Introduction
Many women with renal disease wish to have a baby. In the past renal disease was often considered a contraindication to pregnancy, but times have changed and many women with significant renal problems now embark on a pregnancy.
This chapter provides clinicians with practical advice in relation to management and counseling of such women. We begin with a description of renal physiology and anatomic changes in normal pregnancy and relate these to clinical interpretation issues. We then focus on how to counsel the woman with known renal disease in advance of a pregnancy about likely pregnancy outcomes and how she will be managed during the pregnancy. The following sections deal with those renal problems which arise de novo during pregnancy and then the less common but important areas of managing women on dialysis or with a renal transplant before and throughout their pregnancy. The final section provides suggested models of care, emphasizing the team-based approach to management, integral to any successful “high-risk” pregnancy.
Changes in renal physiology in normal pregnancy
Management of renal disorders in pregnancy begins with an understanding of what changes usually occur in kidney function and structure in normal pregnancy.
Pregnancy causes a major change in systemic hemodynamics, detectable as early as 8 weeks gestation, characterized by reduced systemic vascular resistance and increased cardiac output with resting tachycardia [1]. These changes result in a small reduction in arterial blood pressure, typically reaching a nadir in the mid-trimester of about 10 mmHg systolic, rising towards pre-pregnancy levels at term.
Renal tract anatomy
The kidneys enlarge during normal pregnancy, increasing in length (by up to 1.5 cm) and volume towards term, due to tissue hypertrophy and greater water content. More important from a clinical perspective is the increase in size of the renal pelvices and ureters, occurring in the first trimester and generally detectable by the second. Hydroureter is often observed by ultrasound, more often on the right than on the left. A number of factors are thought to be important in this change. Progesterone, a smooth muscle relaxant, reduces ureteric tone and peristalsis. The asymmetric dilation of the ureters suggests that extrinsic compression by the enlarging uterus at the pelvic brim, hypertrophy of surrounding connective tissue (Waldeyer’s sheath) and kinking due to ligaments or compression by iliac blood vessels all may contribute to this change.
The clinical relevance is that these changes promote urinary stasis and therefore increase the risk of bacterial growth; this also means that any 24-hour urine collection may be incomplete. A second relevance is to the management of pregnant women who present with symptoms that suggest renal colic but no stone is detectable by ultrasound or by radiographic imaging. In these women, it is imperative to exclude urinary tract infection and to avoid the temptation to insert a nephrostomy tube, despite the hydroureter. Firstly, acute renal failure as a consequence of ureteric obstruction in pregnancy is uncommon; secondly, ureteric dilation is part of normal pregnancy and it is not usually possible to distinguish between this and pathologic dilation. Observation of ureteral “jets” (echogenic streams on ultrasound arising from ureteral orifices and entering the bladder) can suggest that there is no significant upstream ureteric obstruction but they must be done in the patient with a full bladder and are even then not always readily visible [2,3]. The only compelling indications for percutaneous nephrostomy or stenting of hydronephrosis associated with calculi in pregnancy are advancing renal failure for no other reason and pyelonephritis failing to respond to antibiotics. Even very large hydroureter resolves quickly after delivery in normal pregnancy [4].
Progesterone also relaxes the bladder wall. However, the gravid uterus displaces the bladder anteriorly and may result in reduced total capacity. Consequently, symptoms of urinary frequency, a feeling of pressure on the bladder and stress incontinence, dysuria and nocturia are commonly reported. In the absence of urine infection, further investigation of these symptoms during pregnancy is not indicated.
Glomerular filtration rate
Renal plasma flow (RPF) and glomerular filtration rate (GFR) increase early in pregnancy, and by the end of the first trimester RPF increases by as much as 80% and glomerular filtration rate by 50% above baseline levels [5]. Increased RPF is thought to be due to reduced renal vascular resistance, possibly mediated by relaxin. This persists through the mid-trimester, with some reports indicating that GFR falls by 20% towards term, but not necessarily returning to baseline until after delivery [6]. The increment in GFR is mostly due to hemodynamic changes with a small change in ultrafiltration coefficient [7]. The fall in plasma oncotic pressure accompanying the fall in serum albumin may also contribute slightly to this increase in GFR. Generally the hemodynamic changes of pregnancy have resolved by 3 months post partum.
Sodium and water balance
Sodium and water retention occur during pregnancy, partly due to stimulation of the renin-aldosterone system, resulting in increased total body water and plasma volume [8]. A relative hyponatremia occurs, with a fall in sodium of about 5 mmol/L, thought to be due to a “reset osmostat” mechanism (i.e. a lower threshold for release of vasopressin, also known as antidiuretic hormone). This is a normal pregnancy-related physiologic adaptation, which correlates with the rise in release of circulating placental human chorionic gonadotropin but the exact mechanism remains unknown [9]. The normal pregnant woman develops thirst at a lower plasma osmolality and retains water, leading to a new equilibrium around a lower plasma sodium concentration.
