Treatment options for threatened miscarriage

Maturitas 65S (2009) S35–S41

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Treatment options for threatened miscarriage N.S. Qureshi ∗ Birmingham Women’s Hospital, Metchely Park Road, Edgbaston, Birmingham B15 2TG, UK

a r t i c l e

i n f o

Article history: Received 26 August 2009 Received in revised form 28 October 2009 Accepted 28 October 2009

Keywords: Threatened miscarriage Vaginal bleeding Pregnancy Progesterone Dydrogesterone

a b s t r a c t Threatened miscarriage, as demonstrated by vaginal bleeding with or without abdominal cramps, is a common complication of pregnancy. It occurs in about 20% of recognised pregnancies. Risk of miscarriage is increased in older women and those with a history of miscarriage. Low serum levels of progesterone or human chorionic gonadotrophin (hCG) are a risk factor for miscarriage. Other risk factors include heavy bleeding, early gestational age and an empty gestational sac of >15–17 mm diameter. Clinical history and examination, maternal serum biochemistry and ultrasound findings provide valuable information about the prognosis and are important to establish in order to determine potential treatment options. Although bed rest is the most common choice of treatment, there is little evidence of its value. Other options include luteal support with progesterone, dydrogesterone or hCG. There is some evidence from clinical studies indicating that progesterone or dydrogesterone may reduce the rate of miscarriage, although further data from double-blind, randomised-controlled trials are necessary to confirm efficacy. © 2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

2. Risk of miscarriage

Miscarriage is the spontaneous loss of a foetus before it is capable of surviving outside the uterus; this is generally defined as being before 24 completed weeks of gestation. The occurrence of vaginal bleeding during this time is known as threatened miscarriage, provided the cervix is closed and the foetus remains viable and inside the uterine cavity [1]. This bleeding may also be accompanied by abdominal cramps. Threatened miscarriage is a common complication, occurring in about 20% of all clinically recognised pregnancies [2–4]. If bleeding occurs during pregnancy, in the case of a viable foetus, the incidence of miscarriage can be around 20% [5], or even up to 30% [6], depending on the severity and risk factors. Vaginal bleeding during the early stages of pregnancy could be due to a range of conditions including ectopic pregnancy, cervical abnormalities such as polyps or cancer, infection, molar pregnancy or vaginal trauma [7]. A thorough evaluation is therefore essential to establish the diagnosis. Initial laboratory tests should include a complete blood count and blood typing. A pelvic examination will determine whether the cervix is effaced or dilated, indicating imminent miscarriage. Finally, transvaginal ultrasound is crucial to confirm whether or not the foetus is still viable, and to diagnose an incomplete or missed abortion [8,9].

The risk of miscarriage is dependent on a variety of factors including demographic and clinical characteristics, maternal serum biochemistry and ultrasound findings (Table 1).

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2.1. Demographic and clinical characteristics It is well established that advancing maternal age is associated with an increased risk [10–15]. One study of 182 women with threatened miscarriage found a significantly (p < 0.05) higher rate of miscarriage in those aged 31–40 years (27.1%) than in those aged 21–30 years (7.1%) [11]. In another study in 149 women with threatened miscarriage, the odds ratio (OR) of miscarriage in women more than 34 years old was 2.3 (95% confidence interval (CI) 0.76–7.10) [14]. A history of previous miscarriages is also associated with an increased risk [13,16], as is the presence of poorly controlled systemic disease such as diabetes or thyroid dysfunction [11,17,18]. The timing and severity of vaginal bleeding are important prognostic factors in women with threatened miscarriage, with both early and severe bleeding being associated with a higher risk of miscarriage. Bleeding before 6 weeks gestation has been reported to result in a miscarriage rate of 29% compared with 8.2% for bleeding during weeks 7–12 and 5.6% for second trimester bleeding [11]. Another study, conducted in 516 women with first trimester bleeding, found that the rate of miscarriage was more than twice as high in women who presented with bleeding up to week 8 compared with those who had bleeding after week 8 (13.7% vs. 5.9%) [15]. In the First And Second Trimester Evaluation of Risk (FASTER) trial, the

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Table 1 Factors predicting an increased risk of miscarriage. Demographics and history

Advancing maternal age Previous miscarriage(s) Poorly controlled systemic disease Bleeding during early gestational stage Heavy bleeding

