Review Article Singapore Med J 2007; 48 (12) : 1074 CME Article Non-surgical interventions for threatened and recurrent miscarriages Tien J C, Tan T Y T ABSTRACT occurring in 12%–30% of all clinical pregnancies,(1-3) Many surgical and non-surgical inter- and even more if unrecognised biochemical pregnancies ventions are used in the management of are included.(4) A threatened miscarriage is defined threatened and recurrent miscarriages. as vaginal bleeding, usually painless, that occurs in Evidence-based management of recurrent the first 24 weeks in a viable pregnancy without miscarriages requires investigations into cervical dilatation. It is common, especially in the first the underlying aetiology. When a specific trimester, occurring in 14%–21% of all pregnancies.(1,5) cause is identified, directed treatment Recurrent miscarriages are classically defined as three may reduce miscarriage rates. Combined or more consecutive miscarriages. It has been estimated aspirin and heparin for antiphospholipid that 0.5%–1% of women suffer from recurrent syndrome, and screening and treatment miscarriages. More recently, investigations and of bacterial vaginosis between ten and management similar to that for recurrent miscarriages 22 weeks of pregnancy with clindamycin, have been started for women who suffer from two are the only interventions proven to be consecutive miscarriages. This latter group would useful in randomised controlled trials include a larger percentage (2%) of women.(6) (RCTs). The use of periconceptional metformin for polycystic ovarian (PCO) Causes of miscarriages syndrome is promising, though data from Traditional thinking dictates that there is a single cause RCTs are still required. The use of heparin for a miscarriage or recurrent miscarriages. More in inherited thrombophilias, bromocriptine recently, a multifactorial approach to the problem in hyperprolactinaemia and luteinising has been encouraged. In such an approach, all possible hormone suppression in fertile patients with causes of pregnancy loss are considered, and their PCO syndrome are more controversial. In cumulative effects, when exceeding the threshold, threatened miscarriages, or when no cause contribute to a miscarriage.(7) Consideration of the is found, treatment becomes empirical. timing of the miscarriage is important, as different Supportive care may reduce miscarriage causes of miscarriage tend to manifest at different Yong Loo Lin rates. Dydrogesterone, a progesterone School of Medicine, periods of gestation. In first trimester miscarriages, National University derivative, may further reduce miscarriage important causes include chromosomal abnormalities, of Singapore, (8) 10 Medical Drive, rates. Bed rest and avoidance of sexual which occur in about 70% of the cases; maternal Singapore 117597 intercourse, though commonly advised, diseases, including poorly-controlled diabetes mellitus;(9) Tien JC are of no proven benefit. Use of uncontrolled thyroid disease,(10) severe systemic lupus Medical Student uterine relaxing agents, human chorionic (11) (12) erythematosus and antiphospholipid syndrome; Raffles Women’s gonadotrophin, immunotherapy and vitamins poor maternal lifestyle habits (including alcohol Centre, Raffles Hospital, remain controversial in idiopathic recurrent consumption, smoking and use of illicit drugs); and 585 North miscarriages. Bridge Road, exposure to non-steroidal anti-inflammatory drugs #12-00, (NSAIDs) around the time of conception.(13) Second Singapore 188770 Keywords: human chorionic gonadotrophin, trimester miscarriages, on the other hand, are more Tan TYT, MBBS, miscarriage, prospective miscarriage risk, commonly caused by specific types of congenital uterine MMed, MRCOG Consultant and recurrent miscarriage, threatened miscarriage anomalies;(14) cervical incompetence;(15) maternal Foetal Maternal Medicine Specialist Singapore Med J 2007; 48(12):1074–1090 infections;(16) maternal thrombophilic states, such as inherited thrombophilias(17) and antiphospholipid Correspondence to: Dr Tony Tan (18) (8) INTRODUCTION syndrome; and also chromosomal abnormalities, Tel: (65) 6311 1230 Miscarriage refers to the loss of a pregnancy before which account for up to 20% of foetal losses during Fax: (65) 6311 1170 Email: tan_tony@ 24 weeks. It is a common complication of pregnancy, this period. rafflesmedical.com Singapore Med J 2007; 48 (12) : 1075 Fig. 1 Graph shows prospective risk of miscarriage according to the gestational age. Patients with recurrent miscarriages deserve Past obstetric history and miscarriage risk special attention, as the risk of recurrence is higher The impact of previous reproductive history on the and the causes tend to be different from sporadic current pregnancy is relevant because many women miscarriages. There has been no difference found in with previous miscarriage(s) will be anxious about the prevalence and frequency of aetiological how this affects them. In comparison to the baseline factors between those with two or three consecutive risk of miscarriage in the general obstetric population miscarriages.