The Diabetes In Pregnancy Dilemma 2nd ed. Oded Langer

Chapter 35. Diabetic Nephropathy in Pregnancy

Jason G. Umans, MD, PhD

Maisa N. Feghali, MD

Menachem Miodovnik, MD

Superficially, it might be said that the function of the kidney is to make urine; but in a more considered view one can say that the kidneys make the stuff of philosophy itself

—Homer Smith

Key Points

• Pregnancy outcomes, including preeclampsia, prematurity, and intrauterine growth restriction, are worse in women with diabetic nephropathy (DN) than in those with diabetes mellitus(DM) alone.

• Decreased renal function and poorly controlled hypertension before conception and early in pregnancy can predict increased risk of poor outcomes in women with diabetic nephropathy.

• Pregnancy, per se, does not precipitate diabetic nephropathy nor accelerate its course in women with near-normal renal function at baseline.

• Similar to nondiabetic renal disease, pregnancy may accelerate the loss of renal function in women with diabetic nephropathy when renal function is compromised (serum creatinine >1.4 mg/dL or creatinine clearance <75 mL/min) at baseline.

• The diagnosis of preeclampsia is problematic in women with diabetic nephropathy who may exhibit hypertension, proteinuria, and decreased renal function at baseline.

• Outcomes may be improved when blood pressure(BP) and proteinuria are optimized by use of angiotensin-converting- enzyme (ACE) inhibitors until pregnancy is confirmed and by tight BP control throughout pregnancy.

INTRODUCTION

Diabetic nephropathy (DN) is the most frequent cause of progressive proteinuric renal disease and end-stage renal disease (ESRD) in Europe and the Americas. Improved medical care now allows many women with DN due to childhood type 1 diabetes melli- tus (DM) to contemplate pregnancy. Likewise, an epidemic of type 2 diabetes mostly associated with obesity and the so-called “metabolic syndrome” also contributes to DN during childbearing years. In most patients, DN is accompanied by hypertension and other manifestations of macro- and microvascular disease. Maternal and fetal risks are increased in pregnancies complicated by diabetes alone, hypertension, vascular disease, or renal disease of any cause or severity^1,2; these risks may be magnified in women with DN. Furthermore, although it is now clear that pregnancy seldom accelerates the loss of renal function in women with underlying nondiabetic renal disease in those cases where preconception renal function is well preserved and hypertension absent or well controlled,³ it has been uncertain how we should best counsel women with DN regarding the effects of pregnancy on the progression of their renal disease.

In this chapter, we will first review briefly the natural history, classification, and pathophysiology of DN, focusing on the effects of medical intervention in nonpregnant patients and on how the renal physiologic changes which characterize normal gestation may interact with the diabetic kidney. Next, we will examine the available evidence regarding possible effects of pregnancy on the progression of DN, comparing it with studies of pregnancy in nondiabetic renal disease. We will then focus on pregnancy risks in women with DN. We will conclude with suggestions for key research questions whose answers may impact on the optimal care of these women.

NATURAL HISTORY AND PATHOPHYSIOLOGY

DN affects 30%-40% of patients with DM. Its natural history has been described best in patients with type 1 diabetes, and divided by Mogenson into five stages, based on clinical pathological and physiological characteristics.⁴ Subsequently, the National Kidney Foundation developed consensus guidelines to promote recognition and clinical intervention in patients with chronic kidney disease (CKD) of any cause; these guidelines recognize five stages of CKD, based on the presence of renal damage and progressive decrements in glomerular filtration rate (GFR), in some cases subdividing them further.⁵ Although others have suggested modifications to these classification schemes, which will be discussed below, Table 35-1 lists the stages of progressive DN and CKD in these two predominant systems, with key clinical or pathologic findings.