Maternal serum biochemistry

Low progesterone Low hCG and free hCG Low inhibin A High CA-125 High anandamide Low PIBF Hyperhomocysteinemia

Ultrasound findings

Discrepancy between gestational age and crown to rump length Discrepancy between menstrual and sonographic age of >1 week No foetal heart activity Foetal bradycardia Empty gestational sac >15–17 mm diameter Gestational sac ≥13 mm diameter without yolk sac Subchorionic haematoma

incidence and severity of bleeding were recorded in 16,506 pregnant women in the 4 weeks prior to an ultrasound examination at weeks 10–14 of gestation [4]. All women had a viable foetus confirmed at ultrasound. The spontaneous miscarriage rate before week 24 of gestation was 1% in the 2094 women with light bleeding (OR 2.5; 95% CI 1.5–4.3) and 2% in the 252 with heavy bleeding (OR 4.2; 95% CI 1.6–10.9), compared with 0.5% in women without bleeding. The duration of bleeding was also shown to play a role in the risk of miscarriage amongst 200 women with symptoms of imminent miscarriage during weeks 5–12 of gestation [19]. The rate of miscarriage in women with abdominal pain and bleeding for ≥3 days (81%) was significantly (p < 0.001) greater than that in women with abdominal pain only (10%) or abdominal pain and bleeding of <3 days (13%). 2.2. Maternal serum biochemistry Amongst the maternal serum markers with prognostic value, progesterone and hCG have been most widely investigated. Data from 3674 first trimester pregnancies showed an increasing risk of miscarriage with declining serum progesterone levels (Table 2) [20]. Levels of <5 ng/ml were associated with a spontaneous miscarriage in 86% of cases compared with only 8% at levels of 20–25 ng/ml. In a study of 358 women with bleeding and/or abdominal pain in the first 18 weeks of pregnancy, serum progesterone levels were significantly (p < 0.001) lower in women who suffered a miscarriage or an ectopic pregnancy [21]. A cut-off value of 14 ng/ml was shown to differentiate between the viable and noncontinuing pregnancies. Another study of 40 women with bleeding between weeks 6 and 12 of gestation, 15 of whom subsequently miscarried, found that a cut-off value of 21 ng/ml had positive and negative predictive values of 85% and 79%, respectively [22]. As seen with progesterone, low levels of hCG also predict a higher risk of miscarriage. Amongst 398 women with bleeding and/or abdominal pain during the first 18 weeks of pregnancy and 156 control pregnancies, a cut-off value of 20 ng/ml free was found to have 88% sensitivity and 83% positive predictive value in differentiating between viable continuing pregnancies and those that were not viable [5]. In another study of 45 women with first trimester threatened miscarriage and 30 women with normal pregnancies, serum hCG levels were significantly (p < 0.001) lower in those who had a miscarriage than in those in whom the