(19) This supports the initiation of of between 12%–30%,(1-3) the risk of miscarriage investigations in women who have had only two in women who have never had a miscarriage or are consecutive miscarriages. The recommended primigravida, is low at 4%–5%.(23) However, in women investigations for recurrent miscarriages are listed with a history of miscarriage, the risks are significantly in Table I. However, it remains an unfortunate fact increased. In a woman who has experienced one, two, that in half of the women suffering from recurrent three and four miscarriages, the risk of a miscarriage miscarriages, a possible aetiological cause is never in the next pregnancy is 19%,(23) 24%, 30% and 40%, identified, even after exhaustive investigations.(19) respectively.(24,25) Risk of miscarriage Prospective miscarriage risk depends on gestational age The baseline risk of miscarriage in any pregnancy is A useful piece of information to both clinicians and dependent on parental age, past obstetric history and parents would be the prospective miscarriage risk for gestational age. each gestational week. This concept of prospective risk has been similarly used for stillbirths.(26,27) The Parental age and miscarriage risk prospective risk is derived from the number of It is well-known that the risk of miscarriage increases prospective miscarriages occurring from week N with increased maternal age; a pregnancy at the onwards, divided by the remaining pregnancies on maternal age of 40 years will incur double the week N (Fig. 1). We calculated this from the raw data, risk of miscarriage when compared to one at a available from a large community prospective study, maternal age of 20 years.(20) More recently, it of 550 pregnancies seen by general practitioners has also been shown that the risk of miscarriage in a health centre in the United Kingdom. A major also increases with increased paternal age; a paternal limitation of the prospective risks of miscarriage age of above 40 years incurs 1.6 times the risk of derived from this population is that the gestational miscarriage when compared to a paternal age of age at miscarriage is taken as the week in which 25–29 years.(21,22) the woman presented with a miscarriage. While the Singapore Med J 2007; 48 (12) : 1076 Table I. Causes and recommended investigations for recurrent miscarriages.(7,19) Causes Diagnosis Recurrent foetal chromosomal Karyotype of miscarried foetus(es), if possible, and peripheral blood karyotyping of couple. abnormalities, especially unbalanced chromosomal translocations Uterine abnormalities Saline infusion pelvic ultrasonography / hysterosalpingography (HSG) / hysteroscopy / sonohysteroscopy. Uncontrolled thyroid disease fT4 and TSH (if symptomatic). Uncontrolled diabetes mellitus Random blood glucose / OGTT with or without HbA1c (if symptomatic). Polycystic ovary syndrome Clinical diagnostic criteria (2 out of 3):(62) 1. Oligo- or anovulation. 2. Clinical and/or biochemical signs of hyperandrogenism. 3. Polycystic ovaries on ultrasonography. After the exclusion of other aetiologies, such as congenital adrenal hyperplasia, androgen secreting tumours and Cushing’s syndrome. Antiphospholipid antibodies Lupus anticoagulant (LAC). IgG and IgM anticardiolipin antibodies (ACA). Inherited thrombophilias Protein S assay, protein C assay, activated protein C resistance assay, antithrombin III assay, factor V leiden, total homocysteine. Bacterial vaginosis High vaginal swab. absolute risks reflected in Fig. 1 cannot be used to Table II. Risk of miscarriage (%) according to gestational age and amount of bleeding. counsel patients usefully, it is important to understand Amount of bleeding Gestational age (weeks) the concept of prospective risk of miscarriage and to 5–6 7–9 10–12 appreciate the trend of decreasing prospective risk of miscarriage with increasing gestational age. Light No data 1%(5) available Moderate 29%(29) No data Prognosis of threatened miscarriage with 9.3%(30) available expectant management Severe 2%(5) There are many other causes of vaginal bleeding during early viable intrauterine pregnancy, besides the more common diagnosis of threatened miscarriage. These include cervical erosions and/or polyps, decidual 2,094 patients with light bleeding and 252 patients with reaction of the cervix, implantation bleed and heavy bleeding. The rate of foetal demise in the event vaginitis.(28) The prognosis of a threatened miscarriage of light bleeding