Soon after the diagnosis of diabetes, renal and glomerular hypertrophy are the norm and renal hemodynamics are marked by hyperfiltration (increased GFR) with an increased filtration fraction (FF), that is, the increment in GFR exceeds that in renal plasma flow (RPF).⁶ The elevated FF suggests that hyperfiltration is due in large part to increased efferent arteriolar resistance with resulting elevated intraglomerular capillary pressure; this “glomerular hypertension” has been shown to result in progressive scarring and nephron loss in several animal models of hypertension and progressive renal failure.⁷ The progression of histopathologic changes over the first years of diabetes and hyperfiltration include thickening of the glomerular basement membrane, increased capillary wall area, then mesangial expansion.⁸ Exercise-induced proteinuria is increased at the earliest stage of nephropathy, initially without evidence of albuminuria at rest. Clinical manifestations of disease appear reversible at this stage, as tight glycemic control can normalize both hyperfiltration and exercise-induced proteinuria.⁹ The onset of persisting microalbuminuria (see below), readily detected in usual clinical practice, heralds “incipient nephropathy.” Although microalbuminuria is commonly thought a marker of early renal disease, it actually occurs several years into the course of established and progressive diabetic nephropathy. Most patients with microalbuminuria due to type I diabetes appear to be normotensive; however, carefully controlled studies using 24-h blood pressure (BP) monitoring show their BP to be elevated significantly, albeit still within the “normal” range,¹⁰ predicting more significant hypertension later, as renal disease progresses. Without special treatment, microalbuminuria often progresses to macroalbuminuria (>300 mg/d) and “fixed” proteinuria (>500 mg/d), though some studies suggest that tight control of multiple diabetic risk factors, including glycemia may lead to regression, even at this stage of disease.^11,12 DN may result not only in significant proteinuria, but is the most common cause of nephrotic-range proteinuria in adults. Clinically overt diabetic nephropathy is then characterized by hypertension and progressive decrements in GFR, leading to ESRD and markedly increased risk of cardiovascular morbidity and mortality.

The clinical evolution of nephropathy in patients with type 2 diabetes differs in that they are more likely to exhibit hypertension, microalbuminuria, and hyperlipidemia at baseline, or sooner after diagnosis; this may relate in part to the consequences of a prolonged period of insulin resistance before the diagnosis of frank diabetes or to the interacting effects of diabetes and hypertension in obese patients.¹³ Many other patients with type 2 diabetes may suffer significant decrements in renal function, perhaps due to hypertensive nephrosclerosis rather than to DN and escape clinical recognition if physicians only screen for renal disease in patients with evidence of retinopathy or microalbuminuria.¹⁴ Indeed, several recent studies have suggested that a large minority of type 2 diabetic patients with CKD suffer progressive loss of renal function without albuminuria. Unfortunately, there are few studies defining nonalbuminuric CKD in diabetes to determine its overlap with classic diabetic nephropathy or with other comorbid disorders or renal biopsy findings.^15-17

Normal urinary albumin excretion ranges from 1.5-20 μg/min, with microalbuminuria defined as an albumin excretion rate of 20-200 μg/min (30-299 mg/24 h).⁵ Of note, urinary albumin excretion decreases by ~25% with sleep or prolonged recumbency. Urinary albumin excretion may be measured in 24-hour urine collections or estimated from random urine albumin/creatinine ratios. In women, the albumin/creatinine ratio is normally <25 mg/g, with microalbuminuria defined either as noted above or, using these sex-specific norms, as a ratio of 25-355 mg/g.¹⁸ Several studies have noted the increased sensitivity of chromatographic methods for the detection of microalbuminuria; however, these newer methods have not gained wide acceptance thus far, with only limited research use in pregnancy.^19,20 Twenty-four-hour specimens are subject to errors due to undercollection; simultaneous determination of urinary creatinine not only allows estimation of GFR but also provides an index of specimen adequacy, as a complete collection will normally include 10-15 mg creatinine/kg ideal body weight/d.²¹ In addition, simultaneous collection of urine for creatinine clearance and microalbumin excretion provides a baseline albumin/ creatinine ratio that may increase the accuracy of estimates from subsequent random urine determinations. Unfortunately, albumin excretion may vary significantly from day to day, so several determinations may be required to rule out microalbuminuria.²²

