Obstetric disorders

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Chapter8

Obstetric disorders

Henry G. Murray

Hypertensive disorders of pregnancy

Hypertensive disorders remain the commonest complication of pregnancy in the developed world, and are consistently one of the three main causes of maternal death. The incidence varies substantially in different countries and is influenced by a number of factors, including parity, ethnic group and dietary intake. In the UK the condition occurs in 10–15% of all pregnancies and 4–13% of the population will develop pre-eclampsia, i.e. both hypertension and proteinuria. While most episodes of hypertension are specifically related to the pregnancy and will resolve when the pregnancy is completed, some women who suffer from other forms of hypertension, e.g. essential hypertension or that due to renal disease, will also conceive. These diseases may influence the outcome of the pregnancy and the progress of the disease may be influenced by the pregnancy.

In its mildest form, hypertension alone arising in late pregnancy appears to be of minimal risk to mother or child.

In its most severe form, the condition is associated with placental abruption, convulsions, proteinuria, severe hypertension and oedema, and may result in cerebral haemorrhage, renal and hepatic failure as well as disseminated intravascular coagulopathy. This may lead to fetal and maternal death.

The association between convulsions and pregnancy was described in ancient Greek and Egyptian writings. The first description of eclampsia, with the occurrence of convulsions, hypertension and proteinuria, was given by Vasquez in 1897.

Blood pressure is determined by cardiac output (stroke volume × heart rate) and peripheral vascular resistance. Cardiac output increases substantially in normal pregnancy, but blood pressure actually falls in the mid-trimester. Thus the most important regulatory factor is the loss of peripheral resistance that occurs in pregnancy. Without this effect, all pregnant women would presumably become hypertensive!

As sympathetic tone appears to remain unchanged, peripheral resistance is determined by the balance between humoral vasodilators and vasoconstrictors. There is a specific loss of sensitivity to angiotensin II, which is associated with locally active vasodilator prostaglandins. Thus factors that increase the activity of the renin–angiotensin system or reduce the activity of tissue prostaglandins will result in raising of the blood pressure.

In the pre-eclamptic woman there is evidence of a reduced sensitivity to infused angiotensin II associated with downregulation of vascular and platelet AII receptors, and there is evidence that platelet AII receptors are increased.

Current evidence also suggests that pre-eclampsia is a disease of endothelial dysfunction. Nitric oxide (NO) or endothelial-derived relaxing factor (EDRF) is a potent vasodilator. In pre-eclampsia, NO synthesis is reduced, possibly by the inhibition of NO synthetase activity.

A further area of consideration is the damaging effect of lipid peroxides on the endothelium. Normally, the production of antioxidants limits these effects but, in pre-eclampsia, antioxidant activity is decreased and endothelial damage occurs throughout the body resulting in fluid loss from the intravascular space. All these changes occur in the 2nd trimester long before a rise in blood pressure is measurable in the mother.

Once vasoconstriction occurs in the placental bed, it results in placental damage and the release of trophoblastic material into the peripheral circulation. This trophoblastic material is rich in thromboplastins, which precipitate variable degrees of disseminated intravascular coagulation. This process gives rise to the pathological lesions most notably in the kidney, liver and placental bed. The renal lesion results in sodium and water retention, with most of this fluid accumulated in the extracellular space. In fact, the intravascular space is reduced in severe pre-eclampsia as plasma volume diminishes. At the same time, increased sodium retention results in increased vascular sensitivity to vasoconstrictor influences, and therefore promotes further vasoconstriction and tissue damage in a vicious circle of events that may ultimately result in acute renal failure with tubular or cortical necrosis, hepatic failure with periportal necrosis, acute cardiac failure and pulmonary oedema, and even cerebral haemorrhage as blood pressure becomes uncontrolled.

As the disease progresses, the placenta becomes grossly infarcted and this results in intrauterine growth restriction, increased risk of abruption and sometimes fetal death.

Why do some women develop pre-eclampsia and others do not? Is there a genetic predisposition in some women? The answer to this question is almost certainly yes. Longitudinal studies in the US, Iceland and Scotland have shown that the daughters of women who have suffered from pre-eclampsia or eclampsia have themselves a 1 in 4 chance of developing the disease, a risk that is 2.5 times higher than in the daughters-in-law of such women. The data suggests that a single recessive maternal gene is associated with pre-eclampsia. However, the data could also support a hypothetical model of dominant inheritance with partial penetrance. Although various gene loci have been proposed, there are further long-term studies ongoing to try and identify the correct candidate gene. It is in fact unlikely that there is a single pre-eclampsia gene; it is probable that there are interactions between several genes with external environmental factors enhancing this predisposition. These factors include autoimmune conditions, diseases that increase venous and arterial thromboembolic disease (thrombophilias) and the existence of underlying chronic renal disease or essential hypertension. Dietary intake may also be a factor.

