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.

Fig. 18.1 Anomalies of the genital tract.

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.

Clinical types of miscarriage

Threatened miscarriage

The first sign of an impending miscarriage is the development of vaginal bleeding in early pregnancy (Fig. 18.2). The uterus is found to be enlarged and the cervical os is closed. Lower abdominal pain is either minimal or absent. Most women presenting with a threatened miscarriage will continue with the pregnancy irrespective of the method of management.

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).

Distension of the cervical canal by products of conception can cause hypotension and bradycardia (cervical shock).

Incomplete miscarriage

A 32-year-old Asian woman presented with a history of 12 weeks amenorrhoea and vaginal bleeding followed by severe lower abdominal pain. On admission to hospital, she was sweating, pale and hypotensive. Her pulse rate was 68 beats/min. She complained of generalized lower abdominal pain. Initially, a ruptured tubal pregnancy was suspected because of the pain and shock, until vaginal examination revealed copious products of conception protruding from an open cervical os. Removal of these products largely relieved the pain and allowed the uterus to contract, thus reducing the blood loss. Subsequent evacuation of retained products of conception was performed after appropriate resuscitation and preparation.

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.

Fig. 18.4 The empty gestation sac of anembryonic pregnancy seen on ultrasound scan.

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.

Management

Examination of the patient should include gentle vaginal and speculum examination to ascertain cervical dilatation. If there is pyrexia, a high vaginal swab should be taken for bacteriological culture.

Some women may prefer not to be examined because of apprehension that the examination may promote miscarriage, and their wishes should be respected. Management in dedicated early pregnancy assessment units (EPAU) reduces the need for hospital admission and length of stay. An ultrasound scan is valuable in deciding if the fetus is alive and normal. One effect of the routine use of scans in early pregnancy is that the diagnosis of miscarriage may be established before there is any indication that the pregnancy is abnormal. It is sometimes preferable to repeat the scan a week later than proceed to immediate medical or surgical uterine evacuation, to enable the mother to come to terms with the diagnosis.

Miscarriage may be complicated by haemorrhage and severe pain, and may necessitate blood transfusion and relief of pain with opiates. If there is evidence of infection, antibiotic therapy should be started immediately and adjusted subsequently if the organism identified in culture is not sensitive to the prescribed antibiotic.

Septic miscarriage complicated by endotoxic shock is treated by massive antibiotic therapy and adequate, carefully controlled fluid replacement.

If there is evidence of ‘cervical shock’, any products of conception protruding through the cervical os should be removed by grasping them with tissue holding forceps.

Non-sensitized Rhesus (Rh) negative women should receive anti-D immunoglobulin for miscarriages over 12 weeks of gestation (including threatened) and all miscarriages where the uterus is evacuated (whether medically or surgically).

Anti-D immunoglobulin should only be given for threatened miscarriages under 12 weeks gestation when bleeding is heavy or associated with pain. It is not required for cases of complete miscarriage under 12 weeks of gestation when there has been no formal intervention to evacuate the uterus.

There is no evidence that bed rest improves the prognosis in cases of threatened miscarriage, although it may be beneficial in prolonging pregnancy in women at high risk of second trimester loss or where there is prolapse of membranes into the cervical canal as a result of cervical weakness.

Surgical management

Surgical evacuation of retained products of conception involves dilatation of the cervix and suction curettage to remove the products (Fig. 18.5). This is the modality of choice when there is heavy bleeding or persistent bleeding, if the vital signs are unstable or in the presence of infected retained tissue. Serious complications of surgical treatment occur in 2% of cases and include perforation of the uterus, cervical tears, intra-abdominal trauma, intrauterine adhesions and haemorrhage. Intrauterine infection may result in tubal infection and tubal obstruction with subsequent infertility. Screening for infection including Chlamydia trachomatis should be considered and antibiotic prophylaxis given if clinically indicated. If uterine perforation is suspected and there is evidence of intraperitoneal haemorrhage or damage to the bowel, then a laparoscopy or laparotomy should be performed.

Fig. 18.5 Evacuation of retained products of conception.