TABLE 35-1 Progression of Diabetic Nephropathy and Chronic Kidney Disease

Mogensen Stage4 CKD Stage5 Clinical or Pathologic Characteristics
I.		Renal hypertrophy and glomerular hyperfiltration
II.	1 (kidney damage* with GFR ≥ 90 mL/ min/1.73 m2 )	Glomerular basement membrane widening
III. (incipient DN)	1	Microalbuminuria
IV. (overt DN)	1	Albumin excretin > 300 mg/day
Early	2 (GFR 60-89 mL/min/1.73 m2)	Fixed proteinuria > 500 mg/day, often nephritic range, hypertension
Intermediate	3 (GFR 30-59 mL/min/1.73 m2)	Progressive glomerular scarring, nephron loss, worsening hypertension
Advanced	4 (GFR 15-29 mL/min/1.73 m2)	Progressive glomerular scarring, nephron loss, worsening hypertension
V.	5 (GFR < 15 mL/min/1.73 m2)	Uremia, ESRD

CKD, Chronic Kidney Disease; DN, Diabetic Nephropathy; GFR, Glomerular Filtration Rate.

*National Kidney Foundation describes kidney damage as either an abnormal renal biopsy finding or a marker of renal damage found on blood, urine, or imaging studies.

Recent studies of patients with type 1 diabetes suggest a prevalence of microalbuminuria of 31%-52%; higher prevalence in earlier studies was likely because of patient selection bias. Prevalence of microalbuminuria in type 2 diabetes is 12%-32%, in comparison with 5%-40% in patients with essential hyperten- sion.²³ Challenges in the measurement and interpretation of proteinuria in pregnancy have been reviewed recently.²⁴

INTERVENTIONS TO DELAY PROGRESSION OF DIABETIC NEPHROPATHY AND PREVENT CARDIOVASCULAR MORBIDITY

Well-designed prospective trials demonstrated marked decreases in the incidence of DN and other microvascular complications of diabetes with tight glucose control in patients with either type 1 or type 2 diabetes. In the Diabetes Control and Complications Trial (DCCT), there was a 54% reduction in DN when Hemoglobin A1c (HbA1c) was reduced from 9% to 7% in patient with type 1 diabetes.²⁵ Likewise, the United Kingdom Prospective Diabetic Study (UKPDS) demonstrated a 24%-33% decrease in DN when HbA1c was lowered from 7.9%-7.1% in patients with type 2 dia- betes.²⁶ In this latter study, there did not appear to be a threshold HbA1c associated with risk for DN. Indeed, more recent studies have suggested further improvement in renal outcomes with lower HbA1c targets.¹² Unfortunately, only a minority of patients with diabetes routinely achieve a target HbA1c of <7% in clinical practice.²⁷