Tubular function during pregnancy
Serum potassium usually remains in the low normal range, a balance between increased excretion due to both increased urine flow rate and aldosterone, offset by the antimineralocorticoid effect of progesterone [10]. Serum bicarbonate falls slightly as a consequence of a mild respiratory alkalosis induced by progesterone-mediated hyperventilation which then stimulates bicarbonaturia. There is an accompanying metabolic acidosis, probably of fetal origin. The anion gap is slightly reduced in normal pregnancy despite the reduction in serum bicarbonate [11]. Plasma urea falls in association with plasma volume expansion, as does serum albumin, but the fractional excretion of albumin is unchanged, suggesting intact tubular catabolism [12].
Glucose excretion increases during pregnancy, as a consequence of both increased filtered load and altered tubular handling, the latter related somehow to volume expansion.
Urate excretion rises during pregnancy, due to increased filtration, incompletely offset by increased reabsorption, leading to a fall in serum urate of about 25%. Ethnic differences affect serum urate concentration, with higher levels in Pacific Islanders, and higher serum urate levels are also observed in multiple pregnancies, probably due to increased production by placental tissue.
The net result of these changes in normal pregnancy is a slight reduction in serum albumin, hematocrit and hemoglobin, a low normal serum potassium value and reduced plasma sodium and bicarbonate concentration. Plasma pH rises to 7.42–7.44 and arterial PCO2 falls from about 39 to 30 mmHg. Urinary acidification remains normal during pregnancy but there is no indication to test this in usual clinical practice.
Clinical significance of blood tests (Table 7.1)
Table 7.1 Biochemical changes during normal pregnancy∗ (see also Chapter 34)
| Parameter | Pregnant | Nonpregnant |
| Plasma urea | 3.2– 4.4 mmol/L | 4–11 mmol/L |
| 9–12 mg/dL | 11.2–31 mg/dL | |
| Plasma creatinine | <90 μmol/L | <120 μmol/L |
| <1.0 mg/dL | <1.3 mg/dL | |
| Urinary protein excretion (mg/day) | <300 | <150 |
| Plasma Na | 130–140 mmol/L | 135–145 mmol/L |
| 130–140 mEq/L | 135–145 mEq/L | |
| Plasma HCO3 | 18–20 mmol/L | 22–28 mmol/L |
| 18–20 mEq/L | 22–28 mEq/L | |
| Plasma albumin | 25–35 g/L | 35–45 g/L |
| 2.5–3.5 g/dL | 3.5–4.5 g/dL | |
| ∗These ranges are approximate and listed in both SI and conventional units. | ||
The clinical consequences of the above changes are important. First, the definition of renal impairment is modified. The majority of pregnant patients will have creatinines under 76 μmol per litre (1.0 mg/dL) and a serum creatinine above 90 umol/L (1.2 mg/dL) is generally reflective of impaired GFR during pregnancy. A rising urea or creatinine concentration, even within the “normal” range used outside pregnancy, should alert the clinician to the possibility of pre-renal problems such as “effective” or true intravascular volume contraction. Plasma sodium and bicarbonate are typically slightly reduced, potassium should remain low normal, and albumin and urate should be lower than in the nonpregnant state. Increases in plasma sodium to those of nonpregnant women should raise the possibility of (reversible) pregnancy-specific diabetes insipidus (due to excess vasopressinase breaking down vasopressin) [13]. Increments in serum urea, particularly when accompanied by rising hemoglobin or hematocrit, may represent intravascular contraction, typically seen in pre-eclampsia.
Protein excretion
Protein excretion increases in normal pregnancy, predominantly due to an increase in the porosity of the glomerular basement membrane, though the mechanisms leading to this are unknown [7,14]. In association with increased glomerular filtration rate, protein excretion increases such that normal protein excretion during pregnancy is about 200 mg/day, with the upper limit defined as 300 mg per day [15]. Measurement of threshold protein excretion during pregnancy is reliably and rapidly achieved using a mid-stream specimen of urine, a protein/creatinine ratio >30 mg/mmol correlating with >300 mg/day proteinuria [16].
Urine testing in pregnancy
The dipstick urine test is a reasonable screening tool for proteinuria but should not be used alone for this purpose. A dipstick test of “negative” or “trace” protein in most (but not all) studies has a high negative predictive value to exclude proteinuria, whereas “2+” (1 g/L) protein or above strongly correlates with >300 mg/day proteinuria. However, in view of the unreliability of the dipstick, any woman with “1+” (0.3 g/L) protein or above should have formal quantification of protein excretion either with a spot protein/creatinine ratio or 24-hour urinary protein collection. It is important to emphasize that a urinary protein/creatinine ratio above 30 mg/mmol is a good test for detecting proteinuria above the threshold excretion of 300 mg/day but is unproven as being accurate enough to reflect increasing protein excretion as pregnancy progresses, discussed below.