pregnancy continued (17.6 IU/ml vs. 39.4 IU/ml) [6]. A cut-off of 25 IU/ml ␤-hCG has been reported to have a 84% and 73% positive and negative predictive value, respectively [22]. The ratio of bioactive:immunoreactive hCG was also found to be significantly lower in symptomatic women who eventually had a miscarriage, although this measure is too complicated for routine use [23]. Further markers under investigation are the tumour marker CA125, inhibin A, anandamide and progesterone induced blocking factor (PIBF). Elevated levels of CA-125, which can be associated with damage to the deciduous membrane, have also been proposed as an indicator of miscarriage risk. Sequential determinations of CA125 in women with bleeding during gestational weeks 6–12 were able to distinguish between women who subsequently miscarried and those who did not [24]. Other studies have pointed to the prognostic value of single measurements of CA-125. One showed that a cut-off of 125 IU/ml had positive and negative predictive values of 93% and 92%, respectively [22], in women with bleeding between gestational weeks 6 and 12; mean values were 67.3 and 221.0 IU/ml (p < 0.05) in the continuing pregnancy and miscarriage groups, respectively. Another study in women with symptoms of miscarriage also found significantly (p < 0.05) higher levels in those who miscarried compared with those who did not (84.7 IU/ml vs. 21.6 IU/ml) [19]. Inhibin A levels were significantly (p < 0.05) lower in women who miscarried compared with those who did not in a sample of 55 women with bleeding during early pregnancy (0.38 vs. 0.98 multiples of median) [25]. A cut-off value of 0.553 multiples of mean was the best predictor of a failing pregnancy. Anandamide [26] and PIBF [27,28] are both biomarkers that are modulated by progesterone. Anandamide is an endocannabinoid known to participate in reproductive processes. Oestradiol and progesterone have been shown to regulate its production in the rat uterus [29]. In women with successful pregnancy after IVF, plasma anandamide was low during the implantation phase but high in gestational weeks 4 and 5, declining again in week 6 [30]. PIBF mediates the effect of progesterone on the immune system [31]. Progestogens like dydrogesterone increase its production in animal models [32] and in women suffering from threatened miscarriage [28]. Hyperhomocysteinemia, that can for example result from methylenetetrahydrofolate reductase (MTHFR) mutations or as a result of deficiencies of vitamin B and/or folate, is also a risk factor for recurrent pregnancy loss [33]. 2.3. Ultrasound findings Ultrasonography is important in identifying prognostic factors for a poor outcome in women with threatened miscarriage, such as small crown to rump length, an empty gestational sac or foetal bradycardia [7]. A combination of several factors increases the risk of miscarriage still further. For example, logistic regression analysis showed that the chance of miscarriage in women with bleeding between weeks 5 and 12 of gestation was 84% in cases of foetal bradycardia plus discrepancies between crown to rump length and the diameter of the gestational sac, and menstrual and sonographic age; this risk was reduced to 6% if none of these factors were apparent [14]. A smaller than normal crown to rump length for gestational age is a poor prognostic factor in women with threatened miscarriage [34], as is a discrepancy between the menstrual and sonographic age of >1 week [14]. Evaluation of the gestational sac can also give an indication of the viability of the pregnancy, with empty sacs of >15–17 mm diameter and sacs of ≥13 mm without a visible yolk sac suggesting a poor prognosis [35,36]. A study of 781 women who presented with threatened miscarriage found that 211 (28%) had empty gestational sacs [35]. Of these, only 14% were subsequently

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Table 2 Serum progesterone levels as a predictor of spontaneous miscarriage, ectopic pregnancy and intrauterine pregnancy. Serum progesterone (ng/ml)

Spontaneous miscarriage

Intrauterine pregnancy

Ectopic pregnancy

0–4.9 5.0–9.9 10.0–14.9 15.0–19.9 20.0–24.9

1093 (85.5%) 46 (65.8%) 181 (31.3%) 59 (9.8%) 39 (7.7%)

2 (0.2%) 126 (17.8%) 338 (58.4%) 509 (84.4%) 451 (88.8%)

184 (14.4%) 116 (16.4%) 60 (10.4%) 32 (5.3%) 18 (3.5%)

shown to constitute a viable pregnancy. A mean sac diameter of ≥17 mm that lacked an embryo or a mean diameter of ≥13 mm without a yolk sac both showed 100% specificity and 100% predictive value. Large or small gestational sacs and those with distorted shapes are also predictors of subsequent miscarriage [35,37]. Most studies suggest that the risk of spontaneous miscarriage is only around 3–5% if foetal heart activity is detected in women with vaginal bleeding [38–40]. However, foetal bradycardia is a predictor of a poor outcome [41,42]. Absence of foetal heart activity in embryos with a crown to rump length of >5 mm indicates that the pregnancy is no longer viable [7]. Retroplacental haematoma during the first trimester has been linked to an increased risk of miscarriage [43]. It is estimated that about one-fifth of women with threatened miscarriage have a subchorionic haematoma [44], although this study failed to demonstrate any difference in the miscarriage rate between women with and without haematoma. In contrast, other studies have reported that the size and situation of the haematoma have prognostic value. Amongst 516 women with bleeding and subchorionic haematoma in the first trimester, the miscarriage rate was about twice as high in those with a large haematoma (18.8%) compared with small and medium haematomas (7.7% and 9.2%, respectively) [15]. Bleeding near the cord has also been shown to be more likely to result in placental separation and subsequent miscarriage than bleeding in other locations [8].

