Renal and Hepatic Disorders in Pregnancy

Michael Paech

Renal Disease

Introduction

Renal disease in pregnancy is uncommon, having an estimated incidence of 0.1% (1). It may be present as a consequence of renal disease prior to pregnancy (e.g., systemic lupus erythematosus [SLE], glomerulonephritis), occur antenatally or intrapartum as a result of an obstetric disorder that involves the kidney (e.g., preeclampsia, acute fatty liver of pregnancy [AFLP]), or develop shortly after pregnancy (e.g., acute renal failure [ARF] due to trauma, postpartum hemorrhage, or a thrombotic microangiopathy). The kidney is often involved in preexisting multisystem disorders (e.g., diabetic nephropathy, hypertensive nephropathy) because diabetes mellitus and hypertension account for more than 50% of cases of chronic renal failure in the general population. A few renal disorders are specific to the organ (e.g., urinary tract infection, some inherited diseases).

The obstetric outcomes of women with severe renal disease appear to have improved significantly in recent years, largely because of the use of erythropoietin for anemia, better management of hypertension, high-flux dialysis for end-stage or ARF, and progress in neonatal care (2). The anesthetic management of women with renal disease follows the principles that apply to the non-pregnant patient, with a variety of modifications because of the physiologic differences and pharmacologic considerations that pertain during pregnancy.

Changes in Renal Physiology During Pregnancy, and their Implications

There are a number of changes in renal anatomy and function, and in body fluids and electrolytes, during pregnancy (1,3,4,5) (Table 37-1). Kidney volume increases by 30% and size by 1 cm, mainly because of a 75% to 80% increase in renal blood flow that is a consequence of generalized vasodilation, mediated by increased progesterone, estrogen, nitric oxide, and the circulating ovarian hormone relaxin. The renal pelvis and calyces, and the ureters dilate, more markedly on the right side, mainly due to obstruction by the gravid uterus and congested right ovarian vein.

As well as renal blood flow, the glomerular filtration rate (GFR) increases very early in pregnancy—by 50% (from 100 to 150 mL/min) by the second trimester. The marked increase in creatinine clearance, in the presence of unchanged creatinine production, causes serum urea and creatinine to fall (normal range: 40 to 90 μmol/L; upper limit of range: 80 and 90 μmol/L [1.02 mg/dL] in the second and third trimesters, respectively). Proteinuria increases to a normal range maximum of 300 mg/24 h. Tubular reabsorption of glucose decreases, which contributes to the development of gestational diabetes. Women with severe renal disease may be unable to mount an increase in GFR, such that any further insult, such as hemorrhage or the administration of nephrotoxic drugs (e.g., a non-steroidal anti-inflammatory drug [NSAID]), can cause a serious decline in renal function. Tubular reabsorption of bicarbonate decreases, producing a 4 to 5 μmol/L (4 to 5 mEq/L) decrease in serum bicarbonate, which compensates for the respiratory alkalosis of pregnancy. The healthy kidney increases production of vitamin D, renin, and erythropoietin. Total body water increases by 6 to 8 L and plasma osmolality falls. Those who are unable to increase production adequately may develop normochromic normocytic anemia, vitamin D deficiency, and a reduced plasma volume.

Of note, a normal or slightly raised serum urea and/or creatinine during pregnancy may indicate significant renal impairment. A serum creatinine greater than 70 μmol/L (0.8 mg/dL) during the first trimester warrants further assessment of renal function. The physiologic fall in serum albumin and edema of late pregnancy can mimic nephrotic syndrome. Women presenting with early onset preeclampsia, including proteinuria, may have unrecognized chronic renal disease so should be reviewed by a nephrologist. Any proteinuric preeclampsia is associated with an increased risk of postpartum microalbuminemia, although estimated GFRs are similar to healthy women.

The physiologic changes of pregnancy take up to 3 months to disappear, so postpartum monitoring and review of women with renal dysfunction or preeclamptic proteinuria is required.

Chronic Renal Disease: Maternal and Fetal Implications

Chronic renal disease is found in 1 in 750 to 3,000 pregnancies (6). It may be clinically and biochemically silent, but even in early stages impact on pregnancy outcomes. In addition, although the impact may be clinically undetectable, pregnancy adversely affects abnormal renal function, by means of exacerbation of endothelial dysfunction, and alteration in immune function and inflammatory processes.

Most women have mild renal dysfunction (serum creatinine <124 μmol/L or 1.4 mg/dL) (Table 37-2) and well-controlled hypertension prior to pregnancy, and suffer little or no apparent adverse effect on long-term renal function. There is some evidence to suggest they have more obstetric complications such as preterm and cesarean delivery, and need for neonatal intensive care (7), but most women have good outcomes if antenatal care is adequate.