The appearance of glucose in the urine may be normal and is not diagnostic of diabetes mellitus; a formal oral glucose challenge test should be arranged if diabetes is suspected.
Dipstick hematuria during pregnancy is common. Provided the urine sediment is not active, i.e. there are no casts, and the serum creatinine is normal, this is not associated with adverse maternal or fetal outcomes during pregnancy and can be investigated if persistent post partum [17]. Many such cases will resolve after pregnancy. However, the appearance of proteinuria on dipstick or hematuria on microscopic examination of the urine requires further evaluation, and exclusion of urinary tract infection is imperative. Pregnancy may be the first time a woman’s urine is examined, offering the opportunity to diagnose previously undetected renal parenchymal disorders, which may have consequences not only for the pregnancy but for later life.
Chronic kidney disease outside pregnancy
Epidemiology
Chronic kidney disease (CKD) is present in 13.1% of the US population and is increasing in incidence. Although there are many known associations, diabetes, hypertension and cardiovascular disease appear to be the most significant risk factors. Table 7.2 reviews a common classification system for severity of CKD and the estimated prevalence in the US population. Although the minority of these cases occur in women of reproductive age, 1–7% of women of reproductive age on dialysis will become pregnant at some point in their care.
Table 7.2 Staging of chronic kidney disease using the National Health and Nutrition Examination Survey (NHANES)
| Stage | GFR in mL/min/1.73 m2 | Estimated prevalence in the US |
| Stage 1 | GFR is >90 and persistent microalbuminuria | 1.8% |
| Stage 2 | GFR is 60–89 and persistent microalbuminuria | 3.2% |
| Stage 3 | GFR is 30–59 | 7.7% |
| Stage 4 | GFR is 15–29 | 0.35% |
| Stage 5 | GFR is 0–14 (also known as endstage kidney disease (ESKD)) | 2.4% |
GFR, glomerular filtration rate.
Etiology
The leading causes of chronic renal failure in the US are diabetic nephropathy, hypertensive or ischemic nephrosclerosis and various primary and secondary glomerulopathies. Table 7.3 delineates the distinctions between nephrotic and nephritic glomerular renal disease (although there is considerable overlap between these two syndromes) and lists the most common causes of each inx women of reproductive age. Other possible causes of CKD in women of reproductive age are reviewed in Table 7.4, and Table 7.5 reviews the clinical features of four of the most common causes of CKD in patients of reproductive age. Renal biopsy may be necessary to make a definitive diagnosis and is usually warranted for cases of unexplained or rapidly progressive renal failure, in adults with nephrotic syndrome, acute nephritic syndromes or isolated glomerular hematuria with significant proteinuria.
Table 7.3 Features of nephrotic and nephritic renal disease
| Syndrome | Features | Typical causes seen in women of reproductive age |
| Nephrotic syndrome | Urine sediment: inactive Heavy proteinuria (>3.5 g/24 h) Edema, hyperlipidemia, hypoalbuminemia (<30g/L) Biopsy generally does not show prominent inflammation | Minimal change disease Focal glomerulosclerosis Mesangial IgA proliferative GN SLE |
| Nephritic syndrome | Urine sediment: active (i.e. red cells, white cells, granular and red cell casts seen on urine microscopy) Renal insufficiency with variable proteinuria Biopsy does show prominent inflammation | SLE Crescentic GN Postinfectious GN Vasculitis |
GN, glomerulonephritis; SLE, systemic lupus erythematosus.
Table 7.4 Causes of chronic kidney disease (CKD)
| General category | Some specific etiologies that may be seen in women of reproductive age |
| Primary glomerulopathies | Focal glomerulosclerosis Crescentic glomerulonephritis IgA nephropathy Membranoproliferative glomerulonephritis Fibrillary glomerulonephritis Membranous nephropathy |
| Glomerulopathies associated with systemic disease | Diabetes mellitus Hemolytic uremic syndrome Postinfectious glomerulonephritis SLE Wegener’s granulomatosis |
| Hypertension | Ischemic (hypertensive) nephrosclerosis |
| Chronic tubulointerstitial nephropathies | Broad range of causes including: – reflux nephropathy, – medications (e.g. cisplatin, cyclosporine, tacrolimus and lithium) more often a cause of acute kidney injury rather than CKD – genetic (e.g. polycystic kidney disease) – metabolic disturbances (e.g. hypokalemia, hypercalcemia, hyperuricemia) |
| Obstructive uropathies (rare) | Ureteral obstruction (congenital, calculi) Vesicoureteral reflux |
| Renovascular disease | Renal artery stenosis caused by fibromuscular dysplasia in this age group – rarely causes ESKD |
| Hereditary nephropathies | Polycystic kidney disease Alport’s syndrome Familial hyperuricemic nephropathy |
ESKD, endstage kidney disease; SLE, systemic lupus erythematosus; TB, tuberculosis.