Several large, well-designed studies have demonstrated the ability of improved BP control to slow the progressive loss of renal function in patients with DN as well as to decrease both microvascular and macrovascular complications and the occurrence of morbid cardiovascular endpoints.^28-30 Interestingly, tight BP control (goal diastolic BP < 85 mmHg, mean achieved BP 144/82, both in excess of current goals) decreased microvascular diabetic complications more so than tight glucose control in the UKPDS.²⁸ A thoughtful meta-analysis related achieved systolic BP to the rate of decline in GFR (mL/min/y), showing progressively slower renal functional decline with tighter systolic BP control ranging from 180 to 133 mmHg.³⁰ Further benefits accrue with the use of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). For example, captopril decreased the combined endpoint of death, dialysis, or renal transplantation by 50% in patients with type 1 diabetes and overt DN³¹; similar results being observed with other ACE inhibitors.³² A similar benefit due to ARBs has been demonstrated in patients with type 2 diabetes and overt DN.^33-35 Of note, a careful analysis of clinical and experimental animal data suggests that much of the apparent benefit of ACE inhibitors and ARBs may be due to superior BP control rather than to a BP-independent effect on the glomerulus.³⁶ Collectively, this literature had led to the wide acceptance of lower BP goals (<130/<80 mmHg) in patients with DN.³⁷ More recently, reappraisal of clinical trial evidence, particularly the paucity of randomized controlled trials targeting lower BPs or intervention in those with systolic BPs between 130-140 mmHg, has led several groups to temper these recommendations for lower targets in patients with DM, CKD, or DN.^38,39 Even before this recent change, these goals have been difficult to achieve in practice, requiring a median of three separate antihypertensive drugs (including both ACE inhibitors and diuretics) in several clinical trials and being met in only one-tenth to one-fourth of patients in a variety of practice settings.^27,29,30 Beyond patients with DN, meta-analyses of trials in hypertensive patients with nondiabetic renal disease have demonstrated similar benefits of tight BP control in patients with proteinuria, with increased benefit in patients with more severe proteinuria.⁵ Similarly, ACE inhibitors (and ARBs) appear to exert a nephroprotective effect, beyond that due to BP control with other agents, in patients with proteinuria. For example, results from the African-American Study of Kidney Disease (AASK) suggested improved renal outcome with BP < 130/80 and therapy with ACE inhibitors in those patients with >220 mg protein/g creatinine at baseline.⁴⁰ Likewise, long-term follow-up of patients from the modification of diet in renal disease (MDRD) study demonstrated persisting renal benefit from tight BP control (mean arterial pressure, MAP <92 mmHg) seven years after a four year intervention, in patients with >300 mg proteinuria/d.⁴¹ Taken together, it appears that DN may be representative of other proteinuric renal diseases, in that it is progressive, associated with increased cardiovascular risk, and benefits from tight BP control and treatment with ACE inhibitors or ARBs. As noted above, however, this construct has been questioned recently, due to limited benefit in many patients with progressive nephropathy or improvement in cardiovascular outcomes in several recent trials.^38,42-44

RENAL ADAPTATION IN WOMEN WITH NORMAL RENAL FUNCTION, DIABETES, DIABETIC NEPHROPATHY, AND NONDIABETIC RENAL DISEASE

Normal pregnancy is characterized by an early 30%-50% increase in GFR, in proportion to increased RPF, that is, filtration fraction is unchanged.⁴⁵ Invasive micropuncture studies in gravid rats demonstrate that this gestational hyperfiltration is due to balanced afferent and efferent arteriolar vasodilation without any increase in glomerular capillary pressure. Sophisticated modeling studies suggest that glomerular capillary pressure is similarly normal in human gravidas.^46,47 It now appears likely that these renal functional changes are mediated by a signaling cascade which depends on the ovarian hormone, relaxin, leading to stimulation of endothelin B receptors in the kidney with resulting local synthesis of the vasodilator nitric oxide.⁴⁸ GFR then increases progressively, reaching a maximum at 16-20 weeks gestation. Patients with uncomplicated diabetes exhibit similar gestational augmentation in renal function, with increases in GFR of 40%-80% over baseline values⁴⁹ by 26-30 weeks. Since GFR is maintained until term but RPF declines somewhat from 29-37 weeks, it appears that FF increases late in diabetic pregnancy. Most patients with nondiabetic renal disease still exhibit gestational hyperfiltration, sometimes obscuring the diagnosis of underlying CKD. However, as chronic renal insufficiency becomes more advanced, the degree of gestational renal augmentation becomes more variable. It appears striking then that pregnancy increases GFR in only about one-third of women with DN, with the remainder exhibiting either no change in GFR or a loss of renal function as pregnancy progresses.^50,51 Few published studies provide preconception estimates of renal function, most reporting baseline serum creatinine or creatinine clearance data obtained during the first trimester, with follow-up values from the third trimester or postpartum.⁵² Whether the fall in GFR can be ascribed to natural or accelerated progression of DN or to the decreased renal function which accompanies preeclampsia⁴⁷ remains uncertain. Several small studies suggest that the proportion of women with DN whose GFR falls during pregnancy increases along with baseline serum creatinine (see below).

EFFECTS OF PREGNANCY ON DIABETIC NEPHROPATHY

Physiologic considerations suggest the possibility that pregnancy might profoundly alter the course of DN. However, it is difficult to predict the renal outcomes of these pregnancies from physiologic principles, or even from the changes in renal function observed over the course of gestation.

