• 1.
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Smoking in late pregnancy has been shown to have a protective effect against pre-eclampsia, whereas smoking in early pregnancy alone (i.e. quitting early in pregnancy) has no association with risk of pre-eclampsia. A past pregnancy loss is protective against pre-eclampsia, supporting the primipaternity hypothesis that past exposure to the father’s sperm reduces the risk of pre-eclampsia. Prolonged pre-pregnancy co-habitation is protective against pre-eclampsia, again supporting the primipaternity hypothesis that increased exposure to the father’s sperm has a protective effect. Increased risks of pre-eclampsia have been noted at higher elevations within places such as in Colorado and Bolivia compared with lower altitudes, but the mechanism for this increased risk is unknown.

• 2.
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    F b) T c) T d) F e) T

A higher risk of recurrence has been observed after a singleton pregnancy compared with a twin pregnancy. The increased risk of recurrence after pre-eclampsia in a singleton pregnancy is believed to reflect the influence of genetic risk factors associated with a more severe disease subtype, whereas pre-eclampsia caused by transient or modifiable factors, such as multiple pregnancies, is believed to be associated with a milder subtype. The placental pathology typically associated with pre-eclampsia occurs systematically more often when the disease presents at earlier gestational age. Women with onset of pre-eclampsia before 28 weeks have a 24-fold higher risk of mortality than women with later disease onset. Infants born to women with pre-eclampsia at preterm gestational ages are at increased risk of intrauterine growth restriction, whereas infants born to women with pre-eclampsia at term ages are at increased risk of both intrauterine growth restriction and macrosomia.

• 3.
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    F b) F c) T d) F e) F

The proposition that pre-eclampsia is an evolutionary adaptation induced by the fetus as a means to obtain more oxygen and nutrients is known as Haig’s theory. The proposition that increased cortisol levels in fetuses of pregnancies complicated by pre-eclampsia leads to faster lung maturation is known as the stress hypothesis. The fetuses-at-risk hypothesis proposes that as all ongoing pregnancies are at risk of neonatal death after delivery, the correct denominator in the calculation of gestational age-specific neonatal mortality should be the number of ongoing pregnancies at a given gestational age. Under this approach, no survival advantage is observed for preterm infants from pregnancies complicated by pre-eclampsia. Improved antenatal surveillance has not been widely hypothesised to explain the phenomenon. There are no known truly effective ameliorative strategies for pre-eclampsia.

• 4.
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    T b) T c) F d) T e) T

The distribution of risk factors for pre-eclampsia such as increased maternal age, ethnicity or obesity varies between countries, leading to differences in disease incidence. Estimates of pre-eclampsia incidence can be derived from national hospital discharge records, weighted random samples of hospital discharge records, birth certificate data and from birth registries abstracted from medical charts, each of which have different degrees of under-reporting and accuracy. The International Classification of Diseases coding system helps standardise comparisons between countries. The variability associated with use of the ICD codes instead involves changes in definitions between versions of the classification system (e.g. ICD9 vs ICD10). Estimates of disease prevalence from countries are obtained at different time periods, and increases in pre-eclampsia over time can explain some of the differences in between-country comparisons.

• 5.
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    T b) F c) T d) T e) F

Although the 2008 Canadian guideline focuses on diastolic blood pressure ≥90 mmHg for the definition of non-severe hypertension, it states that clinical concern should be raised in women with a systolic blood pressure at or above 140 mmHg. All the other current guidelines use both the diastolic and systolic criteria of 140/90 mmHg. The current national guidelines vary considerably in terms of the definitional criteria for ‘severe’ pre-eclampsia; the Australasian guideline has no such definition. When tested previously within the context of 737 women within the PIERS data set, the 1997 Canadian (gestational age in 2008) and 2000 US definitions were found not to perform well in identifying women and fetuses at risk of adverse outcomes. Guidelines are consistent in the definition of ‘significant’ proteinuria. It has become increasingly evident that the 24-h urine collection should not retain its place as the ‘gold standard.’ Once significant proteinuria has been identified, then clinical decision-making should be guided by serum creatinine not heaviness of proteinuria. Serum creatinine is an independent predictor of adverse maternal outcomes within the fullPIERS model, whereas proteinuria is not. Systolic blood pressure ≥160–170 mmHg is associated with the loss of cerebral arterial auto-regulation and incremental increases in the risk of hypertensive stroke. The Australasian, Canadian, and US guidelines use 160 mmHg as the threshold for ‘severe’ systolic hypertension, whereas the UK guideline uses 170 mmHg. Once these thresholds are crossed, antihypertensive therapy should be instituted to reduce acute stroke risk. It is apparent that the clinical onset of pre-eclampsia remote from term is associated with increased actuarial risks for both mother and fetus. Indeed, disease onset before 32 ⁺⁰ weeks’ gestation is associated with an approximate 20-fold higher risk of maternal mortality than is disease onset ≥37 ⁺⁰ weeks. The current Canadian and US guidelines reflect this less well-recognised fact by using early onset disease as severity criterion. Within the fullPIERS model, gestational age at onset in an independent predictor of adverse maternal outcomes.