The severity of renal impairment and of hypertension correlate with pregnancy outcome (1,6), so for women in stages 3 to 5 (which represents moderate to severe disease with serum creatinine 124 to 220 μmol/L or 1.4 to 2.5 mg/dL) (Table 37-2); or who have heavy proteinuria, poorly controlled hypertension or recurrent urinary tract infection
adapt poorly to the pregnancy-induced increases in renal blood flow. They are more likely to suffer not only poor obstetric outcomes (infertility, miscarriage, perinatal death) but also a subsequent decline in renal function (6,8).

Table 37-1 Changes in Renal Anatomy and Physiology in Pregnancy

Parameter	Direction of Change	Approximate Magnitude
Kidney volume	Increases	30% increase
Urinary tract	Dilates
Renal blood flow	Increases	50%
GFR	Increases	50%
Creatinine clearance	Increases	40–65%
Protein excretion	Increases	Max. normal 300 mg/day
Glucose excretion	Increases
Calcium and amino acid excretion	Increases
Plasma volume	Increases	50%
Total body water	Increases	6–8 L
Plasma osmolality	Decreases	5–10 mOsmol/kg
Anion gap	Decreases	To 5–11
Serum bicarbonate	Decreases	4–5 μmol/L
Serum sodium	Decreases
Serum potassium	No change
GFR, glomerular filtration rate.

About 20% of women with early onset preeclampsia, with proteinuria, have undetected chronic renal disease and of those with established moderate or severe chronic renal disease, 40% to 80% develop preeclampsia (1,4). After preeclampsia, the absolute risk of end-stage renal disease remains very low but preeclampsia is a marker for chronic kidney disease, increasing the relative risk significantly (9).

Most aspects of prognosis and management during pregnancy relate to clinical features and the severity of renal dysfunction, rather than to the specific type of disease. Early antenatal assessment by specialists, monitoring of renal function, blood pressure, and proteinuria (Table 37-3); and when appropriate midstream urine for infection and kidney ultrasound for urologic obstruction, is used to detect problems and guide intervention (4). Ultrasonography is an important imaging tool of the renal tract that is complimented by magnetic resonance imaging, especially for renal masses.

Acute Renal Failure During Pregnancy

ARF in pregnancy has multiple causes (Table 37-4) but is a rare event (incidence 1% to 3%; dialysis required in 1 in 10 to 15,000 pregnancies). Maternal mortality from ARF is 5% to 30%, the higher rate associated with sepsis. ARF is usually a complication of common obstetric complications, such as severe preeclampsia, postpartum hemorrhage or puerperal sepsis but also occurs with very uncommon disorders, for example, AFLP or hemolytic uremic syndrome (HUS). Bilateral renal cortical necrosis in addition to acute tubular necrosis is more likely, especially in older women (8). Patients who show delayed recovery may need renal biopsy, but the vast majority of patients return to normal renal function (10).

Table 37-2 Severity of Chronic Renal Disease

Stage	GFR	Estimated GFR (mL/min/1.73 m²)	Serum Creatinine (μmol/L:mg/dL)
1	Normal	>90	to 90:1.02
2	Mild disease	60–89	106–124:1.2–1.4
3	Moderate disease	30–59	124–220:1.4–2.5
4	Severe disease	15–29	Above 220:2.5
5	Renal failure	<15
GFR, glomerular filtration rate.

Pseudo-renal failure results from systemic reabsorption of urea and creatinine from the peritoneal cavity after bladder rupture, in association with uterine rupture or prolonged vaginal delivery when the bladder has not been catheterized. It presents with ascites, ileus, and laboratory parameters of ARF or is an incidental finding at explorative surgery (11).

Renal Replacement Therapy (Dialysis) During Pregnancy

Acute renal replacement therapy is based on experience in non-pregnant patients and may prove inadequate unless the physiologic changes of pregnancy are taken into account. The anesthesiologist should liaise with the patient’s nephrologist, obstetrician and dialysis nurse to determine the patient’s
current hemoglobin, blood pressure, fluid and electrolyte status, use of anticoagulants and dialysis requirement.