The renal lesion

The renal lesion is, histologically, the most specific feature of pre-eclampsia (Fig. 8.3). The features are:

Fig. 8.3 Renal changes in pre-eclampsia include endothelial swelling (E), apparent avascularity of the glomerulus and fibrin deposition (arrow) under the basement membrane.

• Swelling and proliferation of endothelial cells to such a point that the capillary vessels are obstructed.

• Hypertrophy and hyperplasia of the intercapillary or mesangial cells.

• Fibrillary material (profibrin) deposition on the basement membrane and between and within the endothelial cells.

The characteristic appearance is therefore one of increased capillary cellularity and reduced vascularity. The lesion is found in 71% of primigravid women who develop pre-eclampsia but in only 29% of multiparous women. There is a much higher incidence of women with chronic renal disease in multiparous women.

The glomerular lesion is always associated with proteinuria and with reduced glomerular filtration resulting in a raised serum creatinine. Decreased renal blood flow and proximal tubular changes result in impaired uric acid secretion, leading to hyperuricaemia.

Placental pathology

Placental infarcts occur in normal pregnancy but are considerably more extensive in pre-eclampsia. The characteristic features in the placenta (Fig. 8.4) include:

Fig. 8.4 Placental changes in pre-eclampsia include an increase in syncytial knots, proliferation of cytotrophoblast and thickening of trophoblastic basement membrane.

• increased syncytial knots or sprouts

• increased loss of syncytium

• proliferation of cytotrophoblast

• thickening of the trophoblastic basement membrane

• villous necrosis.

In the uteroplacental bed, the normal invasion of extravillous cytotrophoblast along the luminal surface of the maternal spiral arterioles does not occur beyond the deciduomyometrial junction and there is apparent constriction of the vessels between the radial artery and the decidual portion (Fig. 8.5). These changes result in reduced uteroplacental blood flow and results in placental hypoxia.

Fig. 8.5 Trophoblast invasion of the spiral arterioles results in dilatation of these vessels. This process is defective in pre-eclampsia.

Disseminated intravascular coagulation (DIC)

In severe pre-eclampsia and eclampsia, thrombosis can be seen in the capillary bed of many organs. Multiple platelet and fibrin thrombi can be identified in the brain. Similar changes are seen in the periportal zones of the liver and in the spleen and the adrenal cortex. Thrombocytopenia may occur in some cases, but in only 10% of eclamptic women does the platelet count fall below 100 000/mL. There is an increase in fibrin deposition and in circulating fibrin degradation products as a result of increased fibrin production and impaired fibrinolysis. There seems to be little doubt that, while these changes are not the cause of pre-eclampsia, they do play an important role in the pathology of the disease.

Other associations with pregnancy hypertension

It has been postulated that pre-eclampsia may be due to an abnormality of the fetomaternal host response. There is a lower incidence of pre-eclampsia in consanguineous marriages and an increased incidence of hypertension in first pregnancies of second marriages. Levels of human leukocyte antigen (HLA)-G are altered in pre-eclamptic women.

Indices of cell-mediated immune response have also been shown to be altered in severe pre-eclampsia. However, there are many other factors that operate independently from any potential immunological factors, such as race, climatic conditions and the genetic or familial factors. One of these includes raised free fatty acids found in pre-eclampsia and their causative role in the increased incidence of pre-eclampsia in women with diabetes and obesity.

The HELLP syndrome

A severe manifestation of pre-eclampsia occurs in a variant known as the HELLP syndrome. In this syndrome, there is a triad of manifestations that include haemolysis (H), elevated levels of liver enzymes (EL) and a low platelet count (LP). This manifestation is an extension of the DIC causing the haemolysis and low platelets, and the endothelial dysfunction/hypoxia in the liver resulting in release of liver transaminases especially the alanine aminotransferase (ALT).

The thrombocytopenia is often rapidly progressive and if left to become severe may result in haemorrhage into the brain and the liver. The syndrome demands intervention and termination of the pregnancy as soon as any acute manifestations like hypertension are controlled.

Management of gestational hypertension and pre-eclampsia

The object of management is to prevent the development of eclampsia and to minimize the risks of the condition to both the mother and the fetus. The achievement of these objectives depends on careful scrutiny of the condition of both the mother and the fetus and timely intervention to terminate the pregnancy when the risks of continuation outweigh the risks of intervention.

Blood pressure measurement

A rise in blood pressure (BP) is usually the first sign to be noted at the antenatal visit. Blood pressure should be recorded in a constant position at each visit, as it is posture-dependent. The most comfortable position is seated, with a mercury sphygmomanometer and a cuff of an appropriate size applied to the right upper arm. Automated blood pressure machines can be unreliable in measuring BP in pregnancy.