Several studies have attempted to follow women with DN during and after pregnancy to assess outcomes. These pregnancies often lead to marked increases in proteinuria, which usually resolves following delivery, often returning to prepregnancy levels. Indeed, albuminuria and proteinuria may increase markedly in diabetic women, whether or not they exhibited microalbuminuria before conception.^53,54 By contrast, pathologic albumin excretion is rarely observed in women without diabetes or underlying glomerular disease in the absence of preeclampsia.^55,56 As randomized controlled trials to prospectively assess the effects of pregnancy on the deterioration of renal function in women with DN are impossible, studies have instead focused on (1) Longitudinal (retrospective or prospective) comparison of DN progression in women who have experienced one or more pregnancies. The rates of renal functional loss in the pregnancy group are then compared with those in historical or concurrent control groups who have not been pregnant. (2) Case-control studies comparing the prevalence of DN in diabetic women who have been pregnant with women who have never been pregnant. (3) Studies assessing the effect of parity on the incidence of DN or on its progression to renal failure. These studies all suffer from one or more significant limitations. Most include only a small number of subjects or have relatively limited follow up, given the long course of DN. Many studies accrued or followed patients over a course of several years, failing to account for the impact of strategies (e.g., tight BP control, tight glycemic control, ACE inhibitor use in nonpregnant women, control of hyperlipidemia) generally believed to slow the progression of DN or of associated cardiovascular disease. Importantly, very few studies control for the confounding factors which are known to predict the progression of DN or for preconception renal function and BP control, which appear to predict the impact of pregnancy on the subsequent course of nondiabetic renal disease.

Table 35-2 summarizes the longitudinal studies of pregnant women with DN at baseline.^50,51,57-68 Most of the studies showed no apparent increase in the rate of renal functional loss following pregnancy in women with DN, though pregnancy probably accelerated DN progression toward renal failure in women with more advanced nephropathy at baseline. Kitzmiller et al.⁵⁰ assessed renal function in 23 women with type 1 diabetes and overt nephropathy at 9-35 months postpartum. Creatinine clearance decreased in these women at an average rate of 10 mL/min/y, similar to the rates in nonpregnant subjects receiving generally prescribed care during that era. Reece et al.⁵¹ reported on 31 women with diabetes; all had proteinuria during pregnancy with nine women having preexisting overt DN. In these women, and in a second group of 11 women with baseline DN,⁵⁹ loss of renal function was similar to that expected in nonpregnant patients. Kimmerle et al.⁶¹ followed 29 women with DN during pregnancy for up to 10 years postpartum without apparent acceleration in the loss of renal function. Rossing et al.⁶⁵ compared outcomes in 26 women with baseline DN with those in a control group of 67 women with similar serum creatinine, albuminuria, BP, retinopathy, and other cardiovascular risk factors who did not become pregnant during the 16 years (range 3-28) of follow-up. The rate of decline in creatinine clearance (assessed by the slope of 1/creatinine curves) and progression to ESRD or death were similar in both groups, suggesting that pregnancy has no adverse long-term effect on DN. These authors concluded that renal function deteriorates after pregnancy in women with overt nephropathy, but the rate of deterioration is no different from that expected without pregnancy. By contrast, Gordon et al.⁶² reviewed the outcome of 29 patients with DN (defined in their study as >400 mg proteinuria/24 h) at baseline with a mean follow-up of 2.8 years postpartum. Creatinine clearance decreased faster than the expected 10 mL/min/y in 12/28 patients, suggesting the possibility of accelerated progression of DN due to the index pregnancy.

