribution amongst the patients (n = 154). Table 1 Baseline characteristics Dydrogesterone (n = 74)
Control (n = 80)
p-value
Race (n) Malay Chinese Indian Others
42 25 5 2
49 22 7 2
0.842
Mean age (years) Mean gravida (n) Mean gestation (weeks)
30 2.5 8.4
29 2.4 8.5
0.225 0.880 0.896
3.3. Foetal heart activity
Of the 154 patients enrolled, 14 had a miscarriage (3 in the dydrogesterone group and 11 in the control group); this difference between the groups was statistically significant (p = 0.037) (Table 2). All 14 patients required evacuation. The odds ratio indicated a preference for dydrogesterone treatment, although the 95% confidence interval (CI) was very wide. The baseline characteristics and ultrasound findings in relation to success rate are summarised in Table 3.
The majority (61%) of the patients (n = 94) had demonstrable viability of the pregnancy at the time of presentation as shown by the presence of foetal heart activity. The successful pregnancy outcome at 20 weeks in the dydrogesterone group was 97.8% compared with 91.8% in the control group; this difference was not statistically significant for the presence of foetal heart activity alone. 3.4. Presence of yolk sac In the presence of yolk sacs (n = 77), only 2 miscarriages occurred, both of which were in the control group. The successful pregnancy outcome at 20 weeks in the dydrogesterone group was therefore 100% compared with 95.1% in the control group; this difference was not statistically significant.
Table 2 Effect of dydrogesterone or control treatment on the continuing pregnancy rate Continuing pregnancy
Dydrogesterone (n = 74) Control (n = 80)
Yes
No
71 (95.9%) 69 (86.3%)
3 (4.1%) 11 (13.8%)
p-value
Odds ratio
95% CI
0.037
3.773
1.009–14.108
CI: confidence interval. Table 3 Presenting symptoms and ultrasound findings in relation to success rate: total group (dydrogesterone/control groups)
Vaginal bleeding Vaginal spotting Foetal heart activity Presence of yolk sac Regular IUGS Foetal heart activity + presence of yolk sac IUGS: intrauterine gestational sac.
Success (n)
Miscarriage (n)
%
p-value (dydrogesterone versus control)
66 (29/37) 88 (45/43) 65 (31/34) 48 (23/25) 12 (7/5) 29 (13/16)
8 (2/6) 6 (1/5) 4 (1/3) 1 (0/1) 5 (2/3) 1 (0/1)
12.1 (6.9/16.2) 6.8 (2.2/11.6) 6.2 (3.2/8.8) 2.1 (0/4) 41.7 (28.6/60) 3.4 (0/6.3)
0.250 0.106 0.615 1.000 0.558 1.000
424
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3.5. Regular intrauterine gestational sac The highest proportion of miscarriages occurred in the group with only a regular gestational sac at the time of presentation. This might be due to the fact that the presence of a regular gestational sac at the time of presentation was not absolutely representative of a viable pregnancy, but rather of an early missed miscarriage or a blighted ovum, both of which are difficult to exclude.
4. Discussion Vaginal bleeding complicates 20% of diagnosed pregnancies [9]. About 15% of all clinically recognized pregnancies end in spontaneous miscarriage [10] and 75% of the losses occur in the first eight weeks of gestation. However, after a viable foetus has been detected with ultrasound in the tenth week of an uncomplicated pregnancy, the reported loss is only 2–6% [11,12]. In threatened miscarriage with a viable foetus, only 12% will end in miscarriage [13]. In this study, the prevalence of miscarriage in pregnancies with a viable foetus at five weeks gestation was 7.1%. In almost 60% of cases, the cause of foetal loss is related to a chromosomal disorder of the conceptus [14]. For most other cases, the causes are unknown, but some may be related to endocrine disorders. Laboratory studies have suggested that progesterone plays an important role in the maintenance of pregnancy, but clinical studies have not shown any beneficial effects of progestogens in early pregnancy [15,16], perhaps because of the limited role of this hormonal disorder in the aetiology of early miscarriage. Furthermore, there is no reliable method for selecting patients who might benefit from hormonal treatment. Although the precise role of progesterone is still debatable, further support for its therapeutic possibilities comes from the hormonal profile of women who experience recurrent miscarriage without any obvious non-hormonal aetiology. In addition, luteal phase defect has been shown to occur more frequently among women with recurrent miscarriage [17]. Because of this evidence, it is not unreasonable to suppose that treatment in very early pregnancy might have an effect on the risk of pregnancy failure. It is not surprising that progestogens have indeed been prescribed by many clinicians with just such aims in mind and a large number of trials, controlled and otherwise, have been undertaken to discover whether or not the supposed benefits were real. In this study, dydrogesterone was used and the aim was to see whether it improves pregnancy outcome in the treatment of threatened abortion in early pregnancy. The result of this study showed progestogens, administered to women with threatened miscarriage in the first trimester but without a history of recurrent miscarriage, to be beneficial in the maintenance of pregnancy beyond 20 weeks gestation. The pregnancy success rate, in terms of viable pregnancies at 20 weeks, was 95.9% in the women