• 6.
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    F b) T c) F d) F e) T

Although severe hypertension (≥160–170/110 mmHg) must be treated, there is no evidence that controlling blood pressure below that threshold offers any advantages to women without co-morbid conditions over the following days to weeks. Blood pressure is not a component of the fullPIERS model, although it is for the current interim miniPIERS model (which is purely symptom- and sign-based). Although the fullPIERS model requires external validation, it accurately describes and stratifies maternal risks for up to 7 days. This can be used when counselling woman about balancing the perinatal advantages of expectant management at this gestational age against her own personal risk. Heavy proteinuria should not be used as an indication for delivery, and should be substituted by serum creatinine for provision of renal function surveillance. Even in pregnancies known to be complicated by fetal growth restriction, gaining an additional 1 week gestational age (the period for which fullPIERS is effective) will improve the chances of intact perinatal survival (i.e. without major morbidity) from about 61% to 77%. Neither the fullPIERS model nor the PETRA trial modelling effectively identify markers of maternal risk that are effective beyond 7 days. Inputting gestational age, symptoms (presence or absence of chest pain or dyspnoea), SpO ₂ , platelet count, serum creatinine and AST into the PIERS calculator ( https//:piers.cfri.ca ) assigns a probability that this woman will suffer an adverse outcome over the 48 h to 7 days of 6.6%.

• 7.
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    T b) F c) T d) F e) T

(a), (c), and (d) are well-described mechanisms in the pathophysiology of pre-eclampsia.

As a consequence of endothelial dysfunction, massive volume shifts from the intravascular to interstitial compartments occur, which may manifest as haemo-concentration and oliguria. Increased peripheral vascular resistance is also seen in women with pre-eclampsia; dysregulation of the renin–angiotensin–aldosterone system and enhanced responsiveness to angiotensin II and endothelin have been described. The thrombocytopaenia and microvascular thrombosis seen in haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome results from platelet activation and subsequently, consumption. Again, the underlying pathology seems to be endothelial activation and dysfunction. Although the haemolysis seen in HELLP is considered to be a form of microangiopathic haemolytic anaemia, it is thought to be secondary to mechanical destruction of erythrocytes passing through microvasculature, which are partially occluded by thrombi. Although there may also be a role for complement dysregulation in this process, evidence for an antibody-mediated component in the pathogenesis of the haemolytic anaemia is less compelling.

• 8.
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    T b) T c) T d) F e) T

There is good evidence, from in-vitro and animal models that decidual natural killer cells have a critical role in normal placental development through both contact-dependent and independent mechanisms. Statements (a), (b) and (d) are all supported by experimental literature. Decidual natural killer cells are not capable of ingesting apoptotic trophoblast debris. In contrast, this is a role postulated for decidual macrophages, which may become activated and have a deleterious effect upon trophoblast invasion if they are exposed to large quantities of apoptotic debris.

• 9.
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    T b) T c) T d) T e) F

Experimental evidence supports statements (a), (b) and (c). The role of sFlt-1 in mediating glomerular endotheliosis through antagonism of vascular endothelial growth factor has been demonstrated using in-vitro and animal models. Although the pathophysiology of hepatic dysfunction in HELLP syndrome is less clearly related to anti-angiogenic molecules, the current hypothesis is that endothelial dysfunction in the sinusoids results in obstruction of hepatic blood flow and, consequently, ischaemia. Although more than one theory exists to explain the pathophysiology of eclampsia, the most likely cause is autonomic dysregulation of the cerebral vasculature due to rapid changes in systemic blood pressure. PRES may also occur in the context of non-severe hypertension, suggesting that the relative change in blood pressure or perhaps the degree of endothelial dysfunction may also contribute. Statement (e) is incorrect for a number of reasons. First, pulmonary oedema usually develops post-partum. Second, although decreased plasma colloid pressure does contribute to pulmonary oedema, the most common cause is actually iatrogenic volume overload. Left ventricular dysfunction may contribute in some cases as well.