Other studies have suggested that pregnancy may accelerate loss of renal function in women with more advanced DN. Biesenbach et al.⁶⁰ studied five women with type 1 diabetes and DN, creatinine clearance <75 mL/min at baseline, and hypertension. Creatinine clearance declined more rapidly than expected, both during pregnancy (22 mL/min/y) and postpartum (17 mL/min/y). Hypertension worsened in all five women during pregnancy, and all had progressed to ESRD within 42 months postpartum. The authors suggested that the accelerated decline in renal function may have been related to worsened hypertension during pregnancy. Similarly, Purdy et al.⁶³ found that, in patients with moderate to severe nephropathy (10 women with serum creatinine 1.4-1.7 mg/dL and one with serum creatinine 4.1 mg/dL), there was a 40% risk of accelerated, permanent decline in renal function during pregnancy; this would lead to accelerated progression to ESRD, compared with nonpregnant women with nephropathy of comparable severity. Irfan et al.⁶⁷ reviewed pregnancy and remote clinical outcomes in 35 women who had DN and a mean serum creatinine of 1.8 (1.4-4.1) mg/dL during the first trimester. In addition, their cohort had a high prevalence of macroscopic proteinuria, hypertension, anemia, retinopathy, and inadequate diabetic control. The mean serum creatinine increased to 2.5 (1.5-4.2) mg/dL by the third trimester with creatinine clearance remaining stable in 27% of women, worsening transiently in 27%, and demonstrating a permanent decline in 45%. This latter group demonstrated an accelerated progression of DN during pregnancy based on comparison of the slope of their 1/creatinine curves with that observed either before or following pregnancy. Three quarters of all pregnancies were complicated by preeclampsia or worsened hypertension. Sixty-four percent of the total group progressed to dialysis 26 (6-57) months postpartum, mostly attributable to accelerated decline of renal function during pregnancy. By contrast, in another small study, Mackie et al.⁶⁴ followed six women with baseline serum creatinine 1.4-2.8 mg/dL for up to eight years postpartum, finding no consistent effect of pregnancy on the progression of DN.

TABLE 35-2 Pregnancy and Progression of Diabetic Nephropathy

Citation	Subjects (n)	Follow-up (mo)	Accelerated Progression	Progressed to ESRD (n)
Kitzmiller, 198150	23	9-35	No	3
Dicker, 198657	5	6-12	No	0
Grenfell, 198658	20	6-120	No	2
Reece, 198851	31	1-86	No	6
Reece, 199059	11	10-45	No	0
Biesenbach, 199260	5*	13-42	Yes	5
Kimerle, 199561	29	4-108	No	8
Gordon, 199662	34	34 (mean)	Yes	3
Purdy, 199663	11*	6-138	Yes	7
Mackie, 199664	6*	6-96	No	3
Kaaja, 199668	6	84 (mean)	No	0
Rossing, 20 0 265	26	36-164	No	5
Bagg, 20 0366	14	12-192	No	5
Irfan, 200467	35*	6-57	Yes	22
*Serum creatinine >1.4 mg/dL or creatinine clearance <75 mL/min at baseline.

All told, the effect of pregnancy on long-term renal survival in DN appears to parallel that in women with nondiabetic renal disease. In these women, although the incidence of worsened hypertension, superimposed preeclampsia, preterm birth, and intrauterine growth restriction are all high, live births are the norm and renal functional loss is seldom accelerated in women whose baseline serum creatinine is less than 1.4 mg/dL.³ This similarity in satisfactory outcomes is supported by a report comparing outcomes in women with DN, nondiabetic renal primary renal disease, and renal allograft recipients, all with well-preserved renal function; in these women, hypertension was the best predictor of adverse outcomes during pregnancy.⁶⁹ By contrast, several studies of women with more severe renal insufficiency have demonstrated that approximately 30%-40% will suffer irreversible acceleration of renal insufficiency during pregnancy with many of these women progressing rapidly to ESRD^70-72; further elevations of

baseline serum creatinine (>2.5 or 2.8 mg/dL) or uncontrolled hypertension each predict poorer renal and pregnancy outcomes.⁷³