Table 37-3 Monitoring of Renal Disease During Pregnancy

Parameter	Details
Urine	4–6 weekly checks for infection, proteinuria, hematuria
Blood pressure	Regular review aiming for 120–140 systolic and 70–90 diastolic blood pressure, with treatment
Renal function	Check serum urea and creatinine, more frequently in grade 3–5 disease and later pregnancy. Protein:creatinine ratio estimation is convenient (>30 mg/μmol abnormal).
Blood count/picture	Check hemoglobin aiming for 100–110 g/L with iron and erythropoietin
Renal tract	Ultrasound at 12 wks gestation and repeat if suggestion of obstruction

Among women already on dialysis, pregnancy rates are low (incidence 1.5%) (8) but improvements in dialysis regimens (12) and the widespread use of erythropoietin (in higher doses) has reduced anovulation and improved fertility rates and pregnancy outcomes (2,13). Protein restriction can be decreased, which improves maternal and fetal nutrition.

Dialysis may also be required in women with renal impairment who become pregnant and then reach end-stage renal failure—this population produces babies of higher birth weight (14). Indications for dialysis include refractory volume overload, hyperkalemia, maternal blood pH <7.2, serum creatinine of 350 to 400 μmol/L (4 to 4.5 mg/dL) or a GFR below 20 mL/min (1). Maternal hypertension occurs in 30% to 50% of dialyzed women, 10% develop preeclampsia and hypertension worsens in 20%. Anemia is common, because red blood cell production is outstripped by the increase in plasma volume, such that up to a 2-fold increase in erythropoietin dose may be required to maintain an adequate concentration of hemoglobin (5,15).

Successful pregnancy outcomes are increasing in these women, with better outcomes generally among those who have been on dialysis for shorter periods before becoming pregnant and those who reach later gestations before requiring dialysis. Preterm delivery (spontaneous or iatrogenic), polyhydramnios, and growth retardation are very common and combined fetal and neonatal death rate continues to be approximately 30% (2,13,14). Attention has been directed to improving fetal outcome by increasing the time spent on dialysis, usually by increasing its frequency (often daily to achieve >20 hours per week) and a predialysis serum urea of 5 to 8 μmol/L (30 to 50 mg/dL) (5,12). Heparinization should target the lowest therapeutic level to reduce the risk of obstetric hemorrhage and low-dose aspirin may be warranted to prevent preeclampsia in women at risk (5). The success of pregnancy among women receiving continuous ambulatory peritoneal dialysis, and the associated perinatal mortality, appears similar to that among women receiving hemodialysis (15). Peritonitis develops in a small percentage, is likely to cause miscarriage or premature labor (2,14), and, in addition to hemoperitoneum, may indicate surgery.

Table 37-4 Causes of Acute Renal Failure During Pregnancy

Severe preeclampsia

Acute fatty liver of pregnancy

Acute deterioration of chronic renal disease

Renal insults, especially sepsis and obstetric hemorrhage, but also drug toxicity and hyperemesis gravidarum

Urinary tract obstruction

Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura

Multiple myeloma and other myeloproliferative disorders

Renal Transplantation

Although they remain lower, pregnancy rates improve dramatically among women of reproductive age who have been transplanted, especially if they are stable, with no or minimal proteinuria, well-controlled blood pressure, no pelvicalyceal distension, serum creatinine <133 μmol/L (1.5 mg/dL) and on low doses of prednisolone, azathioprine, and cyclosporine (5). Successful pregnancy is also possible after simultaneous pancreas–kidney transplant (16).

Short-term graft function is maintained during pregnancy too, provided renal function is good and immunosuppression regimens are stable (4,17). Long-term graft function is rarely adversely affected (17). Triple immunosuppressive therapy should be continued throughout pregnancy, although mycophenolate mofetil is contraindicated based on recent evidence of adverse fetal and neonatal outcomes (4,18).

The most common maternal problems are preexisting and steroid-induced hypertension, urinary tract infection, preeclampsia and steroid-induced impaired glucose tolerance (5). Birth defects are not increased but fetal loss can be high as a result of preterm birth, small for gestational age infants and neonatal mortality. Long-term childhood development of children of transplanted mothers appears normal. Acute rejection during pregnancy is rare, but should be treated with steroids and immunoglobulin, with the safety of anti-lymphocyte globulins and rituximab unknown (5,19).

Kidney donors have similar obstetric outcomes to the general population but compared to predonation pregnancies have a higher fetal loss (approximately 20% vs. 10%), gestational diabetes, gestational hypertension, and preeclampsia (20).