• 10.
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    T b) T c) F d) T e) F

• 11.
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    F b) F c) F d) F e) F

The areas under the summary receiver operating characteristic curves for blood-pressure measurement in the first and the second trimester are all below 0.80. Blood-pressure measurements in the first and second trimester at the first antenatal visit for healthy normotensive women do not help predict pre-eclampsia. Uric acid has low sensitivity for predicting pre-eclampsia. The accuracy of the available evidence is insufficient to recommend uric acid as a predictor of pre-eclampsia. Using the total proteinuria as a predictive test for the occurrence of pre-eclampsia is not useful, with a sensitivity of 35% (95% CI 13 to 68%) and a specificity of 89% (95% CI 79 to 94%). Circulating levels of vascular endothelial growth factor and maternal serum concentrations of PlGF are significantly lower in women with pre-eclampsia compared to healthy control participants. Using angiogenic biomarkers such as PlGF as a predictive test for the onset of pre-eclampsia or for the onset of early onset pre-eclampsia, the sensitivity and specificity of these tests are in a wide range, and are therefore not useful in daily practice. Maternal serum alpha-fetoprotein is a common test used for screening of fetal aneuploidy and abnormalities. It has a low sensitivity in predicting pre-eclampsia.

• 12.
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    T b) F c) F d) F e) F

Activation of platelets and the clotting system occurs early in the course of pre-eclampsia, before the development of clinical symptoms. Anti-platelet agents may prevent or delay the development of pre-eclampsia. In moderate- and high-risk women, aspirin has shown significant reduction in the risk of pre-eclampsia. The optimal dosage for preventing pre-eclampsia is in the range of 60–100 mg. Rest has been proposed to have a beneficial effect on the prevention of pre-eclampsia. There is insufficient evidence to recommend rest to women to reduce pre-eclampsia. Marine oils are rich sources of n − 3 long chain polyunsaturated fatty acids (omega-3 fatty acids). Marine oil fatty acids have the potential to down-regulate vasoconstriction and endothelial damage responses of pre-eclampsia through direct competition with the thromboxane A2 precursor, arachidonic acid. No beneficial effect has been shown from the use of marine oils in the prevention of pre-eclampsia. Abnormal placental development in pre-eclampsia leads to reduced placental perfusion, and mediates a state of oxidative stress. Antioxidants (such as vitamin C and vitamin E) have been proposed to protect proteins and enzymes from oxidation and destruction by free radicals, and help to maintain cellular membrane integrity. There is no evidence that anti-oxidants are effective in preventing pre-eclampsia.

• 13.
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    F b) T c) T d) T e) T

The presence of normal fetal growth and normal amniotic fluid in women with severe pre-eclampsia remote from term suggests minimal fetal involvement with adequate placental function without reduction in placental perfusion. When severe pre-eclampsia develops before 26 weeks’ gestation, high perinatal morbidities and mortality occur with expectant management. In addition, maternal morbidity such as haemolysis elevated liver enzymes low platelets syndrome, abruptio placentae, pulmonary oedema, and acute renal failure is almost 50%. The onset of vaginal bleeding during expectant management of severe pre-eclampsia can signify the development of abruptio placentae. Its presence usually dictates immediate delivery. The presence of absent reverse end diastolic Doppler flow in the umbilical artery indicates the presence of increased resistance in the placental circulation. In general, most fetuses with this finding will require delivery within 72 h. The development of seizures during expectant management confirms a diagnosis of eclampsia. The onset of eclampsia is associated with increased maternal morbidity, such as aspiration, hypoxia, and potential cerebral injury.

• 14.
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    F b) F c) T d) F e) T

The baseline risk of major malformations is 1–5% of all pregnancies. It is still controversial whether any of the angiotensin-converting enzyme inhibitors increase the risk above the baseline. However, early pregnancy exposure to an angiotensin-converting enzyme inhibitor is not an indication for termination of pregnancy. Antihypertensive treatment for non-severe hypertension is not associated with a decrease in the incidence of pre-eclampsia or any of its associated complications, such as preterm birth. Antihypertensive treatment is associated with lower blood pressure and a decrease in the incidence of blood pressure measurements of 160–170/100–110 mmHg. Blood pressure typically falls during the first half of pregnancy, reaching a nadir at about 20 weeks, and then rises again towards pre-pregnancy levels by term. Methyldopa is the traditional drug of choice on the basis of its long history of use and a well-known, reassuring neurodevelopmental study. However, these data are not reliable and the choice of anti-hypertensive agent in pregnancy for non-severe hypertension cannot be based on long-term outcome data. In women without medical co-morbidities, a wide range of blood pressure goals can be considered reasonable, ranging from 130/80 to 155/105 mmHg. Women without a co-morbidity would not have their blood pressure lowered to below 130/80 outside pregnancy. Choosing an upper limit of 155/105 mmHg allows for a 5 mmHg buffer away from severe hypertension (i.e. 160/110), reflecting intra-individual and inter-observer variability in blood pressure and its measurement, respectively.