Medical management

When the uterine contents have not begun to be expelled naturally, the process can be expedited by the use of a prostaglandin analogue such as misoprostol or dinoprostone with or without the antiprogesterone mifepristone. Passage of the products will normally be accomplished in approximately 48–72 hours, but bleeding may continue for up to 3 weeks. Success rates of medical treatment vary between 13% and 96% depending on the type of miscarriage, sac size and dose of prostaglandin. Higher success rates occur in incomplete miscarriage treated with high dose prostaglandins given vaginally. The advantages are that a general anaesthetic is avoided, as are the potential complications of evacuation. Patients undergoing medical management should have 24 hour direct access to hospital services for advice or admission.

Medical and expectant management are an effective alternative to surgical treatment in confirmed miscarriage.

Conservative Management

This is the favoured option for incomplete miscarriages when the uterus is small, or on scan, there is minimal evidence of retained products. It is acceptable management in women with missed miscarriages who do not wish to undergo either of the former options. Success rates depend on similar factors to those for medical management but patients should be warned that it may take several weeks before complete miscarriage.

Whichever method is chosen products should be sent for histological examination, as a small number will prove to be gestational trophoblastic disease.

Sensitive disposal of fetal tissues

A woman or couple should be made aware that information on disposal options is available if they wish to have access to it. The Cremation Regulations do not apply to fetuses under 24 weeks gestation but cremation authorities may cremate them at their discretion. There is no legal duty under burial legislation to bury (or cremate) babies born dead before 24 weeks gestation, but nothing to prevent either option. Communal burial is permitted for fetal tissue.

There is also the option for women or couples to bury at home, provided that certain criteria have been fulfilled.

Any baby, irrespective of gestational age, that is born alive and then dies immediately afterwards is a live birth and neonatal death and should be treated as such in terms of registration and disposal.

Recurrent miscarriage

Recurrent miscarriage should be investigated by examining the karyotype of both parents and, if possible any fetal products. Maternal blood should be examined for lupus anticoagulant and anticardiolipin antibodies on at least two occasions 6 weeks apart. An ultrasound scan should be arranged to assess ovarian morphology for PCOS and the uterine cavity. Women with persistent lupus anticoagulant and anticardiolipin antibodies can be treated with low dose aspirin and heparin during subsequent pregnancies. Those with karyotypic abnormalities should be referred to a clinical geneticist. Cervical cerclage carried out at 14–16 weeks in cases of cervical incompetence reduces the incidence of preterm delivery, but has not been shown to improve fetal survival. An alternative approach to the use of prophylactic cerclage is serial ultrasound measurement of the length of the cervical canal with treatment only if this drops below 25 mm. There is increasing evidence that progesterone (which has anti-inflammatory properties) is effective in prolonging high risk pregnancies. Bacterial vaginosis has been associated with second trimester losses and preterm delivery. Treatment of this condition with clindamycin (not metronidazole) does appear to reduce the risk of preterm delivery, but there is no evidence to support empirical antibiotic use in women with second trimester loss or for other infections.

Genetic abnormalities are the commonest cause of isolated miscarriage but a relatively uncommon cause of recurrent pregnancy loss.

Psychological aspects of miscarriage

In Western Europe most women confirm their pregnancies considerably earlier than in previous generations. A spontaneous miscarriage is often regarded medically as not serious, and is rarely investigated when it occurs for the first time. Follow-up is often left in primary care, and few women receive gynaecological attention or an explanation of their loss. Although there is no evidence to associate miscarriage with an overall increased risk of psychiatric morbidity, almost half of all women are considerably distressed at 6 weeks following miscarriage, and often feel angry, alone and guilty. Women who have had a previous miscarriage and no live child, women who have had a previous termination of pregnancy and those with a previous psychiatric history are most at risk of becoming depressed in the months that follow miscarriage. Women who have had many miscarriages are particularly vulnerable, and should probably receive gynaecological support and counselling.

Ectopic pregnancy

The term ‘ectopic pregnancy’ refers to any pregnancy occurring outside the uterine cavity.

The most common site of extrauterine implantation is the Fallopian tube, but it may occur in the ovary as an ovarian pregnancy, in the abdominal cavity as an abdominal pregnancy, or in the cervical canal as a cervical pregnancy (Fig. 18.6).