Table 7.5 Clinical features of four of the more common causes of renal disease in women of reproductive age
| Disease | Clinical features |
| IgA nephropathy | IgA nephropathy is the most common primary GN in the developed world. It presents typically in the second of third decade of life Presentation is typically with hematuria following a viral upper respiratory tract infection or on the basis of a routine screening urinalysis. Diagnosis is made on immunoflourescence staining of renal biopsy which reveals prominent clumps of IgA deposits in the mesangium Most patients have slowly progressing disease, although those with proteinuria tend to have worse prognosis. 25–50% of patients with IgA nephropathy have renal insufficiency or ESKD 20 years into the diagnosis Most patients are managed with risk factor modifications listed in Table 7.6 |
| SLE-related nephropathy | SLE is associated with 6 distinct types of glomerular disease, each with its own prognosis and management. These types are: I. minimal mesangial, II. mesangial proliferative, III. focal, IV. diffuse, V. membranous, VI. advanced sclerosing lupus nephritis. This has been further classified according to chronicity and whether changes are global or segmental Class I and II have a good prognosis and do not require treatment. Classes III–IV require steroid and other immunosuppression therapy such as mycophenolate or cyclophosphamide. Class V may sometimes need this therapy if the nephrotic syndrome is severe or progressive. Class VI has a high risk of ESKD and does not respond to immunosuppressive treatment as the sclerosis changes are not reversible |
| Reflux nephropathy | Renal damage that occurs from childhood vesicoureteral reflux with or without associated recurrent urinary tract infections leading to interstitial scarring and presenting as asymptomatic renal insufficiency and scarred small kidney(s) in an adult who may or may not have been known to have recurrent UTI in childhood. Urine sediment is often not active but proteinuria is apparent as CKD progresses and there is typically hypertension |
| Focal segmental glomerulosclerosis | The most common cause of nephrotic syndrome in adults and the most common primary glomerular disease to cause ESKD in the US It presents typically as nephrotic syndrome or at least heavy proteinuria and will generally lead to ESKD if not treated Treatment is often with prednisone, with cyclosporine an option for steroid-resistant cases |
CKD, chronic kidney disease; ESKD, endstage kidney disease; GN, glomerulonephritis; IgA, immunoglobulin A; SLE, systemic lupus erythenatosus; UTI, uterine infection.
Management of CKD outside pregnancy
Management of patients with CKD involves treating or removing any underlying cause (e.g. obstruction, recurrent urinary infections, HIV, SLE, chronic infection) and preventing or slowing progression. The treatment of specific etiologies of CKD varies considerably and is not suitable for a summary, but the general management of established CKD is more uniform and is summarized in Table 7.6 both for the nonpregnant patient and with any modifications for pregnancy. The rate of progression of CKD is highly variable even for specific etiologies but each of the interventions listed in the table is viewed to have some role in preventing progression to endstage renal disease.
Table 7.6 Management of CKD in nonpregnant patients
| Intervention | Method | Modification of intervention for pregnancy |
| Interventions to prevent progression of CKD | ||
| Maintain good blood pressure | Antihypertensive therapy to bring BP <130/80 or lower (an ACE inhibitor or ARB is preferred in diabetic patients) | Stop ACE inhibitors and ARB prior to conception or early in pregnancy |
| Not clear what goal BP should be in pregnancy but consider target of 130/80 and avoid hypotension | ||
| Methyldopa, labetalol or oxprenolol probably preferred agents in pregnancy | ||
| Quit smoking | No change | |
| Nutrition | Keep at least 0.8–1.0 g/kg per day to avoid protein malnutrition and ensure adequate calorie and nutrient intake | Liberalize dietary protein to at least 1–1.2 g/kg/day of preconception weight |
| Treat hyperlipidemia | Typically achieved with both diet and a statin to bring the LDL to <70–100 mg/dL or 1.8–2.6 mmol/L. This guideline is the subject of ongoing clinical trials and not yet of proven benefit | Stop statins and other lipid-lowering drugs after first missed period or positive pregnancy test Correct hyperglycemia (which can cause hypertriglyceridemia) with insulin in a patient with diabetes |
| Correct metabolic acidosis | Typically done by administering sodium bicarbonate in a daily dose of 0.5–1 mEq/kg/day to maintain a serum bicarbonate of >22 mEq/L | Serum bicarbonate normally drops in pregnancy to 18–20 mEq/L and should not be corrected above this level |
| Interventions to prevent complications of CKD | ||
| Potential complications | Preventive measure/treatment | Pregnancy adjustments |
| Volume overload | Salt and fluid restriction Loop diuretics | Use diuretics with caution to ensure no decrease in intravascular volume that could impair placental perfusion. |
| Avoid diuretics in the setting of preeclampsia where intravascular volume is likely to be decreased | ||
| Hyperkalemia | Dietary potassium restriction If necessary, low-dose daily administration of a potassium-binding resin (e.g. kayexalate) | No change |
| Hyperphosphatemia | Dietary restriction of phosphate to <800 mg/day Administration with each meal of a phosphate binder such as calcium phosphate | No change |
| Renal osteodystrophy (a bone disease related to alterations in phosphate and vitamin D metabolism in CKD) | Dietary restriction of phosphate to <800 mg/day and phosphate binders as above Administration of the vitamin D metabolite calcitriol | No change |
| Anemia | Managed when necessary with administration of erythropoietin | No change |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; LDL, low-density lipoprotein.