• 15.
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    F b) F c) T d) T e) F

Candidates for outpatient care must have blood pressure control, and this woman has severe hypertension. It is possible that she may become a candidate for outpatient care, but she is not a candidate at present. Hydralazine has been associated with an excess of maternal hypotension compared with other antihypertensive agents. The data are not definitive enough to regard parenteral hydralazine as inappropriate for treatment of severe hypertension in pregnancy, but the drug cannot be considered as the agent of first choice. Oral nifedipine (primarily capsules but there is also one trial of intermediate-acting tablets) has been effective for treating severe hypertension in pregnancy, comparing favourably to other antihypertensive agents. Oral labetalol has also been used as part of an effective regional strategy for treating severe pre-eclampsia. MgSO ₄ is indicated for seizure prophylaxis in women with severe pre-eclampsia. This is the likely diagnosis in this patient. It should be emphasised, however, that MgSO ₄ is not an antihypertensive per se , and it cannot be relied upon to result in an effective and sustained decrease in blood pressure. Any risk of an interaction between MgSO ₄ and nifedipine is less than 1%, and the treatment is 1 ampoule of calcium gluconate, which is available in all delivery suites for treatment of magnesium toxicity of any variety. Too few drugs have been studied for treating severe hypertension in pregnancy to restrict therapeutic choices unnecessarily.

• 16.
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    T b) F c) F d) F e) T

Neuraxial haematoma can lead to permanent neurological impairment if untreated. Anaesthetists determine the likelihood of bleeding on the basis of absolute number and trend in platelet count, together with the clinical and laboratory picture of coagulopathy. Regional techniques can be carried out in women taking low-dose aspirin. Caution must be exercised if the parturient is also taking other drugs that affect coagulation. European and American guidelines recommend delaying epidural insertion for at least 24 h after a therapeutic dose of low molecular weight heparin. Doppler ultrasound studies have shown increased umbilical artery blood flow after epidural anaesthesia. Studies have found no detrimental effect on blood pressure or uteroplacental blood flow after spinal anaesthesia. Some anaesthetists prefer epidural anaesthesia as it provides slower onset of anaesthesia and potentially lower risk of hypotension, as well as providing an option for postoperative analgesia. The guideline for removal of an epidural is similar to insertion due to the risks of bleeding.

• 17.
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    F b) T c) T d) F e) F

Studies have clearly demonstrated that both gestational age and birth weight remain the most predictive features of perinatal outcome.

• 18.
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    T b) F c) F d) F e) F

Two previous trials have shown an increased risk of hospital admission and of Caesarean section with decreased fetal movements but no evidence exists to back up the other statements.

• 19.
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    F b) F c) T d) F e) F

A randomised-controlled trial evaluating the use of biophysical profile in this setting is urgently needed and none of the other statements has been reliably shown with BPP.

• 20.
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    T b) F c) F d) F e) F

Only the first statement has been shown to be true.

• 21.
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    T b) F c) T d) T e) T

Benchmarking is only effective when ‘apples are compared with apples’. Benchmarking is cyclical in nature and all aspects of the process need to be undertaken for the process to be successful and result in meaningful practice change. Pivotol to its success is reliable data. Benchmarking is not a process that is merely undertaken for research purposes, as it should be undertaken by both researchers and clinicians in order to motivate clinical practice improvement.

• 22.
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    F b) T c) F d) F e) F

From the benchmarking work cited in this paper, it is possible for the incidence rate for acute pulmonary oedema to be zero cases in units with over 5000 births a year, with pre-eclampsia rates of 5% of all births. Logistic regression techniques accounting for all known potential confounders resulted in the identification of large volumes of intravenous fluid being the causative factor in the development of acute pulmonary oedema in this study.

• 23.
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    F b) T c) T d) F e) T

A lack of communication on multiple levels is the most commonly cited reason in what are determined as ‘preventable deaths’. Medication errors play a large part in these deaths as well as in ‘near miss’ incidents. Magnesium sulphate administration has been well documented as a problematic area in the care of women with hypertension.