Fig. 18.6 Sites of implantation of ectopic pregnancies.

Tubal pregnancy occurs in 1 in 100 pregnancies in the UK, although this incidence varies substantially in different populations. Ectopic pregnancy remains an important cause of maternal mortality (1 per 300 000 cases) in the first trimester with 10–12 women dying every 3 years from the condition in the UK. Sadly, there is evidence of substandard care in the majority of these cases. Tubal pregnancy may occur in the ampulla, the isthmus and the interstitial portion of the tube and the outcome will depend on the site of implantation.

Predisposing factors (Table 18.1)

The majority of cases of ectopic pregnancy have no identifiable predisposing factor, but a previous history of ectopic pregnancy, sterilization, pelvic inflammatory disease (PID) and subfertility all increase the likelihood of an ectopic pregnancy. The increased risk for an intrauterine device (IUD) applies only to pregnancies that occur despite the presence of the IUD. Because of their effectiveness as contraceptives, ectopic rates per year in IUD users are lower than in women not using contraception.

Table 18.1

Risk factors for ectopic pregnancy

	Relative risk
Previous history of PID	4
Previous tubal surgery	4.5
Failed sterilization	9
IUCD in situ	10
Previous ectopic pregnancy	10–15

Clinical presentation

Acute presentation

The classical pattern of symptoms includes amenorrhoea, lower abdominal pain and uterine bleeding. The abdominal pain usually precedes the onset of vaginal bleeding, and may start on one side of the lower abdomen, but rapidly becomes generalized as blood loss extends into the peritoneal cavity. Subdiaphragmatic irritation by blood produces referred shoulder tip pain and syncopal episodes may occur.

The period of amenorrhoea is usually 6–8 weeks, but may be longer if implantation occurs in the interstitial portion of the tube or in abdominal pregnancy. Clinical examination reveals a shocked woman with hypotension, tachycardia and signs of peritonism including abdominal distension, guarding and rebound tenderness. Pelvic examination is usually unimportant because of the acute pain and discomfort, and should be undertaken with caution. This type of acute presentation occurs in no more than 25% of cases.

Acute presentation

An 18-year-old woman, para 0, was brought into casualty collapsed with lower abdominal pain. On admission she was shocked with a blood pressure of 80/40, a pulse of 120 beats/min and a tender, rigid abdomen. Vaginal examination revealed a slight red loss, bulky uterus and marked cervical excitation with a tender mass in the right fornix. At laparotomy, 800 mL of fresh blood was removed from the peritoneal cavity, and a ruptured right tubal ectopic pregnancy was found. Subsequently, a history of recurrent pelvic infections and irregular periods was elicited.

Subacute presentation

After a short period of amenorrhoea, the patient experiences recurrent attacks of vaginal bleeding and abdominal pain. Any woman who develops lower abdominal pain following an interval of amenorrhoea should be considered as a possible ectopic pregnancy. In its subacute phase, it may be possible to feel a mass in one fornix.

Subacute presentation

A 22-year-old woman, para 0, was admitted with vaginal bleeding after 8 weeks of amenorrhoea. She reported a positive home pregnancy kit test, and described passing some tissue per vaginam. Ultrasound scan showed an empty uterus, although serum βhCG was still positive. A presumptive diagnosis of incomplete miscarriage was made, and evacuation of uterus carried out uneventfully. She was discharged the following day, but readmitted that night with lower abdominal pain; a ruptured ampullary ectopic was found at laparotomy. Some days later, histology of the original curettage was reported as ‘decidua with Arias–Stella type reaction, no chorionic villi seen’.

Pathology

Implantation may occur in a variety of sites, and the outcome of the pregnancy will depend on the site of implantation. Abdominal pregnancy may result from direct implantation of the conceptus in the abdominal cavity or on the ovary, in which case it is known as primary abdominal pregnancy, or it may result from extrusion of a tubal pregnancy with secondary implantation in the peritoneal cavity, which is known as secondary abdominal pregnancy. Implantation of the conceptus in the tube results in hormonal changes that mimic normal pregnancy. The uterus enlarges and the endometrium undergoes decidual change. Implantation within the fimbrial end or ampulla of the tube allows greater expansion before rupture occurs, whereas implantation in the interstitial portion or the isthmic part of the tube presents with early signs of haemorrhage or pain (Fig. 18.7).