In addition to the complications listed in Table 7.6, patients with endstage kidney disease (ESKD) may also suffer from uremic bleeding due to platelet dysfunction, uremic pericarditis, uremic neuropathy, thyroid dysfunction and malnutrition. In general, these complications are avoided with current treatment by early dietary intervention and commencement of dialysis before such a late stage of CKD. Patients with ESKD and these complications are managed with hemodialysis, peritoneal dialysis or renal transplant. The usual indications for beginning dialysis in nonpregnant patients with CKD are listed in Box 7.1.
Management of pre-existing renal disease in pregnancy
Management of the pregnant woman with chronic renal disease ideally begins prior to pregnancy with time for appropriate counseling regarding the potential risks and likely outcomes not only of the pregnancy but for the woman post partum. Attitudes have changed over the past 20–30 years, with chronic renal disease no longer seen as an automatic contraindication to pregnancy [18]. However, the data we use to counsel women today are still those derived from a few key studies published 10–20 years ago [19–26], summarized clearly in two key reviews [5,27]. A recent review searched the literature from January 1990 through December 2005 and found 23 publications relevant to this topic [28]. None were randomized clinical trials or meta- analyses and the comment was made that most outcome studies lacked an appropriate control group. Nevertheless, these authors agreed with previous reviewers that the two key issues in pre-pregnancy counseling are assessment of:
- the degree of renal insufficiency at the time of conception
- control of hypertension pre-pregnancy and throughout pregnancy.
Imbasciati et al. [29] recently reviewed 49 women with GFR less than 60 mL/min before conception, (i.e. at least stage 3 chronic kidney disease), whose pregnancy proceeded beyond 20 weeks. They noted that as a group, GFR was lower after pregnancy than before conception but the fall in GFR was predicted by the combined presence of a preconception GFR below 40 mL/min and proteinuria greater than 1 g per day, not by GFR alone.
Box 7.1 Indications for renal replacement therapy in nonpregnant patients with endstage renal disease
Life-threatening clinical indications
- Fluid overload unresponsive to diuretics
- Hypertension refractory to medication
- Uremic pericarditis or pleuritis
- Uremic encephalopathy or neuropathy
- Clinically significant bleeding due to uremia
- Metabolic disturbances refractory to medical treatment (hyperkalemia, acidosis, hyperphosphatemia, hyper/hypocalcemia)
- Malnutrition or weight loss
Laboratory parameters
- GFR <15 mL/min/1.73 m2 (National Kidney Foundation
- Dialysis Outcomes Quality Initiative) or <8–10 mL/min/1.73 m2 (European Best Practice Guidelines)
GFR, glomerular filtration rate.
In broad terms, women with mild renal impairment and controlled hypertension will have a successful pregnancy outcome while those with moderate to severe renal insufficiency, particularly when accompanied by hypertension, have a lower chance of having a live baby, will certainly have more maternal complications during the pregnancy and have an accelerated rate towards dialysis or transplantation following the pregnancy. Some believe that only pre-existing hypertension predicts the pregnancy outcome [30] but the study quoted as evidence for this opinion was conducted largely in women with mild renal impairment. Counseling needs to occur around the following issues:
- chances of fertility in relation to the degree of renal impairment
- progress of renal disease during the pregnancy
- likelihood of prematurity or fetal growth restriction
- likelihood of livebirth
- control of hypertension and development of superimposed pre-eclampsia
- progression to endstage renal failure after delivery.
There are no true estimates of the likelihood of fertility in women with moderate to severe renal impairment; in general, these women have a reduced fertility rate though even women on dialysis may become pregnant and should be advised to use contraception unless truly planning a pregnancy. Contraceptive options for women with renal insufficiency include barrier methods, progesterone-only pills, injections and implants and tubal ligation. The use of the combined oral contraceptive pill is reasonable in women with renal disease who do not have nephrotic range proteinuria, have well-controlled hypertension and no history of thrombosis.
The likelihood of progression of renal disease during the pregnancy depends only partly on the intrinsic nature of the renal disorder but significantly on the baseline GFR (Boxes 7.2 and 7.3), control of hypertension and the development of superimposed pre-eclampsia. The natural history of most chronic renal disorders during pregnancy is that progressive deterioration during a 40-week interval is unlikely, the main exception being SLE which by its nature can flare, leading to accelerated renal disease during the pregnancy. About 50% of women with moderate renal insufficiency have a significant rise in serum creatinine in the third trimester and if this occurs, almost one in four progresses to endstage renal disease within 6 months after delivery.