• 24.
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    F b) T c) T d) F e) F

Expectant management improves perinatal outcome in a select group of women with severe pre-eclampsia with gestational age between 24 and 34 weeks. For women below or above these gestational ages, both maternal and perinatal outcome are poor. Therefore, expectant management is generally contraindicated in such women. The presence of severe hypertension may lead to stroke and congestive heart failure. Thus, when the blood pressures are in the severe range, parenteral intravenous medications such as hydralazine, labetalol, or both, should be used to keep systolic blood pressure below 160 mm Hg and diastolic blood pressure below 110 mm Hg. Women with severe pre-eclampsia have about 1–2% chance of progressing to eclampsia. Several randomised trials and a recent meta-analysis reveal that prophylactic use of magnesium sulfate in such women reduces the likelihood of seizure by about 50%. When the gestational age is less than 34 weeks, neonatal complications such as respiratory distress syndrome and intraventricular haemorrhage are markedly increased. Several studies and meta-analyses suggest that prenatal administration of corticosteroids at 26–34 weeks gestation is associated with a significant reduction of the rates of respiratory distress syndrome and intraventricular haemorrhage.

• 25.
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    T b) T c) F d) F e) F

Findings from patient surveys suggest that patients prefer having information; analyses of eclampsia cases suggest a greater understanding of the warning signs can improve health outcomes (e.g. reduce incidence of eclampsia). No such effect has been found on perinatal outcome.

• 26.
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    T b) T c) T d) T e) T

Beyond the usual service of providing patient support, advocacy organisations in many disease areas have a long history of materially affecting the research and development process, and improving health outcomes via public policy, public awareness and driving the research agenda. User groups are now commonly used to help develop guidelines.

• 27.
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    T b) T c) F d) F e) F

Magnesium sulfate is more effective than diazepam, phenytoin and the lytic cocktail. The WHO has listed magnesium sulfate as an Essential Medicine. The MAGPIE trial showed that magnesium sulfate reduced the risk of eclampsia by 58%. The NNT was 100 (95% CI 50,100). The MAGPIE trial included women with BP ≥140/90 and proteinuria ≥1. In an LMIC setting, particularly, it should be used in all women with pre-eclampsia regardless of the severity. There was no clear difference in neonatal mortality seen in the MAGPIE trial. Maternal mortality appeared to be lower. Overall, maternal and perinatal morbidity was not significantly different except for a reduced risk of placental abruption. Despite being listed in the WHO essential medicines list, magnesium sulfate is not always available and remains underutilized. There are numerous barriers to its use and these barriers occur at multiple levels.

• 28.
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    T b) F c) F d) T e) F

Calcium supplementation has been shown to have a modest reduction in pre-eclampsia in women with low calcium intake. Calcium does not improve biochemical parameters that are commonly increased in pre-eclampsia. It does, however, reduce the severe manifestations of pre-eclampsia. Existing RCTs have only looked at calcium supplementation after 20 weeks gestational age. One hypothesis that explains the apparent contradiction that calcium supplementation reduces the incidence of pre-eclampsia without affecting biochemical measures and that calcium supplementation in the second half of pregnancy reduces blood pressure. Although women in LMIC are generally deficient in calcium, there are a number of challenges around calcium supplementation. Financial cost, acceptability of the formulation and adherence are barriers. Many women in LMIC may be concurrently supplemented with calcium and iron; however, large studies have not shown an interaction between them.

• 29.
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    T b) T c) T d) F e) T

Currently, there is no evidence to support that women with pre-eclampsia should be screened with novel markers for cardiovascular disease. Therefore, they should be screened for traditional cardiovascular risk factors such as hypertension, diabetes and dyslipidemia. There is Grade A evidence that lifestyle intervention decreases the risk of cardiovascular disease. Women with a history of pre-eclampsia should be treated for cardiovascular risk factors according to locally accepted thresholds. There is no existing evidence to support that women with pre-eclampsia should be treated more aggressively and at lower target thresholds. Approximately 20% of women retain 5 kg postpartum. Women should be encouraged to lose weight as obesity is a risk factor for cardiovascular disease.

• 30.
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    F b) T c) F d) F e) F

Gestational hypertension increases the risk of cardiovascular disease two-fold. Women who develop pre-eclampsia prior to 37 weeks gestational age have the highest risk of premature ischemic heart disease. The relative risk is approximately 8 compared to women who do not develop pre-eclampsia. Severe pre-eclampsia increases the risk by two times. The relative risk of fatal or non-fatal ischemic heart disease in women with mild pre-eclampsia after 37 weeks was over twice that of women without pre-eclampsia. A woman who did not develop a hypertensive disorder of pregnancy has the same baseline risk of heart disease as the general population with similar risk factors.