Pulmonary oedema (PED) is an accumulation of fluid in the lung interstitium and alveoli. PED is typically divided into cardiogenic and non-cardiogenic mechanisms. Cardiogenic PED, or congestive heart failure, occurs when the heart is unable to pump the blood returning from the lungs to the body effectively, either as a result of intrinsic heart dysfunction or external effects such as hypertension causing increased afterload. Non-cardiogenic PED, also known as acute respiratory distress syndrome (ARDS), occurs due to changes in capillary membrane permeability, resulting in the accumulation of fluid in the alveoli and interstitium. PED complicates between 0.08% and 0.5% of pregnancies.
Pulmonary oedema (PED) is an accumulation of fluid in the lung interstitium and alveoli. PED is typically divided into cardiogenic and non-cardiogenic mechanisms. Cardiogenic PED, or congestive heart failure, occurs when the heart is unable to pump the blood returning from the lungs to the body effectively, either as a result of intrinsic heart dysfunction or external effects such as hypertension causing increased afterload. Non-cardiogenic PED, also known as acute respiratory distress syndrome (ARDS), occurs due to changes in capillary membrane permeability, resulting in the accumulation of fluid in the alveoli and interstitium. PED complicates between 0.08% and 0.5% of pregnancies. The normal physiologic adaptions to pregnancy, discussed below, may predispose pregnant women to the development of PED under certain conditions. Causes of PED in pregnancy are cited as 25% related to tocolytic use (although this is becoming less frequent), 25% due to underlying cardiac disease, 21% to fluid overload and 18% due to pre-eclampsia.1
Approximately 11–14% of pregnancies are complicated by pre-term labour. Birth prior to 37 weeks of gestation is the leading cause of neonatal morbidity and mortality. The use of tocolytic agents to suppress labour may prolong pregnancy for enough time to administer antenatal steroids to the mother so as to enhance lung maturation in the fetus and newborn.1 Recent changes in practice patterns regarding tocolysis have resulted in reduced reliance on β agonists and magnesium sulfate, and increased use of calcium channel blockers and indomethacin. It is suggested that this has resulted in a reduced incidence of PED in pregnancy.2
Pre-eclampsia is classically defined as the triad of proteinuria, oedema and hypertension occurring in pregnancy. The cause of pre-eclampsia is believed to be an abnormality of placentation, though the mechanism is incompletely understood. Worldwide, pre-eclampsia contributes significantly to maternal and fetal morbidity and mortality. The only cure for pre-eclampsia is delivery, which may result in the birth of a pre-term infant. The physiologic perturbations associated with pre-eclampsia place the gravida at increased risk of PED.
Physiologic Adaptations to Pregnancy that Predispose to Pulmonary Oedema
Pregnancy is a time of rapid physiologic change designed to support the developing fetus. These changes may increase the probability of developing PED in the setting of stressors that in non-pregnant patients would be tolerated without adverse effect:
Increased blood volume: plasma volume begins to expand at 6 weeks to reach a maximal increase of 45% above pre-pregnancy values by 32 weeks. Red blood cell mass increases 20–30% due to increased production. The increase in plasma volume is disproportionately larger than the increase in red cell mass, creating a physiologic anaemia.
Decreased peripheral resistance: progesterone mediates increased venous compliance with a resultant decrease in systemic vascular resistance. Blood pressure begins to decrease by week 7. Pregnancy is a condition of maximal venous dilation such that pregnancy is often described as a ‘high flow, low resistance’ state.
Increased cardiac output: cardiac output (heart rate × stroke volume) increases due to an increase in ventricular wall mass and in end diastolic volume. Maternal heart rate increases beginning at 5 weeks’ gestation, up by 15–20% by 32 weeks. Increased cardiac workload and an increased metabolic rate result in increased oxygen consumption.
Decreased colloid oncotic pressure: colloid oncotic pressure is a measure of the attraction of large protein molecules for plasma or water. It is considered dogma that ‘where proteins go, water will follow’. In pregnancy, albumin accounts for the majority (75%) of colloid oncotic pressure. The concentration of albumin is decreased due to haemodilution so that colloid oncotic pressure is approximately 3 mmHg lower in pregnancy than pre-pregnancy. Thus pregnant women are less able to keep fluid intravascular, resulting in the development of oedema.