Box 7.2 Maternal renal outcomes according to pre-pregnancy serum creatinine
Creatinine <130 μmol/L (<1.5 mg/dL)
- Permanent loss of GFR in <10% women
- Major determinant of ESRF progression is hypertension
Creatinine 130–220 μmol/L (1.5–2.5 mg/dL)
- Expect initial pregnancy increase in GFR then decline
- Permanent loss of GFR in 30% (increased to 50% if uncontrolled hypertension)
- 10% ESRF soon after pregnancy
Creatinine >220 μmol/L (>2.5 mg/dL)
- Progression to ESRF highly likely during or soon after pregnancy
ESRF, endstage renal failure; GFR, glomerular filtration rate.
Box 7.3 Fetal outcomes according to maternal serum creatinine before pregnancy
Creatinine <130 μmol/L (<1.5 mg/dL)
- Livebirths in >90%
Creatinine 130–220 μmol/L (1.5–2.5 mg/dL)
- Livebirths in about 85% unless uncontrolled hypertension (MAP >105 mmHg) at conception
- Sixty percent prematurity, mainly iatrogenic (pre-eclampsia/fetal growth restriction)
Creatinine >220 μmol/L (>2.5 mg/dL)
- fetal loss high – estimates uncertain
MAP, mean arterial pressure.
Prematurity, fetal growth restriction and stillbirth are not major concerns for women with mild renal impairment unless superimposed pre-eclampsia develops. On the other hand, fetal survival ranges from 65% to 85%, fetal growth restriction 35–45% and prematurity 30–85% in the group with moderate to severe renal impairment [28]. Uncontrolled hypertension at conception is a poor prognostic feature in terms of fetal outcome.
Based upon these estimates of outcomes for mother and baby, the key principles of antenatal care in women with pre-existing chronic renal disease are:
- management of hypertension
- interpretation and management of changes in GFR
- measurement, interpretation and management of proteinuria, including nephrotic syndrome
- consideration of the primary underlying renal disease and its peculiar problems
- identification and management of urinary tract infection
- clinical assessment and maintenance of volume homeostasis
- consideration of appropriate “renal” and antihypertensive medications throughout pregnancy
- identification of superimposed pre-eclampsia
- assessment of fetal well-being.
Each of these items is discussed below.
Hypertension
Most women with chronic renal disease will not exhibit the usual early fall in blood pressure and many will undergo an increase in blood pressure as the pregnancy progresses. Pregnancy is accompanied by significant volume expansion which under normal circumstances does not induce hypertension. However, in the context of chronic renal impairment outside pregnancy, there is often an inability to excrete a sodium load, with accompanying hypertension, and it is likely that this mechanism is partly involved in the development of hypertension in these women during pregnancy. Regardless of the cause, persistence of hypertension is an adverse factor in pregnancy outcome [31] and it is therefore imperative that considerable attention is paid to the blood pressure of women with chronic renal disease during their antenatal care.
Measurement of blood pressure has been traditionally done by mercury sphygmomanometry but this is slowly being replaced by a range of automated blood pressure recorders. It is probable that most of the automated blood pressure recorders used in routine clinical practice have not been validated for use in pregnancy. Where possible, blood pressure should still be recorded using mercury sphygmomanometry, recording the phase 5 sound (the pressure at which the sounds disappear) as the true diastolic pressure [32]. Hypertension is generally defined as a blood pressure above 140/90 mmHg and in pregnancy treatment is generally reserved for blood pressures above this level. However, it is important to remember that the target blood pressure for most women with chronic renal impairment is below 130/80 mmHg and a period of 40 weeks or so of blood pressures above this level may lead to progressive renal impairment after the pregnancy.
Most women with chronic renal impairment, particularly those with proteinuria above 1 g per day, will be receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin 2 receptor antagonists before pregnancy. These must be discontinued, preferably before pregnancy and certainly once pregnancy is diagnosed, due to increased risks of fetal growth restriction, oligohydramnios, neonatal renal failure and probably cardiac and neurologic development abnormalities [33,34]. Suitable antihypertensives include methyldopa, labetalol, nifedipine, hydralazine and the beta-blockers oxprenolol (where available), pindolol and (from the editors’ perspective but not the authors’) metoprolol. Failure to use antihypertensives in pregnancy can be associated with poorer pregnancy outcomes, at least in women with renal transplants [35]. Target blood pressures in this population should probably be in the order of 110–140/80–90 mmHg, though there is no solid research to support this recommendation.
It is important to appreciate that blood pressure will often rise significantly soon after delivery; therefore blood pressure measurement should be just as diligent in the early postpartum period as during pregnancy.