Anesthetic Considerations for Pregnant Women with Renal Disorders

Preoperative Assessment

Severe renal impairment affects most body systems, mandating a systematic preoperative assessment. In the cardiovascular system, symptoms and signs of hypertension and accelerated atherosclerosis are common. Hyperkalemia, hypermagnesemia and chronic metabolic acidosis are common biochemical features. Intestinal absorption of calcium is decreased and phosphate excretion impaired, so hyperphosphatemia develops, calcium is deposited in soft tissues, and in chronic renal failure, osteomalacia occurs. The electrocardiogram should be reviewed for signs of hyperkalemia, which may cause ventricular dysfunction and acute arrhythmias; and for Q–T prolongation, reflecting hypocalcemia.
In chronic renal failure, hypoalbuminemia and low plasma oncotic pressure predispose to the development of pulmonary edema in the presence of fluid overload. A decrease in surfactant production increases the risk of postoperative atelectasis and impaired response to infection increases the risk of pneumonia.

Table 37-5 Safety of Drugs Used in Pregnancy-related Renal and Liver Disease

Drug	FDA Category	Comments
Antiemetics
Metoclopramide	B	Appears safe in pregnancy
Ondansetron	B	More first trimester information required, appears safe thereafter
Prochlorperazine	C	Reports of anomalies but causation uncertain. Extrapyramidal effects possible in neonates.
Promethazine	C	Possible neonatal respiratory depression
Anticoagulants
Aspirin	C/D	Low dose may be safe. Potential growth retardation, bleeding, and acidosis. Near delivery use and premature closure of ductus arteriosus.
Enoxaparin	B	Inadequate evidence but widely used.
Heparin	C	Does not cross placenta
Anti-hypertensives
ACE inhibitors, ARBs	C/D	Avoid. Major anomalies in first trimester and later oligohydramnios, renal failure, skull hyperplasia, death
β-blockers	C/D	Growth retardation, bradycardia, hypotension
Calcium channel blockers	C	Animal embryopathy but inadequate human data
Other
Ursodeoxycholic acid	B	Low risk
Prednisolone	C	Low risk. Possible increase cleft palate, adrenal insufficiency
Azathioprine	D	Low risk
Cyclosporine	C	Low risk
Tacrolimus	C	Probably safe
Lamivudine	C	Low risk
Interferon	C	Not recommended
Mycophenolate mofetil	C	Limited data but not recommended
C/D, C in first trimester and D in second and third trimesters; ACE, angiogenesis-converting enzyme; ARB, angiogenesis receptor blocker.

Glucose intolerance and gestational diabetes mellitus are common, as is normochromic normocytic anemia, although widespread use of recombinant erythropoietin has decreased the incidence of chronic anemia. There is an increased risk of gastric irritation and gastrointestinal hemorrhage. Nausea and vomiting are common in the uremic patient, but more likely to have other etiologies in the pregnant woman with renal disease. Central nervous system manifestations of renal dysfunction, such as confusion or convulsions, are rarely encountered during pregnancy, and are sinister signs of end-stage disease.

Drug Therapy

Knowledge about drug safety during pregnancy is important (Table 37-5). Of particular clinical relevance is the fact that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) cause a 3-fold increase in teratogenic effects and up to 25% fetal and neonatal loss, not only in early pregnancy but with administration in the second and third trimesters, so are contraindicated. Any drug with activity at the fetal renin–angiotensin–aldosterone axis should be discontinued or avoided during pregnancy. NSAIDs are nephrotoxic and must also be avoided. Diuretics are usually avoided except for women with diabetic nephropathy and volume-dependent hypertension. Nifedipine is probably preferable to a β-agonist for tocolysis, because the latter drugs cause hypokalemia and are dangerous in salt-losing interstitial renal diseases. Magnesium sulfate undergoes renal excretion, so infusion rates in preeclampsia and eclampsia need to be reduced and serum concentrations monitored (1).

Immunosuppressive drugs such as cyclophosphamide and mycophenolate mofetil are fetotoxic, but cyclosporin, azathioprine, tacrolimus, and steroids are non-teratogenic and considered safe, with sirolimus unknown (4,5,16,21,22).

Renal dysfunction alters the pharmacokinetics of many drugs. Low serum albumin and metabolic acidosis may increase the free-drug concentration of some drugs, volumes of distribution are often increased, renal replacement therapy may alter drug concentrations and the activity of drugs eliminated in part or largely by the kidneys is prolonged. This may mandate monitoring of drug levels and dose adjustment (Table 37-6), including during general anesthesia.

Breast-feeding is recommended despite chronic renal failure. Most drugs of relevance, for example, prednisolone (prednisone), ACE inhibitors, and azathioprine, have negligible breast milk transfer and are considered safe. Others such as the

immunosuppressive drugs cyclosporin and tacrolimus transfer into breast milk but are also considered acceptable to use during lactation.