3. Consequences of threatened miscarriage Threatened miscarriage causes considerable stress and anxiety for a pregnant woman. It can cause anxiety and depression, and may be experienced as a traumatic life event [45,46]. Although pregnancies advancing after a threatened miscarriage may be associated with more complications such as preterm delivery and prelabor rupture of membranes than other pregnancies [47], the evidence for the association between threatened abortion and birth defects is limited and inconsistent. A study in 16,506 pregnant women, of whom 2346 experienced first trimester bleeding, showed that bleeding was an independent risk factor for preterm delivery, Caesarean delivery, preeclampsia, placental abruption, intra-uterine growth restriction and preterm premature rupture of the membranes [4]. The babies born to women reporting bleeding also had a significantly (p < 0.05) lower birth weight and mean gestational age at delivery. Similar findings were reported in a subsequent retrospective study that compared the obstetric outcome in 7627 women with first trimester bleeding and 31,633 controls [48]. There was a significantly (p < 0.05) higher risk of Caesarean delivery (OR 1.30; 95% CI 1.14–1.48), placenta previa (OR 1.77; 95% CI 1.09–2.87), other antepartum haemorrhage (OR 1.83; 95% CI 1.73–2.01) and manual removal of the placenta (OR 1.40; 95% CI 1.21–1.62) in the women with bleeding. Perinatal outcome also tended to be worse in these women, with a significantly (p < 0.05) greater chance of preterm delivery (OR 1.56; 95% CI 1.43–1.71), malpresentation (OR 1.26; 95% CI 1.13–1.40) and low birth weight (OR 1.22; 95% CI 1.09–1.37). The risk of premature delivery (OR 2.29; 95% CI 1.4–4.6) and preterm prelabor rupture of the membranes (OR 3.72; 95% CI 1.2–11.2) was signifi-

cantly (p < 0.05) increased with threatened miscarriage in another study comparing 214 women with first trimester bleeding with 214 controls [47]. 4. Treatment options Miscarriage is a difficult and distressing event for a woman and her partner and can result in depression, anxiety, anger and marital breakdown [45,49,50]. There is therefore a clear medical need to prevent miscarriage whenever possible. However, it is essential to ensure that the pregnancy is viable before any treatment is considered. This is best achieved with a combination of serum hCG levels and ultrasound, which have been shown to provide an accurate diagnosis [7]. The most widely used of the currently available treatment options include bed rest and luteal support with progestogens or hCG. 4.1. Bed rest Bed rest is conventionally the most commonly used management technique for threatened miscarriage. Despite this, there is little evidence of its value. Physical activity is rarely associated with an increased risk of miscarriage, and indeed a lack of activity can lead to a number of other complications such as thromboembolic events, back pain, muscle atrophy and bone loss [51–54]. Evidence also suggests that women may experience emotional, familial and economic stress during bed rest, as well as self-blame if they fail to comply and subsequently suffer a miscarriage [55–57]. Very few studies have specifically assessed the efficacy of bed rest. Amongst those that have, a retrospective analysis of 230 women with threatened miscarriage who presented with subchorionic haematoma on ultrasound found fewer miscarriages in women who adhered to bed rest than in those who continued their normal lifestyle [58]. However, another retrospective analysis of data from 226 women who were hospitalised for threatened miscarriage showed that 84% of those who underwent bed rest continued their pregnancy beyond week 20 compared with 80% of those who were not prescribed bed rest [59]. A recent Cochrane review also came to the conclusion that there is insufficient evidence to support a policy of bed rest to prevent miscarriage [60]. A search of the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Library, MEDLINE, POPLINE, LILACS and EMBASE revealed only two trials, conducted in a total of 84 women, which compared bed rest with alternative care or no intervention in women at high risk of miscarriage. There were no statistically significant differences in the risk of miscarriage between the two groups (relative risk 1.54; 95% CI 0.92–2.58). Looking at the two studies individually, one randomised 61 women with vaginal bleeding and a viable embryo of <8 weeks gestational age to treatment with bed rest at home, placebo or 5000 IU hCG twice weekly [61]. Miscarriage before week 16 was most common in the bed rest group (15/20 women) compared with placebo (10/21) and hCG (6/20), the difference between bed rest and hCG reaching statistical significance (p < 0.01). The other randomised study compared bed rest (at home and in hospital) and normal activity in 23 pregnant women between weeks 7 and 14 of gestation who had