Glomerular filtration rate
Glomerular filtration rate should rise by about 50% during normal pregnancy, typically apparent by the end of the first trimester. Under experimental conditions, ensuring both adequate hydration and urine output, GFR is measured as either creatinine clearance or inulin clearance. From a practical point of view, clinicians rely upon serum creatinine as the main measurement of GFR during pregnancy, discussed above. Measurement of creatinine clearance requires 24-hour urine collection, which is cumbersome and even when conducted diligently may be inaccurate due to ureteric dilation which results in pooling of urine and an incomplete collection, as outlined above. Cystatin C has been used to measure GFR during pregnancy [36] as has beta-2 microglobulin. However, there are problems with both measurements and serum creatinine remains the standard of assessing GFR during pregnancy.
Several equations have been developed to estimate GFR without collecting a 24-hour urine. The MDRD (modification of diet in renal disease study equation) formula for estimating GFR is now used widely outside pregnancy [37] but has not been validated for use in pregnant women. Similarly, the Cockcroft–Gault [38] formula has not been validated for use in pregnancy; this formula depends on bodyweight as a reflection of muscle mass and bodyweight changes considerably during pregnancy, not so much due to changes in body muscle mass but largely due to volume expansion, maternal fat and the fetus.
For practical purposes, serum creatinine should still be used to assess GFR in pregnancy despite the fact that it will not identify patients with mild decreases in GFR. Although the majority of pregnant women will have creatinines under 76 μmol/L (1.0 mg/dL), a value above 90 μmol/L (1.2 mg/dL) is definitely abnormal for pregnancy, reflecting impaired GFR, as above.
Proteinuria and nephrotic syndrome
In the nonpregnant woman daily protein excretion is generally less than 150 mg per day, composed of up to 20 mg per day albumin and the remainder other proteins, often of tubular origin [7]. Albumin excretion during normal pregnancy appears to be unchanged but total protein excretion is increased across all trimesters, with an upper limit of excretion around 300 mg per day. The mechanisms of this increased excretion are unclear but appear to relate to increased porosity [14] rather than to substantial changes in glomerular hemodynamics.
Recent evidence has shown that production of soluble fms-like tyrosine kinase-1 (sFLT), a protein which inhibits vascular growth by binding circulating vascular endothelial growth factor (VEGF), is increased from the placenta of pregnancies complicated by pre-eclampsia and that this production may predate the clinical appearance of the disorder [39]. It is clear from animal experiments that sFLT reduces the levels of VEGF, resulting in disrupted glomerular endothelial cells, loss of endothelial cell fenestrations in the glomerulus and significant proteinuria [40]. To date, no such studies have been undertaken in women with primary renal disease during their pregnancy but it is possible that such women who develop superimposed pre-eclampsia have resultant changes in glomerular structure and renal function as a result of sFLT and perhaps other angiogenic factors such as endoglin.
As mentioned above, there has been a shift in nephrology practice outside pregnancy to measure urinary protein excretion as the spot urine protein/creatinine ratio instead of 24-hour urinary protein excretion. Urinalysis alone is a poor predictor of protein excretion in pregnancy [16,41,42] and use of spot protein/creatinine ratio in pregnancy has become a popular and reasonably reliable method of determining whether protein excretion is abnormal, i.e. above 300 mg per day, most often needed to diagnose the presence of pre-eclampsia. There have been no studies to date testing whether serial spot protein/creatinine ratio during pregnancy in a woman with renal disease is a reliable method of predicting changes in 24-hour urinary protein excretion in that woman. Whilst it is likely that this would be the case, 24-hour urine protein excretion remains the gold standard for assessing true changes in protein excretion during pregnancy within an individual woman. A reasonable practical approach given both the cumbersome nature of 24-hour urine testing and the evolving literature on protein/creatinine ratios in pregnancy is to measure 24-hour urinary protein and creatinine excretion at the original visit and determine the protein/creatinine ratio at that stage. Subsequent protein/creatinine ratios will give a guide to that woman’s protein excretion, though it needs to be acknowledged that this is a guide only. Urine protein/creatinine ratios, when calculated using protein and creatinine measured in mg/dL, have a correlation to the protein excretion in g/day (i.e. an approximate protein/creatinine ratio of 0.4 mg/mg very roughly correlates with 0.4 g of protein in 24). This relationship between protein/creatinine ratio and 24-hour urine protein is by no means linear, however, and the spot urine protein/creatinine ratio is best used to see if the patient has crossed the threshold from normal to abnormal rather than to quantitate abnormal proteinuria.