Table 37-6 Drug Dosing in Renal Failure

Analgesics
Fentanyl, alfentanil, remifentanil	No change
Morphine, diamorphine	Not cleared by dialysis. Avoid because of accumulation of active metabolites morphine-3-glucuronide and morphine-6-glucuronide
Codeine, dihydrocodeine	Accumulation of morphine metabolites may prolong effect
Oxycodone	Decrease dose by approximately 50%
Buprenorphine	No change
Acetaminophen (paracetamol)	No change
Non-steroidal anti-inflammatory drugs	Contraindicated due to further reduction in GFR
Tramadol	Reduce dose or increase dose interval because active metabolites accumulate
Anesthetics
Propofol, thiopental, ketamine	No change
Isoflurane, desflurane	No change
Sevoflurane	Avoid due to potential fluoride accumulation and toxicity
Succinlycholine (suxamethonium), atracurium, cisatracurium	No change
Vecuronium, rocuronium, pancuronium	No change but avoid repeat dosing due accumulation
Drugs with Sedative Effects
Midazolam	Reduce dose
Clonidine	No change
Phenothiazines, butyrophenones	No change
Antibiotics
Penicillins, cephalosporins	Reduce dose by approximately 50%
Gentamicin	Reduce dose, increase dose interval and monitor levels
Cardiovascular Drugs
α-adrenergic blockers, calcium channel blockers, nitroglycerin (glyceryl trinitrate)	No change
β-adrenergic blockers	Reduce dose
Anti-arrhythmic drugs	No change
Digoxin	Reduce dose and monitor levels
Methyldopa	Prolonged duration due renal excretion
Diuretics	Usually avoid
Other Drugs
Metoclopramide	No change
Ranitidine	Reduce dose by approximately 50%
Low molecular weight heparins	Reduce dose
Oxytocin	No change but caution with fluid overload
Ergonovine, ergometrine	No change
Magnesium	Reduce dose and monitor levels
Cyclosporin, tacrolimus	Avoid if possible but increase dose if required
Azathioprine	Avoid if possible and use minimum effective dose if required

Anesthetic Assessment and General Anesthesia

Patients with mild renal disease but normal renal function and blood pressure present no particular concerns. In contrast, there are many factors to consider when anesthetizing women with moderate to severe renal impairment, end-stage renal failure, or on dialysis. Such patients should be identified as high risk early in pregnancy and appropriate monitoring and management plans established, in liaison with obstetric, nephrology and anesthetic colleagues. For obstetric anesthesia, general recommendations in non-pregnant patients apply (23), but specific issues need consideration (24).

The maternal intravascular volume should be assessed with a view to maintaining blood pressure, renal and placental perfusion. Large fluid or blood volume loss may be poorly tolerated and central venous pressure monitoring can be considered. Arterial blood pressure monitoring is useful if there is severe hypertension or large blood loss is anticipated or occurs. Electrolyte disorders may need correction, with hyperkalemia (>6.0 mEq/L or 6.0 μmol/L) treated using intravenous glucose, insulin, β-adrenergic agonists or dialysis.

Treatment of diabetes is likely to require insulin and dextrose infusions and anemia should be sought and corrected, taking care to avoid blood transfusion of patients who have adapted to low hemoglobin levels. Erythropoietin, initially at a dose increase of 50%, is indicated if hemoglobin concentration is <8 g/dL (80 g/L), aiming to achieve a target of 10 to 11 g/dL (100 to 110 g/L) or a transferrin saturation >30% (1,5). Intravenous iron infusion may be indicated but smaller doses should be given to minimize the risk of fetal iron toxicity. Renal patients are prone to delayed gastric emptying and full precautions against gastric aspiration are advisable. Drugs that are primarily excreted by the kidneys should be avoided or the dosage altered (Table 37-6).

Patients on steroids are at increased infection risk and if taking doses above 7.5 to 10 mg/day, additional steroid cover is required (1). Infection control is particularly important in transplanted or other immunosuppressed women, who have higher rates of urinary tract and cytomegalovirus infection (1).

Prolonged responses to succinylcholine (suxamethonium) have been reported due to pseudo-cholinesterase deficiency despite normal genotype. During ventilation, hypercarbia leads to extracellular acidosis, causing intracellular potassium to move into the extracellular compartment and exacerbate hyperkalemia. In the presence of hypermagnesemia, non-depolarizing muscle relaxants are potentiated. Potassium release following the use of succinylcholine is not increased, but normal potassium release may evoke arrhythmias. Uremia disrupts the blood–brain barrier, resulting in exaggerated responses to induction agents. Neuromuscular blocking drugs with renal excretion should be avoided, making atracurium and cisatracurium preferable to vecuronium or rocuronium. Smaller doses of epidural morphine are advised because of impaired excretion of morphine 3- and 6-glucoronide, so fentanyl is the preferred systemic opioid because it has no active metabolites. NSAIDs are renotoxic and should not be used.