If the pressure is elevated, the measurement should be repeated after a short period of rest. If the blood pressure remains elevated, then continuing close observation is essential. This may be achieved by hospital admission if significant pre-eclampsia is suspected, a visit to a ‘day ward’ for hypertension of uncertain significance, or by careful scrutiny at home by a visiting midwife or doctor for the possibility of white coat hypertension. The woman should be advised to rest. However, although bed rest improves renal blood flow and uteroplacental flow and commonly results in a diuresis and improvement in the blood pressure, it has not been shown to improve overall outcomes in the mother or the fetus.

The development of more than 1+ proteinuria or a spot urinary/creatinine ratio of more than 30 mg/mmol is an absolute indication for hospital admission as this change constitutes the dividing line between minimal risk and significant risk to both mother and baby.

If the hypertension persists or worsens, and the mother is at or close to term the fetus should be delivered. If it is considered that the fetus would benefit from further time in utero and there is no maternal contraindication, treatment with antihypertensive drugs should be considered. It must be remembered that prolonging the pregnancy in pre-eclampsia is solely for the benefit of the fetus.

Antihypertensive drug therapy

In the presence of an acute hypertensive crisis, controlling the blood pressure is essential but, in the case of mild gestational hypertension and moderate pre-eclampsia, their role is more contentious. There is, however, convincing evidence that the treatment of mild or moderate chronic hypertension in pregnancy reduces the risk of developing severe hypertension and the need for hospital admission.

In women with gestational hypertension, treatment with antihypertensive drugs should be confined to those women who fail to respond to conservative management including stopping work if that is possible. Early treatment possibly reduces the risk of progression to proteinuric hypertension. Management is based on the principle of minimizing both maternal and fetal morbidity and mortality. Blood pressures of more the 170 mmHg systolic or 110 mmHg diastolic must be treated as a matter of urgency to lower the risk of intracerebral haemorrhage and eclampsia. Until recently it was believed that if blood pressure stays above 160/100, antihypertensive treatment is essential as there is a risk of maternal cerebral haemorrhage. Data from the UK maternal death enquiry 2011 clearly shows that treatment is warranted at levels above 150/100.

The drugs most commonly used are:

• methyldopa (oral)

• hydralazine (oral and IV)

• combined alpha- and beta-blockers such as labetalol (oral or IV)

• alpha-blocker such as prazosin (oral)

• calcium channel blockers such as nifedipine (oral).

Note: angiotensin-converting-enzyme (ACE) inhibitors are contraindicated in pregnancy.

Where acute control is required, an intravenous bolus of hydralazine 5 mg or labetalol 20 mg should be administered. Oral medications can take a variable time to control blood pressure.

Steroids: where a woman is less than 34 weeks gestation and her hypertensive disease is severe enough that early delivery is contemplated, betamethazone 11.4 mg IM, 2 doses 12–24 hours apart should be given to minimize neonatal consequences of prematurity like respiratory distress syndrome (RDS), intraventricular haemorrhage and necrotizing enterocolitis.

Maternal investigations

The most important investigations for monitoring the mother are:

• The 4-hourly measurement of blood pressure until such time that the blood pressure has returned to normal.

• Regular urine checks for proteinuria. Initially, screening is done with dipsticks or spot urinary protein/creatinine ratio but, once proteinuria is established, 24-hour urine samples should be collected. Values in excess of 0.3 g/L over 24 hours are abnormal.

• Maternal serum screening for pre-eclampsia.

Laboratory investigations

• Full blood count with particular reference to platelet count.

• Tests for renal and liver function.

• Uric acid measurements: a useful indicator of progression in the disease.

• Clotting studies where there is severe pre-eclampsia.

• Catecholamine measurements in the presence of severe hypertension, particularly where there is no proteinuria to rule out phaeochromocytoma.

Case study

Mrs F was pregnant with her first child after a long history of subfertility. She had been admitted to hospital before her pregnancy for tubal evaluation by dye laparoscopy, but at no time then or subsequently during her pregnancy had she shown any evidence of hypertension. At 32 weeks gestation, she was admitted to hospital at 10 pm with acute headache and severe hypertension, with a blood pressure reading of 220/140. There was no proteinuria and no hyper-reflexia. There was no evidence of fetal growth restriction. Despite initial attempts to control her blood pressure with hydralazine and labetalol, her hypertension remained severe and uncontrollable and she went into high-output cardiac failure and died at 7 am the following morning. Autopsy revealed a large phaeochromocytoma in the right adrenal gland.