Fig. 18.7 Penetration of the tubal wall by trophoblastic tissue.

Trophoblastic cells invade the wall of the tube and erode into blood vessels. This process will continue until the pregnancy bursts into the abdominal cavity or into the broad ligament, or the embryo dies, thus resulting in a tubal mole. Under these circumstances, absorption or tubal miscarriage may occur. Expulsion of the embryo into the peritoneal cavity or partial miscarriage may also occur with continuing episodes of bleeding from the tube.

Diagnosis

Ectopic pregnancy should always be suspected where early pregnancy is complicated by pain and bleeding.

Whilst the diagnosis of the acute ectopic pregnancy rarely presents a problem, diagnosis in the subacute phase may be much more difficult. It may be mistaken for a threatened or incomplete miscarriage. It may also be confused with acute salpingitis or appendicitis with pelvic peritonitis. It may sometimes be confused with rupture or haemorrhage of an ovarian cyst.

If sufficient blood loss has occurred into the peritoneal cavity, the haemoglobin level will be low and the white cell count will be usually normal or slightly raised. Serum hCG measurement will exclude ectopic pregnancy if negative with a specificity of greater than 99%, and urinary hCG with modern kits that can be used on the ward will detect 97% of pregnancies. In the presence of a viable intrauterine pregnancy, the serum hCG will double over a 48 hour period in 85% of cases (compared with 15% of ectopic pregnancies). A normal intrauterine pregnancy will usually be visualized on scan where the serum hCG level is more than 1000 iu/L (the discriminatory zone). Serial measurements of serum hCG levels in conjunction with ultrasound diagnosis can distinguish early intrauterine pregnancy from miscarriage or ectopic pregnancies in up to 85% of cases. Ultrasound scan of the pelvis may demonstrate tubal pregnancy in 2% of cases (Fig. 18.8) or suggest it by other features such as free fluid in the peritoneal cavity, but is mainly of help in excluding intrauterine pregnancy (Table 18.2). Intrauterine pregnancy can usually be identified by transabdominal scan at 6 weeks gestation and somewhat sooner by transvaginal scan at 5–6 weeks gestation. Occasionally, there may be no clinical signs of an ectopic pregnancy but if curettage samples submitted for histopathology show evidence of decidual reaction and the Arias–Stella phenomenon is present then it is advisable to consider laparoscopy.

Table 18.2

Features of intrauterine and ectopic pregnancy on transvaginal scan

Intrauterine pregnancy	Ectopic pregnancy
Intrauterine gestation sac (4–5 weeks) Yolk sac (5–6 weeks) Double decidual sign (5 weeks) Fetal heartbeat (7 weeks)

Empty uterus

Poorly defined tubal ring with fluid in pouch of Douglas

Pseudosac in uterus

Tubal ring with extra uterine heartbeat

Fig. 18.8 Ultrasound image of an ectopic pregnancy. The uterus and endometrial cavity can be seen centrally. A fetal pole can be seen in the cavity to the left of the uterus.

Performing a urinary pregnancy test

Although the exact configuration of the various home kits vary the principle steps are (Fig. 18.9):

Fig. 18.9 (Adapted from commons.wikimedia.org.)

(A) A sample of the patients urine is placed on the sample area.

(B) The urine is drawn along the kit by capillary action towards an area containing mouse immunoglobulin that binds to the hCG molecule if present in the urine. These antibodies are also conjugated to an enzyme that catalyzes a colour change.

(C) Bound and unbound mouse antibodies are drawn up the kit by capillary action to a second area containing fixed polyclonal antibodies to hCG and dye. Any mouse antibodies bound to hCG will be trapped here and the enzyme conjugated to them will cause a colour change (a positive result).

(D) Any remaining unbound antibodies will carry on past this area to the control strip zone where they will be trapped by anti-mouse antibodies and catalyze a colour change (this will occur whether the urine contains hCG or not but helps to show that the test is working properly and that a negative result in the first area is due to an absence of hCG.