who were treated with dydrogesterone and 86.3% in women who was treated conservatively; this difference was statistically significant (p = 0.037). In this study, almost equal numbers of patients achieved continuity of pregnancy following presentation with either vaginal bleeding (93.1% in the dydrogesterone group and 83.8% in the control group) or spotting (97.8% in the dydrogesterone group and 88.4% in the control group). Chung et al. [18] have shown that clinical assessment of threatened miscarriage is unreliable in most cases and should be superseded by an ultra-sonography assessment. A history of having passed a tissue mass, the presence of products of conception in the vagina and an open cervix were the only signs or symptoms associated with greater than a 90% chance that the pregnancy was non-viable. Patients with these signs or symptoms were excluded from this study. All patients in this study had the viability of their foetuses confirmed by ultrasound. With ultrasound, a correct diagnosis of the in-utero situation was reported to be made on admission in 93% of cases and this increased further after one week to 99% of cases [19]. In another study, a single examination with ultrasound alone provided a correct prognosis of the pregnancy in 78% of cases with threatened abortion [20]. Hormonal measurement is a complementary method that may confirm or refute the un-favorable prognosis. In addition, hormonal measurement may provide some insight as to the subsequent evolution of the threatened pregnancy, even in the presence of normal ultrasounds. In conclusion, treatment of first trimester threatened abortion (without a history of recurrent miscarriage) with dydrogesterone appeared to be efficacious in improving the chances of the pregnancy advancing beyond 20 weeks gestation. However, the study is not very powerful as the sample size was not sufficiently large and the 95% CI of the odds ratio was too wide. Further large randomized trials are needed to establish the role of dydrogesterone and to evaluate the impact of hormonal levels in first trimester threatened miscarriage. References [1] F. Fuch, A.R. Fuch, Induction and inhibition of labour in the rabbit, Acta Endocrinol. 26 (1958) 615–624. [2] A.L. Csapo, M.O. Pulkien, B. Ruttner, J.P. Sauvage, W.G. Wiest, The significance of the human corpus luteum in pregnancy maintenance, Am. J. Obstet. Gynecol. 112 (1972) 1061–1067. [3] A.L. Csapo, M.R. Henzi, H.L. Kaihola, Suppression of uterine activity and abortion by inhibition of prostaglandin synthesis, Prostaglandins 7 (1974) 39–47. [4] A.L. Csapo, Effects of progesterone, prostaglandin F and its analogue ICI 81008 on the excitability and threshold of the uterus, Am. J. Obstet. Gynecol. 124 (1976) 367–378. [5] A.J. Wilcox, C.R. Weinberg, R.E. Wehman, E.G. Armstrong, R.E. Canfield, B.C. Nisula, Measuring early pregnancy loss: laboratory and field methods, Fertil. Steril. 44 (1985) 366–374. [6] P. Goldstein, J. Berrier, S. Rosen, H.S. Sacks, T.C. Chalmers, A meta-analysis of randomized control trials of progestational agents in pregnancy, Br. J. Obstet. Gynecol. 96 (1989) 265–274.
M.H. Omar et al. / Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 421–425 [7] M.J.N.C. Keirse, Progestogen administration in pregnancy may prevent preterm delivery, Br. J. Obstet. Gynecol. 97 (1990) 149–158. [8] S. Daya, Efficacy of progesterone support for pregnancy in women with recurrent miscarriage. A meta-analysis of controlled trials, Br. J. Obstet. Gynecol. 96 (1989) 275–280. [9] B.A. Strobino, J. Pantel-Silverman, First trimester vaginal bleeding and the loss of chromosomally normal and abnormal conceptions, Am. J. Obstet. Gynecol. 157 (1987) 1150–1154. [10] G.M. Stirrat, Recurrent abortion-a review (Commentary), Br. J. Obstet. Gynecol. 90 (1983) 881–883. [11] B. Gustavii, Chorionic biopsy and miscarriage in first trimester, Lancet I (1984) 562. [12] F.R. McFadyen, Missed abortion and later spontaneous abortion in pregnancies clinically normal at 7–12 weeks, Eur. J. Obstet. Gynecol. Reprod. Biol. 20 (1985) 381–384. [13] L.M. Hill, D. Guzick, J. Fries, J. Hixson, Fetal loss rate after ultrasonically documented cardiac activity between 6 and 14 weeks menstrual age, J. Clin. Ultrasound 19 (1990) 221–223. [14] J.G. Lauritsen, Etiology of spontaneous abortion, Acta Obstet. Gynecol. Scand. 52 (Suppl.) (1976) 24–29.
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