Patients with renal impairment are prone to thrombosis, so anti-thrombotic therapy is frequently indicated. They are also at increased risk of infection, so strict asepsis is required when undertaking invasive procedures. Great care must be taken of arteriovenous fistulae, which should be protected and padded during childbirth or anesthesia. Intravenous cannula must be sited well away from fistulae, using the opposite limb whenever possible.

Patients with osteomalacia are prone to fractures, especially under regional block, so careful attention to positioning and movement is needed. Postoperative sodium and water retention is exaggerated if the concentrating ability of the kidney is impaired, yet hypovolemia may result from fluid loss as a result of pyrexia, vomiting, surgery or hemorrhage.

Consideration must be given to the most appropriate care setting after delivery. High-dependency care, where close monitoring of fluid and electrolyte balance can continue, is often required.

Neuraxial Techniques

Peripheral neuropathies should be documented preoperatively prior to a regional technique, and the possibility of co-existing autonomic neuropathy with delayed gastric emptying remembered.

There is no evidence supporting additional benefits from regional versus general anesthesia in pregnant women with renal impairment. The safety of neuraxial block is not proven but appears acceptable in the absence of platelet or coagulation abnormalities. Before regional block, fluid loading is best avoided, because small increases in end-diastolic volume may result in pulmonary edema. Epidural insertion is generally considered safe in renal patients and has also been used for patients undergoing renal transplantation (25), but a number of potential hazards exist, including epidural hematoma (26). The activity of concomitant low molecular weight heparin therapy must be considered and the platelet count may be normal or low, especially when superimposed preeclampsia exists. Although standard coagulation tests tend to be normal, patients with moderate to severe renal disease can have reduced von Willebrand factor activity (27), so ideally specific hematologic tests will have been performed during early pregnancy.

At acute presentation for labor or delivery, thromboelastography has been suggested but is of unproven utility (28). Abnormal bleeding can be treated with D-desmethyl-arginine vasopressin (DDAVP) and the role of recombinant factor VIIa should be considered.

The disposition of epidural bupivacaine is unaltered, even among those having renal transplantation (25). As a result of a hyperdynamic circulation and acidosis on the binding and pharmacokinetics of local anesthetics, the onset of subarachnoid block may be faster, the dermatomal spread increased by one or two segments, but the duration of the block reduced (29).

Diseases with Renal Involvement in Pregnancy

Diabetic Nephropathy

This develops after 10 to 15 years in type 1 diabetics, and complicates approximately 5% of insulin-dependent diabetic pregnancies. Preconception assessment and monitoring are recommended. Although diabetic nephropathy increases the perinatal risk, the babies of women with microalbuminuria and well-preserved renal function have a very good prognosis (5). ACE inhibitors need to be stopped and anti-hypertensive therapy switched to safer drugs such as methyldopa, labetalol, or nifedipine. Pregnancy is more likely to be complicated by preeclampsia (especially if overt nephropathy is present) and urinary infection, but does not appear to affect disease progression. Given that few diabetic women of reproductive age have significant renal impairment, maternal outcomes are also usually excellent (30).

Glomerulonephritis

This term is a non-specific descriptor of a range of conditions in which the glomerulus is inflamed, whether as a primary renal disease or part of a systemic illness. Diagnosis and
division into pathologic sub-categories is based on clinical findings and renal biopsy, which has a low complication rate in pregnancy but may not be indicated unless it alters therapy. Patients present with acute symptomatic disease (hematuria, edema, rising creatinine) or chronic asymptomatic disease (microhematuria, proteinuria, slow rising creatinine). Nephrotic syndrome is associated with diuretic-resistant edema and hypertension may require treatment with ACE inhibitors and ARBs, though these increase the risk of acute kidney injury and hyperkalemia. Thromboembolism can occur due to increased loss of anticoagulants.

Post-infectious glomerulonephritis is unusual in pregnancy, but occurs particularly after streptococcal throat infection (31). Pregnancy outcome is determined by the severity of renal impairment and the presence of lupus nephritis (32).