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vaginal bleeding [62]. Miscarriage occurred in 2/14 women allocated to bed rest and 1/9 who continued normal activity. Neither of these studies assessed the potential adverse consequences of bed rest. 4.2. Luteal support Progesterone secreted by the corpus luteum is essential for the maintenance of early pregnancy [63], and it has been proposed that corpus luteum deficiency may be responsible for some cases of miscarriage. Direct supplementation with progestogens, or exogenous administration of hCG, should therefore have beneficial effects in women with threatened miscarriage. Unfortunately, luteal phase defect is notoriously difficult to diagnose reliably [64]. One diagnostic criterion is low serum progesterone, but levels vary widely during early pregnancy and any later decline may be attributed to a dysfunctioning placenta. Other criteria including a pre-ovulatory follicle diameter of <17 mm and the absence of a post-ovulatory rise in basal body temperature are imprecise, and the validity of endometrial histological diagnosis has been called into question [65]. Nevertheless, luteal support is widely used for the management of threatened miscarriage [66]. 4.2.1. Progesterone The complex role of progesterone in pregnancy is becoming increasingly recognised. One relatively recently discovered mode of action is modulation of the maternal immune response [28,67]. During normal pregnancy, there is a shift towards a protective Thelper (Th)-2 dominated cytokine balance (e.g. interleukin (IL)-4 and IL-10) and away from Th-1 cytokines (e.g. IL-12 and interferon␥) [68]. This shift towards Th-2 cytokines is promoted by PIBF, which is synthesised by activated lymphocytes in the presence of progesterone [69]. Other mechanisms by which PIBF prevents inflammatory and thrombotic reactions towards the foetus include an increase of asymmetric non-cytotoxic blocking antibodies [70] and blockade of natural killer (NK) cell degranulation [71]. Studies have confirmed that PIBF levels fail to increase in pregnancies that end in miscarriage [72,73]. Progestogens also have a direct pharmacological effect by reducing the synthesis of prostaglandins, thereby relaxing uterine smooth musculature and preventing inappropriate contractions that may result in miscarriage [74,75]. There is no evidence to suggest that progesterone supplementation during pregnancy has any adverse consequences for the foetus [64]. Although a case–control study reported an association between maternal exposure to progestogens and hypospadias [76], the data was based on interviews with the mothers who often could not specify the type or dose of progestogen. Moreover, the indication for the use of progesterone has itself has been related to an increased risk of hypospadias [77]. Other studies have found no link between maternal progesterone exposure and defects of the external genitalia [78–80]. A recent Cochrane review conducted to assess the efficacy and safety of progestogens in threatened miscarriage identified only two studies that were suitable to include in a meta-analysis, both of which compared progesterone with placebo [81]. The Cochrane Pregnancy and Childbirth Group’s Trials Register, Cochrane Central register of Controlled Trials, MEDLINE, EMBASE and CINAHL were searched for randomised or quasi-randomised-controlled trials comparing a progestogen with no treatment, placebo or any other treatment regimen. The two studies that met the inclusion criteria were double-blind and included a total of 84 women treated with vaginal progesterone or placebo. Although the meta-analysis suggested a reduced risk of miscarriage with progesterone (relative risk 0.47), the small sample size meant that the 95% confidence interval was too wide (0.17–1.30) to draw any conclusions. In addition, the methodological quality of both studies was considered