Management

In patients who are haemodynamically compromised, blood should be taken for urgent cross matching and transfusion. Laparotomy should be performed as soon as possible with removal of the damaged tube.

Non-sensitized Rh negative women should receive anti-D immunoglobulin in any ectopic pregnancy regardless of the mode of treatment.

Surgical management

Once the diagnosis is confirmed, the options for treatment are:

• Salpingectomy: If the tube is badly damaged, or the contralateral tube appears healthy, the correct treatment is removal of the affected tube. If implantation has occurred in the interstitial portion of the tube, then it may be necessary to resect part of the uterine horn in addition to removing the tube.

• Salpingotomy: Where the ectopic pregnancy is contained within the tube, it may be possible to conserve the tube by removing the pregnancy and reconstituting the tube. This is particularly important where the contralateral tube has been lost. The disadvantage is the persistence of trophoblastic tissue requiring further surgery or medical treatment in up to 6% of cases.

Subsequent intrauterine pregnancy rates are similar after both types of treatment, although the risk of recurrent ectopic pregnancy is greater after salpingotomy. Both can be carried out as an open procedure or laparoscopically. The laparoscopic approach is associated with quicker recovery time, shorter stay in hospital and less adhesion formation, and is the method of choice if the patient is stable.

Medical management

Medical treatment of an ectopic pregnancy involves the administration of methotrexate, either systemically or by injection into the ectopic pregnancy by laparoscopic visualization or by ultrasound guidance. Medical treatment is not suitable for all cases of ectopic pregnancy. It is most effective where the ectopic is less than 2 cm in size and the hCG less than 1500 iu/L. Systemic side effects occur in 20% of cases and abdominal pain in 75%. Tubal rupture requiring surgery occurs in 5–10% of cases.

After an ectopic pregnancy treated by any method, 85–90% of subsequent pregnancies will be intrauterine, but only 60% of women will manage to conceive spontaneously, reflecting global tubal disease.

Pregnancy of unknown location

This is defined as a positive pregnancy test where there are no signs on ultrasound of either an intrauterine or ectopic pregnancy, or retained products of conception and occurs in 10% or pregnancies. This may represent an intrauterine pregnancy that is too small to see on ultrasound but requires follow up to exclude ectopic pregnancy. Conservative management with serial hCG measurement and repeat ultrasound is safe for asymptomatic women. A serum progesterone level of less than 20 nmol/L is predictive of pregnancy failure but does not help in predicting pregnancy location.

Management of other forms of extrauterine pregnancy

Abdominal pregnancy

Abdominal pregnancy presents a life-threatening hazard to the mother. The placenta implants outside the uterus and across the bowel and pelvic peritoneum. Any attempt to remove it will result in massive haemorrhage that is extremely difficult to control. The fetus should be removed by laparotomy and the placenta left in situ to reabsorb or extrude spontaneously.

Cervical pregnancy

Cervical pregnancy often presents as the cervical stage of a spontaneous miscarriage. Occasionally, it is possible to remove the conceptus by curettage but haemorrhage can be severe, and in 50% of cases it is necessary to proceed to hysterectomy to obtain adequate haemostasis.

Trophoblastic disease

Abnormality of early trophoblast may arise as a developmental anomaly of placental tissue, and results in the formation of a mass of oedematous and avascular villi. There is usually no fetus but the condition can be found in the presence of a fetus. The placenta is replaced by a mass of grapelike vesicles known as a hydatidiform mole (Fig. 18.10).

Fig. 18.10 Vesicles of a hydatiform mole.

Invasion of the myometrium without systemic spread occurs in about 16% of cases of benign mole, and is known as invasive mole or chorioadenoma destruens. Frankly malignant change occurs in 2.5% of cases, and is known as choriocarcinoma.

Incidence

The overall prevalence of this condition is about 1.5 in 1000 pregnancies in the UK, but is much higher in Asia and South-east Asia. It is relatively more common at the extremes of reproductive age.