Table 35-3 summarizes studies assessing the association of pregnancy with development of DN.^68,74-78. Miodovnik et al.⁷⁴ studied 182 women with type 1 diabetes, 46 with overt DN. All women were treated with intensive insulin therapy throughout pregnancy, and followed for a median of 9.1 (3-16) years postpartum. Of the 136 women without nephropathy at the time of pregnancy, only 13 (10%) eventually progressed to DN, a mean of 10.1 years after the index pregnancy. New proteinuria or poor glycemic control during pregnancy, but not parity per se, were each significantly associated with the subsequent development of DN. Of the 46 women with DN at baseline, 12 (26%) progressed to ESRD after a median of six years, unassociated with parity. The overall risk for developing nephropathy was 44% after 27 years of diabetes and the risk of progressing to ESRD was 30% after 10 years of overt DN. Thus, neither pregnancy nor parity appeared to increase either the risk for developing DN in women with type 1 diabetes, or accelerate the progression of DN to renal failure. Kaaja et al.⁶⁸ compared the prevalence of DN and its progression in 28 women (six with DN at baseline) with type 1 diabetes, seven years after an index pregnancy, with that in 17 nulliparous controls followed over a similar interval. Neither the development of DN nor its progression appeared to differ between groups. Bagg et al.⁶⁶ reported outcomes for 24 pregnancies in 14 women with DN but well-preserved renal function before pregnancy (mean serum creatinine = 0.8 mg/dL). In accord with earlier studies, these pregnancies were complicated by an excess of hypertension and premature delivery, but not by accelerated progression of nephropathy. Nevertheless, 36% of these women had progressed to dialysis a median 7 (3-12) years after the last pregnancy, with additional morbidity and mortality due to retinopathy, coronary-, cerebral-, and peripheral vascular disease. These authors remind us that, even when short-term outcomes are good, we must counsel our patients regarding the morbid natural history of diabetic nephropathy and CKD.

TABLE 35-3 Pregnancy and Development of Diabetic Nephropathy

Citation	Subjects (n)	Follow-up (mo)	Increased Risk?	Study Design
Carstensen, 198275	22	7-211	No	Cross sectional
Chaturvedi, 199578	582	NA	No	Cross sectional
Hemachandra, 199577	80	NA	No	Cross sectional
Hemachandra, 199577	30	12 (mean)	No	Case-control
Kaaja, 199668	22	84 (mean)	No	Case-control
Miodovnik, 199674	136	36-193	No	Observational
Miodovnik, 199 876	23	14-43	No	Prospective

NA, Not applicable.

Carstensen et al.⁷⁵ performed a cross-sectional study of 22 pairs of women with type 1 diabetes matched by age and duration of the disease, comparing the prevalence of microvascular complications in women who had never completed a pregnancy with those who had completed one or two pregnancies. They observed no differences in outcome up to 17.7 years after the birth of the oldest child and up to 24 years after the onset of diabetes. Similarly, Miodovnik et al.⁷⁶ prospectively compared 23 pregnant and 23 nonpregnant women with type 1 diabetes without evidence of microvascular disease at baseline. All women were managed identically during the 9-month pregnancy period (or a comparable control period in the nonpregnant women). None of the women progressed to DN during the subsequent two years of prospective follow-up, suggesting that pregnancy does not precipitate the development of DN. Likewise, Hemachandra et al.⁷⁷ compared the prevalence of microvascular complications in 80 pairs of women, either parous or nulliparous, all with type 1 diabetes of similar duration and matched for age and ethnicity. They found no differences in microvascular outcomes between the two groups. They also followed a subgroup of 30 primiparous women for a mean of 11.8 months postpartum, matched to a group of 30 nulliparous women followed for the same period. As in the study by Miodovnik et al.,⁷⁶ there were no differences between the two groups in the postpartum incidence of DN.

Chaturvedi et al.⁷⁸ performed a cross-sectional study examining the prevalence of microalbuminuria and macroalbuminuria in 776 nulliparous women with type 1 diabetes compared with 582 parous women with type 1 diabetes (352 with a single pregnancy and 229 with two or more). After adjusting for age and duration of the disease, there were no significant differences between groups with respect to the presence of microalbuminuria, whereas the prevalence of macroalbuminuria was actually lower in parous women (6%) than in nulliparous women (10%).