Risk Factors for Pulmonary Oedema Tocolytics
β-Agonists (Terbutaline, Ritodrine, Salbutamol)
β-agonists increase plasma arginine vasopressin levels and activate the renin-angiotensin system, causing increased resorption of sodium and fluid retention. The retained fluid dilutes serum factors, causing decreased colloid oncotic pressure and increased pulmonary capillary pressure. β-agonists also cause general vasodilation and a drop in systolic blood pressure, compensated by an increased heart rate, stroke volume and cardiac output. This is the likely mechanism for the development of pulmonary oedema.
Calcium Channel Blockers (Nifedipine, Magnesium Sulfate, Nicardipine)
Use of calcium channel blockers, whether for fetal neuroprotection, seizure prophylaxis or tocolysis is associated with an increased risk of developing PED. In a case series of four patients who developed PED after IV nicardipine tocolysis, none had pre-existing heart disease and all, had quick resolution with diuretics.3 In a study by Xiao nifedipine did not increase the risk of PED. However, nifedipine combined with magnesium sulfate, or magnesium sulfate alone was associated with increased risk of PED.4 In the Pulmonary Edema Pre-eclampsia Evaluation (PEPE) study, use of magnesium sulfate for seizure prophylaxis was associated with a tenfold increase in the risk of PED.5 Ogunyemi et al. found that each tocolytic was independently associated with the occurrence of PED (magnesium OR = 14; nifedipine OR = 13; indomethacin OR = 6 and terbutaline OR=6).6
The normal volume increase of pregnancy combined with large volumes of administered fluids and an associated disease process such as pre-eclampsia or infection may overwhelm the ability to compensate with diuresis resulting in PED. Samol and Lambert found that patients who developed PED on magnesium sulfate received higher amounts of infused fluids and suggested that the increased fluid rather than the drug was the cause of PED.7 Sciscione found that iatrogenic fluid overload accounted for 21.5% of cases of PED and that this was the most common cause of post-partum PED.1 These studies imply that judicious fluid management when using calcium channel blockers can significantly reduce or eliminate the risk of PED.
ARDS has been associated with pyelonephritis, chorioamnionitis, endomyometritis, septic abortion and appendicitis during pregnancy. The mechanism is believed to be alveolar capillary membrane damage from endotoxin. Pregnancy and/or delivery may produce an inflammatory environment in the lung, predisposing to the development of ARDS on exposure to a second insult.
In multiple gestation (twins and above) there is an increase in blood volume up to 2500 ml compared to 1600 ml for a singleton.8 Multiple gestations experience an increased cardiac workload, have an increased risk of developing pre-eclampsia and are at increased risk of pre-term labour and exposure to tocolytics. The combination of expanded blood volume plus greater likelihood of both pre-eclampsia and tocolytic use puts these women at particularly high risk of pulmonary oedema. For example, in one study of 71 triplet pregnancies, 15 developed PED (22%); 14/15 were treated with magnesium sulfate either for tocolysis or seizure (eclampsia) prophylaxis.9
In high-order multiples (three or more fetuses), which are typically delivered by caesarean, increased use of IV fluid prior to caesarean delivery was found to be a risk for post-partum PED.10
Pre-eclampsia is associated with a change in colloid oncotic pressure, due to protein loss in the urine and altered endothelial permeability. The increased afterload (hypertension) and diastolic dysfunction of pre-eclampsia contribute to the development of pulmonary oedema.
The PEPE study was a multicentre trial of women with pre-eclampsia and a confirmed diagnosis of PED. Of 92 women with pre-eclampsia, 28 (30%) developed PED. Several markers of severe pre-eclampsia (low platelets, high uric acid and magnesium sulfate use) were associated with development of PED. Interestingly, women who developed PED received less IV crystalloid than those who did not, however use of IV magnesium conferred a tenfold increase in the risk of PED.5