relatively poor and there was no data on the safety of progesterone. One of the studies included in the meta-analysis randomised 56 women with vaginal bleeding during the first trimester to treatment with 25 mg progesterone or placebo suppositories twice daily until either miscarriage or 14 days after bleeding had stopped [82]. Of the 52 women included in the analysis, 3/26 (11%) given progesterone and 5/26 (19%) given placebo had a miscarriage. However, only the 34 women with foetal viability confirmed by ultrasound before treatment were included in the meta-analysis. There were no miscarriages in the progesterone group and one in the placebo group, resulting in a relative risk of 0.33 (95% CI 0.01–7.65). Serum progesterone levels were significantly increased in women treated with progesterone. The other study evaluated 50 women with an ultrasound diagnosis of threatened miscarriage between 6 and 12 weeks of gestation and a previous diagnosis of luteal phase dysfunction [83]. They were randomised to 90 mg progesterone or placebo vaginal gel daily for 5 days. At the end of treatment, there was a significant reduction in pain and the number of uterine contractions with progesterone. During a 60-day follow-up, significantly (p < 0.05) fewer women miscarried in the progesterone group (4/25; 16%) than in the placebo group (8/25; 32%), resulting a relative risk of 0.50 (95% CI 0.17–1.45). 4.2.2. Dydrogesterone Dydrogesterone is a synthetic progestogen that has a similar molecular structure and pharmacological profile to natural progesterone. In contrast to natural progesterone, however, it is orally active at low dosages. It is therefore not associated with hepatic side effects that have been reported in some cases with the high doses of micronised progesterone necessary for oral dosing [84,85]. Dydrogesterone is highly selective for the progesterone receptor and differs from most other synthetic progestogens in its lack of oestrogenic, androgenic, anabolic and corticoid properties. It is considered particularly suitable for the management of women with threatened miscarriage and other pregnancy-related disorders as it does not suppress the pituitary–gonadal-axis at normal therapeutic doses [86]. This means that it does not affect the normal secretory transformation of the endometrium, does not inhibit formation of progesterone in the placenta during early pregnancy and does not cause masculinisation of the female foetus. Like progesterone, dydrogesterone is able to inhibit the production of Th-1 cytokines and up-regulate production of Th-2 cytokines, thus shifting the balance towards a pregnancy protective Th-2-dominated immune response [33,87–90]. For example, incubation of dydrogesterone with peripheral blood mononuclear cells from women with unexplained recurrent abortion increased PIBF and inhibited the production of Th-1-cytokines tumour necrosis factor-␣ and interferon-␥ whilst increasing that of the Th-2cytokines IL-4 and IL-6 [89]. In a mouse model, stress-induced miscarriage was associated with low levels of progesterone and PIBF [90,93]. Treatment with dydrogesterone before the stress reduced the number of miscarriages, restored PIBF levels and decreased uterine levels of Th-1 cytokines. An early uncontrolled study with dydrogesterone in 111 women showed favourable results, with only 9 subsequent miscarriages [91]. Dydrogesterone (2.5–20 mg daily) was frequently combined with synthetic oestrogens and treatment duration varied from a few weeks to more than 6 months. Amongst more recent studies, dydrogesterone was compared with conservative management in 154 women who had vaginal bleeding before week 13 of gestation [92]. All women received conservative management with bed rest and folic acid, whilst 74 were randomised to also receive oral dydrogesterone (40 mg initial dose followed by 10 mg twice daily) until the bleeding stopped. During follow-up to 20 weeks gestation, the miscarriage rate was significantly (p < 0.05) lower with