Systemic Lupus Erythematosus

SLE is a multisystem autoimmune disease, principally of women of reproductive age. Hypertension is due to lupus nephritis, which is present in 60% of patients within 3 years of initial presentation. Some patients are anti-cardiolipin IgG and IgM antibody positive and others have lupus anticoagulant, which is associated with poorer pregnancy outcomes. Pregnancy increases the risk of a flare in renal or hematologic disease (32). Women with lupus nephritis who conceive are usually in a quiescent phase and adequately controlled, so experience good outcomes. The absence of uterine artery Doppler abnormalities and lupus flares are good prognostic indicators (33). If the nephritis is active, perinatal outcome is poorer and these women show increased organ damage after pregnancy (5). Overall, compared with women without lupus nephritis, those with nephritis are more likely to have fetal abnormalities, pregnancy-induced hypertension and low birth weight infants, but pregnancy outcomes are otherwise similar (34).

Management is based on low-dose steroid therapy (<20 mg/day reduces the risk of inducing hypertension or gestational diabetes), acceptable drugs such as hydroxychloroquine and azathioprine, and in those with lupus anticoagulant, aspirin and low molecular weight heparin (given twice daily to account for increased excretion during pregnancy) (35).

Approximately 2% of the children of mothers with SLE will develop the disease, which is polygenic with environmental precipitants.

Anti-phospholipid Syndrome

Anti-phospholipid syndrome, which occurs in isolation or is associated with other autoimmune diseases, is characterized by significant pregnancy morbidity, especially recurrent pregnancy loss and recurrent arterial and venous thromboses. The kidney is a major target, with pathology including nephropathy, renal artery stenosis and thrombosis, renal infarction and widespread renal vasculature changes (36). During early pregnancy, aspirin is recommended, as is low molecular weight heparin, especially if there have been previous complications. Women with SLE who are also anti-phospholipid antibody positive have higher rates of nephritis and hypertension (37).

Urinary Tract Infection

Dilatation of the renal tract and urinary stasis predispose to this infection, which is the most common cause of abdominal pain in pregnancy and which may trigger preterm labor (3,38).

Bacteriuria is present in 3% to 7% of pregnant women, urinary tract infection in 2% to 30% and acute pyelonephritis in 1%, usually presenting during the second trimester (3,39). Women experiencing recurrent infection should be monitored closely for deterioration of renal function, using renal ultrasound and laboratory testing. Prophylactic antibiotic therapy may reduce further infections and preserve renal function. Pyelonephritis is most often caused by Escherichia coli and group B Streptococcus, so ceftriaxone is a good initial choice of antibiotic. Urinary tract infection is associated with preterm delivery and growth retardation but not increased perinatal mortality (40).

Some women present with septic shock, hemolysis, thrombocytopenia, pulmonary edema and adult respiratory distress syndrome, mandating intensive care (41). It is postulated that low colloid osmotic pressure and plasma fibronectin concentrations during pregnancy explain the apparent increase in vulnerability to pulmonary complications (42).

A rare complication of obstruction and urinary tract infection is non-traumatic rupture of the renal tract. In one series, five patients required nephrectomy; one died before surgery and there were two fetal intrauterine deaths (43).

Reflux Nephropathy and Urinary Stone Disease

Hydronephrosis is a normal physiologic change that commences in the first trimester of pregnancy. It promotes urinary stasis and predisposes to urolithiasis, urinary tract infection and pyelonephritis. These complications are associated with abortion, hypertension, preterm delivery, and fetal growth retardation (40).

Reflux nephropathy is common in women of child-bearing age and renal scarring is an important cause of urinary tract infection and later renal impairment. Some women with severe reflux may benefit from ureteric re-implantation prior to pregnancy or from early dialysis to improve fetal outcome. Scarring occurs in 50% of women who experience bacteriuria in pregnancy, so if bacteriuria is detected, rotating courses of antibiotics are appropriate to prevent symptomatic infection (38).

Urinary tract obstruction may also arise from pelvo-ureteric junction obstruction, ureterocele or most commonly, calculi. Symptomatic calculi are not more common in pregnancy (incidence 1 in 1,500 to 2,500), because excretion of both stone-forming substances and inhibitors (magnesium, citrate, glycosaminoglycans, acute glycoproteins) is increased (3,44). Ureteric stones are twice as common as renal and are mostly calcium phosphate (hydroxyapatite), followed by calcium oxalate (44). The diagnosis of renal colic is difficult because flank pain and other symptoms mimic several other conditions in pregnancy, but overt or microscopic hematuria is almost always present (44,45). Enhanced spiral CT has replaced intravenous urography as the imaging modality of choice in non-pregnant patients but despite the sensitivity and specificity being far less, routine ultrasound evaluation is performed first in pregnancy, to avoid issues of radiation exposure (46). Up to 40% of patients with symptomatic urolithiasis go into preterm labor (45,46).