Pathology

Molar pregnancy is thought to arise from fertilization by two sperm, and can be diploid with no female genetic material (complete mole) or it may exhibit triploidy (partial mole). Benign mole remains confined to the uterine cavity and decidua. The histopathology exhibits a villous pattern, which is also found in the invasive. However, invasive molar tissue penetrates the myometrium deeply and may result in serious haemorrhage. Choriocarcinoma comprises plexiform columns of trophoblastic cells without villous patterns. Widespread blood-borne metastases are a feature of this disease which, until recent years, carried a very high mortality rate. Metastases may occur locally in the vagina but most commonly appear in the lungs. Theca lutein cysts occur in about one-third of all cases as a result of high circulating levels of hCG. These regress spontaneously with removal of the molar tissue. Fifty percent of cases of choriocarcinoma are not associated with molar pregnancy.

Clinical presentation

Molar pregnancy most commonly presents as bleeding in the first half of pregnancy, and spontaneous miscarriage often occurs at about 20 weeks gestation. Occasionally, the passage of a grape-like villus heralds the presence of a mole. The uterus is larger than dates in about half the cases, but this is not a reliable sign as it may sometimes be small for dates. Severe hyperemesis, pre-eclampsia and unexplained anaemia are all factors suggestive of this disorder. The diagnosis can be confirmed by ultrasound scan and by the presence of very high levels of hCG in the blood or urine.

Management

Once the diagnosis is established, the pregnancy is terminated by suction curettage. Adequate replacement of blood loss is essential. Although there is an increased risk of blood loss there is a theoretical concern over the routine use of oxytocic agents because of the potential to disseminate trophoblastic tissue through the venous system. If possible these should be commenced once the evacuation has been completed. Occasionally repeat evacuation may be required if there is persistent bleeding or a raised serum hCG, but routine second evacuation is not helpful. All cases of molar pregnancy in the UK should be registered with one of the trophoblastic disease screening centres who will arrange follow up. Serial estimations of hCG are followed for a period of 6 months or 2 years, initially every 2 weeks. If hCG levels reach normal within 8 weeks of evacuation of the mole follow-up will be for 6 months, otherwise follow-up will be for 2 years but in the second samples are collected at intervals of 3 months.

If the histological evidence shows malignant change, chemotherapy with methotrexate and actinomycin D is employed and produces good results. In the UK, management of these cases is concentrated in specialized centres.

It must be remembered that choriocarcinoma sometimes can occur following a miscarriage or a normal term intrauterine pregnancy.

Pregnancy is contraindicated until 6 months after the serum hCG levels fall to normal. Oestrogen-containing oral contraceptives and HRT can be used as soon as hCG levels are normal. The risk recurrence in subsequent pregnancies is 1 in 74 and serum hCG levels should be checked 6 weeks after any subsequent pregnancy.

Trophoblastic disease

A 27-year-old primigravid woman attended the clinic with a history of 12 weeks of amenorrhoea, complaining of bright vaginal blood loss and lower abdominal discomfort. Abdominal examination revealed that the uterine fundus was 16 weeks in size. There was fresh blood in the vagina, and the cervical os was closed. There was a high titre of hCG in the urine, and an ultrasound scan showed a snowstorm appearance with the uterine cavity filled with echoes but no evidence of fetal parts (Fig. 18.11). Suction evacuation of molar tissue was performed the following day, and recovery was uneventful.

Fig. 18.11 Hydatiform mole. The typical snowstorm appearance of molar tissue is apparent.

Vomiting in early pregnancy

Nausea and vomiting are common symptoms in early pregnancy (affecting 80% and 50% of women, respectively) usually starting between 4 and 10 weeks gestation, and resolving before 20 weeks. Symptoms persist beyond 20 weeks in 13% of cases but new symptoms appearing after the 12th week should not be attributed to hyperemesis. Hyperemesis gravidarum is defined as persistent pregnancy-related vomiting associated with weight loss of more than 5% of body mass and ketosis. Affecting 0.3–3% of all pregnant women, this is associated with dehydration, electrolyte imbalance and thiamine deficiency.

Aetiology

The aetiology of hyperemesis is uncertain, with multifactorial causes such as endocrine, gastrointestinal and psychological factors proposed. Hyperemesis occurs more often in multiple pregnancy and hydatidiform mole, suggesting an association with the level of hCG. Although transient abnormalities of thyroid function are common this does not require treatment in the absence of other clinical features of hyperthyroidism. Infection with Helicobacter pylori, the organism implicated in gastric ulcers, may also contribute. Women with a previous history of hyperemesis are likely to experience it in subsequent pregnancies.