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dydrogesterone (3/74; 4.1%) than with conservative management only (11/80; 13.8%). The odds ratio was 3.773 (95% CI 1.01–14.11). This study was not considered suitable for inclusion in the recent Cochrane meta-analysis of progestogens [81] as more than 20% of the 194 women who were originally included were lost to follow up and excluded from the analysis (n = 40; 20.6%). A smaller study, which was published in 2007 and was therefore too recent to be included in the meta-analysis, compared oral dydrogesterone with vaginal micronised progesterone [93]. This double-blind study randomised 53 women with threatened miscarriage at up to 12 weeks gestation to treatment with dydrogesterone 30 mg or micronised progesterone 300 mg daily for 6 weeks. There were fewer miscarriages in the dydrogesterone group (2/24; 8.3%) than in the progesterone group (4/29; 14%), although the difference was not statistically significant. Another recent study randomised 191 women with vaginal bleeding up to week 16 of pregnancy to treatment with dydrogesterone (40 mg stat followed by 10 mg twice daily) or conservative management [94]. Dydrogesterone treatment resulted in significantly (p < 0.05) fewer miscarriages up to 20 weeks of gestation than did conservative management (12.5% vs. 28.4%). A significantly (p < 0.05) lower incidence of miscarriage with dydrogesterone was also observed in a study of 146 women who presented with mild or moderate bleeding during the first trimester of pregnancy [95]. All women received standard supportive care, whilst 86 were randomised to additional treatment with dydrogesterone (10 mg b.i.d.). The incidence of miscarriage was 17.5% in the dydrogesterone group compared with 25.0% in the control group. The effect of dydrogesterone on urinary PIBF and serum progesterone and cytokines has also been evaluated in women with threatened miscarriage [29,96]. A total of 27 women with threatened miscarriage were treated with dydrogesterone 30–40 mg daily for 10 days and the cytokine and PIBF levels compared with those in 16 women with normal healthy pregnancies. There was no statistically significant difference between the treated women with threatened miscarriage and the healthy controls with regard to pregnancy outcome (missed abortion 2/27 vs. 1/16 and preterm delivery 2/27 vs. 0/16). At baseline, PIBF levels were significantly lower in women with threatened miscarriage than in healthy controls (453 pg/ml vs. 1058 pg/ml; p < 0.01). After treatment with dydrogesterone, there was no statistically significant difference between the threatened miscarriage and control group (1292 pg/ml vs. 1831 pg/ml, respectively). Women who subsequently had a miscarriage had lower PIBF and progesterone levels than those who progressed to a successful pregnancy. Serum Th1 and Th2 cytokine levels did not differ significantly between women with threatened miscarriage and healthy controls. A recent review of birth defects reported between 1977 and 2005 following maternal use of dydrogesterone during pregnancy found no link between dydrogesterone and birth defects [97]. It is estimated that, during this 28-year period, foetuses were exposed to dydrogesterone in utero in more than 10 million pregnancies. 4.2.3. Human chorionic gonadotrophin The rationale for the use of hCG is its potential to stimulate progesterone production by the corpus luteum and feto-placental unit. Initial early studies showed promise in women with early threatened miscarriage [98,99], and the small randomised study conducted by Harrison [61] showed hCG to be significantly more effective than bed rest (p < 0.01). Based on these findings, a doubleblind, randomised, placebo-controlled study was conducted in 183 women with first trimester vaginal bleeding and a viable foetus as confirmed by ultrasound [100]. The women received either intramuscular injections of 5000 IU hCG or placebo weekly until week 14 of gestation. There was no significant difference in the eventual incidence of complete miscarriage between the hCG and placebo

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groups (12% vs. 11%); nor were there differences between the groups in mode of delivery, antenatal complications or health status of the babies. Post-treatment serum progesterone levels were higher in the hCG than in the placebo group, although the levels increased from baseline in both groups. Unfortunately, recruitment to the study was slow; the eventual sample size was therefore smaller than planned and the follow-up was incomplete in 25% of women. This was due partly to women’s reluctance to attend hospital for weekly injections, especially once they were reassured that their pregnancy was ongoing. It is therefore possible that the sample size was too small to reveal any differences in effect between hCG and placebo. 4.3. Uterine muscle relaxants Uterine muscle relaxing drugs, which include beta-agonists and atropine-like antispasmodic agents, are rarely used today. A recent search of the Cochrane Pregnancy and Childbirth Group Trials register and Central Register of Controlled Trials confirmed that there is insufficient evidence to support their use [101]. Only one small randomised study was identified that compared the beta-agonist buphenine hydrochloride with placebo in 170 women [102]. Although buphenine was associated with a lower rate of intrauterine death, the methodological quality of the study was considered poor and hence the results should be interpreted with caution. 5. Conclusion Miscarriage is a physically and mentally traumatic event that frequently has long-term psychological consequences. Every effort should therefore be made to maintain viable pregnancies in women with threatened miscarriage. Our understanding of pregnancy has advanced considerably in recent years, and the quality of much of the evidence available regarding the efficacy and safety of the various treatment options is not in line with current standards. Nevertheless, there is some evidence that luteal support with a progestogen, such as progesterone and dydrogesterone, may help to prevent miscarriage in at least a subpopulation of these women. The wide spread use of progesterone and dydrogesterone over many years also suggests that there are no safety problems with these treatments. In conclusion, although data from clinical studies suggest efficacy for luteal support with progesterone and dydrogesterone, there is a need for double-blind, randomised-controlled trials in line with modern standards to confirm these findings. Contributor N.S. Qureshi is the sole contributor. Competing interest There is no actual or potential conflict of interest. Acknowledgements The author acknowledges assistance from Jane Irons in the technical, linguistic and style editing of the manuscript. The author would like to thank Solvay Pharmaceuticals for their sponsorship of this work. References [1] Cunningham FG. Reproductive success and failure. William’s obstetrics. New York: McGraw-Hill; 2005.

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