A third of patients with stones require intervention and those with sepsis and obstruction may need drainage and stone retrieval in addition to intravenous fluids, antibiotics, and analgesics. Seventy to 90% of these patients recover after conservative treatment, such as epidural analgesia or β-adrenergic blockade to stimulate ureteric contractility (44). Even non-calculus hydronephrosis may require ureteric stents or percutaneous nephrostomy, which can be performed with ultrasound or fluoroscopic guidance (with pelvic shielding), under regional or general anesthesia. Extracorporeal lithotripsy may induce labor or harm fetal hearing, so is best avoided, but flexible ureteroscopy with stone baskets or pneumatic or laser lithotripsy is safe and has high rates of success (44,47).

Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder of membrane proteins with incomplete penetrance and a 5% new mutation rate, resulting in a prevalence of 1 in 400 to 1,000 live births (48). Fifty percent of patients ultimately require renal replacement therapy as a consequence of renal cyst enlargement, making the disease the most common genetic cause of renal failure. Cysts are also commonly found in the liver and pancreas but are usually asymptomatic. Intracranial aneurysms are found in 1 in 20 patients but hypertensive or ischemic stroke is more common than hemorrhage. Mitral valve prolapse can occur. New pharmacotherapies are being developed based on animal models of the disease and include tolvaptan, a vasopressin type 2 receptor antagonist, octreotide, rapamycin, sirolimus, and everolimus (48).

The clinical presentation is typically later in life, so pregnant women are usually asymptomatic, declining renal function being associated with increasing multiparity and moderate to severe disease at conception. The aims of preconception counseling and specialist referral are control of hypertension and treatment of complications, because 25% of affected women develop hypertension and 11% develop preeclampsia. Normotensive women with normal renal function generally have uncomplicated pregnancies (49).

Systemic Sclerosis (Scleroderma)

Pregnancy, in women with systemic sclerosis (scleroderma) that is stable, is usually uneventful, although risks include hypertension, renal crises and fetal intrauterine growth retardation. Symptoms other than gastro-esophageal reflux may improve, but monitoring for renal and cardiovascular complications is warranted (50,51). Therapy with oral hydroxychloroquine and intravenous immunoglobulin, but not cyclophosphamide, is appropriate and appears safe.

Tuberous Sclerosis

Tuberous sclerosis is a multisystem autosomal dominant disorder characterized by benign growths in the skin, brain, kidney, and lungs. These hamartomas may cause seizures or renal hemorrhage if angiomyolipomas, which are present in 50% of patients and often multiple and bilateral (52). Few pregnancies in women with tuberous sclerosis have been reported, although anesthesia is usually not a concern and both epidural analgesia and general anesthesia for cesarean delivery are described (52). The management of a pregnant woman with chronic non-malignant pain from the disease is also reported (53).

Vasculopathic Diseases

Wegener’s granulomatosis and Churg–Strauss syndrome are small vessel vasculitides associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Blood vessel walls become inflamed and necrotic, causing fever, night sweats, and weight loss. Those with Churg–Strauss syndrome develop eosinophilic and granulomatous lesions and asthma worsens, but as the disease mostly affects males, pregnancy is rare (54). In Wegener’s granulomatosis, upper respiratory tract disease, epistaxis, nasal bridge collapse, and ARF are features (55).

Treatment in non-pregnancy is with high-dose steroids and cyclophosphamide, but the latter is contraindicated during pregnancy. Plasma exchange may be required and maternal mortality is high. Patients who enter remission within 4 to 6 weeks become ANCA negative and pregnancy should be avoided until in remission. The placenta appears unaffected by the vasculitic pathology, so fetal mortality and morbidity is low. Moyamoya disease is a vascular stenotic or occlusive disease, predominantly among those of Asian ethnicity. It typically involves the cerebrovascular circulation but renal artery stenosis may be present (56).

Takayasu’s arteritis is a rare chronic inflammatory disease, predominantly of women of child-bearing age, affecting the aorta and its main branches, including the renal arteries. Successful pregnancy while on prednisolone, adalimumab, and initially leflunomide has been described, but generally pregnancy should only be contemplated during remission, because the higher intravascular volume exacerbates aortic regurgitation, hypertension, and cardiac failure (57). If anesthesia is required, organ ischemia should be evaluated and intravascular volume optimized. Monitoring may be difficult in a pulseless patient. Titrated regional techniques providing stable hemodynamics and allowing monitoring of the cerebral circulation are recommended (57).

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