This is an extremely rare form of hypertension in pregnancy. It has an appalling prognosis unless it is detected early. In this case it presented late. All other antenatal recordings of blood pressure had been normal. Although it would not have helped in this case, where hypertension is severe and presents antenatally it is always worth checking urinary catecholamines.

Fetoplacental investigations

Pre-eclampsia is an important cause of fetal growth restriction and prenatal death and it is therefore essential to monitor fetal wellbeing using the following methods:

• Serial ultrasounds for:

Measurements of fetal growth every 2 weeks. Parameters measured are fetal biparietal diameter, head circumference, abdominal circumference and femur length.

Measurements of liquor volume up to twice weekly.

• Doppler flow studies up to twice weekly. The use of serial Doppler waveform measurements in the fetal umbilical artery and the maternal uterine artery makes it possible to assess increasing vascular resistance and hence impairment of uteroplacental blood flow typical of pre-eclampsia. In the second trimester poor diastolic flow in the uterine artery waveform warns of an increased risk of pre-eclampsia and fetal growth restriction later in pregnancy. In the third trimester, an increase in the systolic/diastole flow ratio in the fetal umbilical artery due to a progressive diminution of flow in diastole warns of worsening placental vascular disease. Absent or reverse flow in diastole indicates severe vessel disease, probable fetal compromise and delivery of the fetus must be considered if the cardiotocography (CTG) is abnormal.

• Antenatal CTG: Used in conjunction with Doppler assessment, the measurement of fetal heart rate in relation to uterine activity provides a useful, but by no means infallible indication of fetal wellbeing. The presence of episodes of fetal deceleration and the loss of baseline variability may indicate fetal hypoxia.

A summary of the various management strategies is shown in Figure 8.6. This flow diagram shows the various pathways of progression and their management. An initial presentation of mild hypertension may get better with conservative management or it may progress rapidly to the severe forms of pre-eclampsia and ultimately eclampsia.

Fig. 8.6 Flow diagram of the management of gestational hypertension and pre-eclampsia. BP, blood pressure; CVP, central venous pressure; PCWP, pulmonary capillary wedge pressure.

Prevention of pre-eclampsia

There is no doubt that careful management and anticipation can largely prevent the occurrence of eclampsia, but preventing pre-eclampsia is much more difficult.

There is some evidence that calcium supplements may reduce the risk but only in populations that have dietary deficiency. Low dose aspirin acts as an inhibitor of cyclooxygenase activity, thromboxane synthesis and of platelet aggregation. Clinical trials show that low-dose aspirin (60–100 mg/day) has moderate benefits when used for prevention of pre-eclampsia and its consequences, especially in women where there is a history of severe early onset disease. In these women, a thrombophilia screen should be undertaken, as there is an incidence of underlying thrombotic tendencies that may also benefit from low-molecular weight heparin therapy.

Symptoms of pre-eclampsia and eclampsia

Pre-eclampsia is commonly an asymptomatic condition. However, there are symptoms that must not be overlooked and these include frontal headache, blurring of vision, sudden onset of vomiting and right epigastric pain. Of these symptoms, the most important is the development of epigastric pain – either during pregnancy or in the immediate puerperium (Fig. 8.7).

Fig. 8.7 Presenting signs of impending eclampsia.

The occurrence of epigastric pain is commonly misdiagnosed or overlooked as a feature of severe pre-eclampsia and impending eclampsia. Presenting often in the late second trimester, an erroneous diagnosis of indigestion, heartburn or gallstones is made and, unless the blood pressure is recorded and the urine checked for protein, the significance of the pain is overlooked until the woman presents with fitting.

Induction of labour

A pregnancy complicated by hypertensive disease should be terminated for maternal or fetal/placental reasons:

• maternal

gestation > 37 weeks

uncontrollable blood pressure

HELLP syndrome

– rising liver dysfunction

– falling platelets

– falling haemoglobin due to haemolysis

deteriorating renal function (creatinine > 90 mmol/L)

eclampsia

acute pulmonary oedema

• fetal/placental

fetal compromise on CTG tracing

absent or reversal of end diastolic flow in the umbilical artery

no fetal growth over more than 2 weeks

placental abruption.

If the decision has been made to proceed to delivery, the choice will rest with either the induction of labour or delivery by caesarean section. Antenatal steroids should be given for gestations of less than 34 weeks to minimize neonatal morbidity.

If the cervix is unsuitable for surgical induction (Bishop score of less than 7), it can often be ripened by the introduction of a prostaglandin E preparation into the posterior fornix or the use of a mechanical balloon catheter (Foley catheter) through the cervix.

If the cervix is ripe, labour is induced by artificial rupture of membranes and oxytocin infusion (see Chapter 11).