Even where there is a true change in protein excretion during pregnancy in women with underlying renal disease, there are very few therapeutic options available apart from ensuring blood pressure control. ACE inhibitors and angiotensin 2 receptor antagonists or aldosterone antagonists cannot be used during pregnancy, though diltiazem may have a small benefit [43]. Therefore, there is no great imperative to keep measuring 24-hour urinary protein excretion in these women. Some advocate increased protein excretion as a marker of superimposed pre-eclampsia in women with underlying renal disease though no studies have been able to confirm this and protein excretion may increase in such women, due to appropriate increases in glomerular filtration, progression of the underlying primary renal disease or suboptimal blood pressure control. In other words, an increase in urinary protein excretion should highlight the need for the clinician to look for other features of pre-eclampsia but by itself is not sufficient to make a diagnosis of superimposed pre-eclampsia. Moreover, increasing proteinuria alone should not be used as an indicator for delivery [44].
The most common cause of nephrotic syndrome during pregnancy is pre-eclampsia but nephrotic syndrome is also a problem for women with underlying primary glomerular disease during pregnancy. Serum albumin normally falls during pregnancy, partly due to volume expansion but values below 30 g/L should raise suspicion of the development of nephrotic syndrome. A spot urine protein/creatinine ratio above 230 mg/mmol (or 2.6 if creatinine and protein are measured in mg/dL) signifies a strong likelihood that protein excretion is above 3 g per day [45] and 24-hour urinary protein and creatinine should then be measured to confirm this. Women with nephrotic syndrome will generally have edema. However, this is a a very nonspecific sign during pregnancy as it accompanies two-thirds of normal pregnancies. There is also little point in measuring serum cholesterol, usually a component of the nephrotic syndrome, as this is often increased during a normal pregnancy.
In pre-eclampsia without underlying chronic renal disease, a retrospective study found that proteinuria above 5 g or even 10 g per day was not associated with any worse maternal outcome than those with lesser degrees of proteinuria, but was associated with earlier onset of pre-eclampsia, earlier gestational age at delivery and higher rates of neonatal complications due to prematurity [46]. Nevertheless, confirmation of true nephrotic syndrome is important as it allows recognition of the other aspects of this syndrome that may accompany the heavy proteinuria and be important to the pregnancy. These include loss of vitamin D-binding protein, transferrin, immunoglobulins, antithrombin (also accompanied by increased hepatic synthesis of other clotting factors) and a propensity for intravascular volume contraction in severe cases. The net results of these changes include calcium deficiency, iron deficiency, increased likelihood of infection, thrombosis, reduced uteroplacental blood flow with fetal growth restriction or death [47] and sometimes reduced renal blood flow with worsening renal function. Treatment requires oral calcium, vitamin D and iron supplementation and subcutaneous prophylactic dose heparin for thrombosis prevention as well as ensuring adequate fetal growth and amniotic fluid by ultrasound and reassessment of maternal serum creatinine on a regular basis. Low molecular weight heparin is suitable provided GFR is near normal, i.e. above 60 mL/min, and unfractionated heparin may be used for patients whose GFR falls below this range. When nephrotic syndrome occurs early in pregnancy and low molecular weight heparin is commenced, at that point we add vitamin D for prophylaxis against subsequent osteoporosis though there are as yet no controlled trials to test the benefit of this practice.
Follow-up of proteinuria after pregnancy is important and ACE inhibitors or angiotensin 2 antagonists should be commenced soon after delivery for their antiproteinuric effect. Enalapril and captopril are both deemed compatible with breastfeeding by the American Academy of Pediatrics.
The primary underlying renal disease and its peculiar problems
It is integral to proper antenatal care of women with underlying renal disease to consider the nuances of their underlying primary disorder. The most common renal diseases predating pregnancy in this age group are primary glomerulonephritis (usually IgA nephropathy or focal segmental glomerulosclerosis (FGS or FSGS)), reflux nephropathy and diabetic nephropathy. Clinical features of the former three conditions outside pregnancy are reviewed in Table 7.5. Given the wide range of causes of renal disease, this section will focus only on a few of the more common conditions and those with particular pregnancy-related concerns.
Most patients with IgA nephropathy in pregnancy do well and the risks of pregnancy correlate with the presence of proteinuria, hypertension and renal insufficiency and not the underlying diagnostic cause. Long-term follow-up of childhood IgA nephropathy showed that later pregnancy was complicated by hypertension in half the cases and prematurity in one-third [48] but again, these outcomes are not peculiar to this form of nephropathy. IgA nephropathy should be managed as for other chronic renal diseases during pregnancy, namely good control of blood pressure as the primary issue. Some cases are familial and if such a history is obtained, the pregnant woman should be informed to have her child screened with a urinalysis in the first few years of life. Macroscopic haematuria is no more likely during pregnancy unless there is intervening respiratory or gastrointestinal tract infection.
The outcome of diabetic nephropathy depends upon the usual factors of pre-existing renal insufficiency and control of hypertension with the added issue of potential congenital abnormalities if blood sugar was not adequately controlled at the time of conception. Reece et al. [49] reviewed the outcomes of these pregnancies in 1998 and found high rates of prematurity, cesarean sections and pre-eclampsia with about 15% progressing rapidly to endstage renal disease. Miodovnik et al.
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