Genetic abnormalities

Chromosomal abnormalities are a common cause of early miscarriage and may result in failure of development of the embryo with formation of a gestation sac without the development of an embryo or with later expulsion of an abnormal fetus. In any form of miscarriage, up to 55% of products of conception will have an abnormal karyotype. The most common chromosomal defects are autosomal trisomies, which account for half the abnormalities, while polyploidy and monosomy X account for a further 20% each. Although chromosome abnormalities are common in sporadic miscarriage, parental chromosomal abnormalities are present in only 3–5% of partners presenting with recurrent pregnancy loss. These are most commonly balanced reciprocal or Robertsonian translocations or mosaicisms.

Endocrine factors

Progesterone production is predominately dependent on the corpus luteum for the first 8 weeks of pregnancy, and the function is then assumed by the placenta. Progesterone is essential for the maintenance of a pregnancy, and early failure of the corpus luteum may lead to miscarriage. However, it is difficult to be certain when falling plasma progesterone levels represent a primary cause of miscarriage and when they are the index of a failing pregnancy. The prevalence of polycystic ovarian syndrome (PCOS) is significantly higher in women with recurrent miscarriage than in the general population. Women with poorly controlled diabetes and untreated thyroid disease are at higher risk of miscarriage and fetal malformation.

Maternal illness and infection

Severe maternal febrile illnesses associated with infections, such as influenza, pyelitis and malaria, predispose to miscarriage. Specific infections such as syphilis, Listeria monocytogenes, Mycoplasma spp. and Toxoplasma gondii also cause miscarriage, but there is no evidence that these organisms cause recurrent miscarriage particularly in the second trimester. The presence of bacterial vaginosis has been reported as a risk factor for preterm delivery and second, but not first trimester, miscarriage. Other severe illnesses involving the cardiovascular, hepatic and renal systems may also result in miscarriage.

Maternal lifestyle and drug history

Antidepressant use and periconceptual non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with miscarriage. Smoking, alcohol (more than 5 units a week), caffeine (more than 3 cups per day), cocaine and cannabis use increase the risk of miscarriage. There is some evidence that stress may also be associated with pregnancy loss.

Abnormalities of the uterus

Congenital abnormalities of the uterine cavity, such as a bicornuate uterus or subseptate uterus, may result in miscarriage (Fig. 18.1). Uterine anomalies can be demonstrated in 15–30% of women experiencing recurrent miscarriages. The impact of the abnormality depends on the nature of the anomaly. The fetal survival rate is 86% where the uterus is septate and worst where the uterus is unicornuate. It must also be remembered that over 20% of all women with congenital uterine anomalies also have renal tract anomalies. Following damage to the endometrium and inner uterine walls, the surfaces may become adherent, thus partly obliterating the uterine cavity (Asherman’s syndrome). The presence of these synechiae may lead to recurrent miscarriage.

Cervical incompetence

Cervical incompetence clinically results in second trimester miscarriage or early preterm delivery. The miscarriage tends to be rapid, painless and bloodless. The diagnosis is established by the passage of a Hegar 8 dilator without difficulty in the non-pregnant woman or by ultrasound examination or by a premenstrual hysterogram. Cervical incompetence may be congenital, but most commonly results from physical damage caused by mechanical dilatation of the cervix or by damage inflicted during childbirth.

Autoimmune factors

Antiphospholipid antibodies – lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) – are present in 15% of women with recurrent miscarriage, but only 2% of women with normal reproductive histories. Without treatment the live birth rate in women with primary antiphospholipid syndrome may be as low as 10%. Pregnancy loss is thought to be due to thrombosis of the uteroplacental vasculature and impaired trophoblast function. In addition to miscarriage there is an increased risk of intrauterine growth restriction, pre-eclampsia and venous thrombosis.

Thrombophilic defects

Defects in the natural inhibitors of coagulation – antithrombin III, protein C and protein S – are more common in women with recurrent miscarriage. The majority of cases of activated protein C deficiency are secondary to a mutation in the factor V (Leiden) gene.

Alloimmune factors

Research into the possibility of an immunological basis for recurrent miscarriage has generally explored the possibility of a failure to mount the normal protective immune response or if the expression of relatively non-immunogenic antigens by the cytotrophoblast may result in rejection of the fetal allograft. There is evidence that unexplained spontaneous miscarriage is associated with couples who share an abnormal number of HLA antigens of the A, B, C and DR loci. Treatment with paternal lymphocytes and immunoglobulins has been shown not to be effective and is potentially dangerous.

Inevitable/incomplete miscarriage

The patient develops abdominal pain usually associated with increasing vaginal bleeding. The cervix opens, and eventually products of conception are passed into the vagina. However, if some of the products of conception are retained, then the miscarriage remains incomplete (Fig. 18.3).

Complete miscarriage

An incomplete miscarriage may proceed to completion spontaneously, when the pain will cease and vaginal bleeding will subside with involution of the uterus. Spontaneous completion of a miscarriage is more likely in miscarriages over 16 weeks gestation than in those between 8 and 16 weeks gestation, when retention of placental fragments is common.

Miscarriage with infection (sepsis)

During the process of miscarriage – or after therapeutic termination of a pregnancy – infection may be introduced into the uterine cavity. The clinical findings of septic miscarriage are similar to those of incomplete miscarriage with the addition of uterine and adnexal tenderness. The vaginal loss may become purulent and the patient pyrexial. In cases of severe overwhelming sepsis, endotoxic shock may develop with profound and sometimes fatal hypotension. Other manifestations include renal failure, disseminated intravascular coagulopathy and multiple petechial haemorrhages. Organisms which commonly invade the uterine cavity are Escherichia coli, Streptococcus faecalis, Staphylococcus albus and S. aureus, Klebsiella, Clostridium welchii and C. perfringens.

Missed miscarriage (empty gestation sac, embryonic loss, early and late fetal loss)

In empty gestation sac (anembryonic pregnancy or blighted ovum) a gestational sac of ≥25 mm is seen on ultrasound (Fig. 18.4), but there is no evidence of an embryonic pole or yolk sac or change in size of the sac on rescan 7 days later. Embryonic loss is diagnosed where there is an embryo ≥7 mm in size without cardiac activity or where there is no change in the size of the embryo after 7 days on scan. Early fetal demise occurs when a pregnancy is identified within the uterus on ultrasound consistent with 8–12 weeks size, but no fetal heartbeat is seen. These may be associated with some bleeding and abdominal pain or be asymptomatic and diagnosed on ultrasound scan. The pattern of clinical loss may indicate the underlying aetiology, for example, antiphospholipid syndrome tends to present with recurrent fetal loss.

Spontaneous second trimester loss

Pregnancy loss occurs between 12 and 24 weeks associated with spontaneous rupture of membranes or cervical dilatation despite the presence of fetal heart activity.

Recurrent miscarriage

Recurrent miscarriage is defined as three or more successive pregnancy losses prior to viability. The problem affects 1% of all women, approximately three times the number that would be expected by chance alone. Most women who have had two or more consecutive miscarriages are anxious to be investigated and reassured that there is no underlying cause for the miscarriage. However, it is important to remember that after two consecutive miscarriages the likelihood of a successful third pregnancy is still around 80%. Even after three consecutive miscarriages, there is still a 55–75% chance of success. This implies that recurrent miscarriage is unlikely to be a random event and that it is necessary to seek a cause.

Surgical management