Diagnosis

It is important to ask about the frequency of vomiting, trigger factors and whether any other members of the family have been affected. A history of vomiting in a previous pregnancy or outside pregnancy should be sought. Smoking and alcohol can both exacerbate symptoms, and should be enquired of. If this pregnancy resulted from fertility treatment or there is a close family history of twins, a multiple pregnancy is more likely. Early pregnancy bleeding or a past history of trophoblastic disease may point to a hydatidiform mole.

The clinical features of dehydration include tachycardia, hypotension and loss of skin turgor. Causes of vomiting not due to pregnancy, such as thyroid problems, urinary tract infection or gastroenteritis, need to be excluded so the abdomen should be palpated for areas of tenderness, especially in the right upper quadrant, hypogastrium and renal angles. A dipstick analysis of the urine for ketones, blood or protein should be performed.

Routine investigations should include full blood count, electrolytes, liver and thyroid function tests. Elevated haematocrit, alterations in electrolyte levels and ketonuria are associated with dehydration. Urine should be sent for culture to exclude infection and an ultrasound arranged to look for multiple pregnancy or gestational trophoblastic disease.

Management

If the vomiting is mild to moderate and not causing signs of dehydration, then usually reassurance and advice will be all that is necessary.

Simple measures include:

• Taking small, carbohydrate meals and avoiding fatty foods.

• Powdered ginger root or pyridoxine (vitamin B₆).

• Avoiding large volume drinks, especially milk and carbonated drinks.

• Raising the head of the bed if reflux is a problem.

A history of persistent, severe vomiting with evidence of dehydration requires admission to hospital for assessment and management of symptoms.

Hypovolaemia and electrolyte imbalance should be corrected by intravenous fluids. These should be balanced electrolyte solutions or normal saline.

Overly rapid rehydration with 5% dextrose can results in water intoxication or central pontine myelinosis.

Thromboprophylaxis with compression stockings and low-molecular weight heparin should be considered. Most women will settle in 24–48 hours with these supportive measures. Once the vomiting has ceased, small amounts of fluid and eventually food can be re-introduced.

Anti-emetic therapy is reserved for those women who do not settle on supportive measures, or who persistently relapse. The use of anti-emetics in pregnancy received widespread publicity when links were found between thalidomide and severe malformations of children born to mothers who had taken the drug for morning sickness. Currently antihistamines are the recommended pharmacological for first-line treatment for nausea and vomiting, no anti-emetic being approved for treatment. Dopamine antagonists (metoclopramide) and phenothiazines (prochloperazine) have not been shown to be teratogenic in humans (though metoclopramide is in animals). 5HT-selective serotonin antagonists such as ondansetron has been used although patient safety data is limited, because it can be given as a wafer and provides an alternative to parenteral administration in patients unable to tolerate other oral therapy.

Vitamin supplements including thiamine should be given, particularly where hyperemesis has been prolonged. If vomiting continues, and the history is suggestive of severe reflux or ulcer disease, endoscopy can be very valuable. It is a safe technique in pregnancy. If severe oesophagitis is confirmed then appropriate treatment with alginates and metoclopramide can be given. Ulcer disease will require H2 antagonist treatment (ranitidine) or if very severe, omeprazole, though there is limited experience of this in pregnancy.

Very occasionally, women do not settle with a combination of the above measures. Some of these women may improve with steroid therapy, though trials are still ongoing. Women in whom there is liver function derangement may benefit particularly. H2 antagonists must be given in conjunction with the steroid treatment. Parenteral nutrition is necessary for some that develop severe protein/calories malnutrition. Specialized nutrition units can be very helpful in this setting.

If hyperemesis is left untreated the mother’s condition worsens. Wernicke’s encephalopathy is a complication associated with a lack of vitamin B₁ (thiamine). Coma and death have been reported because of hepatic and renal involvement. Termination of pregnancy may reverse the condition and has a place in preventing maternal mortality. Hyperemesis persisting into the third trimester should be further investigated as it may be symptomatic of serious illness such as acute fatty liver of pregnancy.

Essential information