In summary, most of the available studies suggest that pregnancy is not associated with development of nephropathy or with accelerated progression of preexisting nephropathy, especially when renal function is well-preserved. However, some limited data suggest that, as in women with more advanced nondiabetic renal disease, pregnancy may accelerate the loss of renal function and progression to ESRD when GFR is decreased before pregnancy.

EFFECTS OF DIABETIC NEPHROPATHY ON PREGNANCY OUTCOME

Pregnancy outcomes are worse in women with DN than in those with uncomplicated diabetes. This appears due to: (1) the increased incidence and severity of hypertensive disorders of pregnancy, (2) increased prematurity due to early delivery in the setting of poorly controlled hypertension or severe preeclampsia, and (3) the increased risk of fetal growth restriction and fetal distress. Since the incidence of preeclampsia is increased in women with insulin resistance,⁷⁹ diabetes alone (without nephropathy, 10%-20%), or chronic essential hypertension (20%-40%), it is not surprising that there is enhanced risk to women with DN whose condition may include all of these abnormalities. Outcomes appear to be worst in those women with more advanced renal insufficiency and less well-controlled hypertension at baseline, as is the case in women with nondiabetic renal disease.^70-72 Table 35-4 summarizes rates of selected perinatal complications in women with DN.^{50-52,58,61,62,69,80-84}

Many women with diabetic nephropathy have preexisting chronic hypertension, and even in those who do not, perinatal complications are frequently associated with hypertension, often severe, that develops during pregnancy. Preeclampsia or superimposed preeclampsia in the setting of underlying hypertension are common complications of DN. That granted, women with DN, many of whom have hypertension, proteinuria, and renal insufficiency at baseline, have all the features which make the clinical diagnosis of preeclampsia uncertain, both in practice and in outcomes research.⁸⁵ These diagnostic difficulties may contribute to some of the variability in reported rates of preeclampsia in studies of women with DN, as shown in Table 35-4. Importantly, they make it difficult for clinicians to accurately diagnose preeclampsia and weigh the risks of expectant management versus early delivery in the setting of worsened hypertension, proteinuria, and renal function.

TABLE 35-4 Pregnancy Outcomes in Diabetic Nephropathy

Citation	Subjects (N)	HTN	PE	PNM	IUGR	Delivery <34 wks	Delivery 34-36 wk	Delivery >36 wk
Kitzmiller50	26	31%	15%	11%	21%	31%	41%	28%
Grenfell58	22	NA	NA	0%	14%	27%	23%	50%
Reece51	31	23%	35%	6%	16%	23%	32%	45%
Pierce81	39	NA	NA	3%	10%	26%	23%	51%
Gordon62	45	27%	53%	0%	11%	16%	35%	49%
Kimmerle61	36	61%	19%	0%	22%	31%	NA	NA
Rosenn82	61	47%	51%	6%	11%	25%	28%	47%
Reece80	27	77%	53%	4%	9%	26%*	0	74%
Bar69	24	46%	46%	4%	21	NA	17%**	NA
Khoury52	39a	NA	41%	5%	8%	7%***	NA	NA
	12b	NA	33%	0%	8%	17%***	NA	NA
	9c	NA	44%	11%	33%	44%	NA	NA
Hopp83	76	NA	71%	9%	39%	NA	NA	NA
Young84	11	18%	64%	0%	40%	NA	64**	NA

HTN, chronic hypertension; PE, preeclampsia; PNM, perinatal mortality; IUGR, intrauterine growth restriction; NA, not available.

#36 wk,**<37,***<32 wk.

^aPatients with baseline creatinine #1.0 mg/dL.

^bPatients with baseline creatinine >1.0 to 1.5 mg/dL.

^cPatients with baseline creatinine >1.5 mg/dL.

There has been an explosion of research elucidating mechanisms which lead to hypertension and to proteinuria in women with preeclampsia.^47,48 It is now clear that proteinuria and the glomerular pathology which is most characteristic or preeclampsia both result from a relative deficiency of the angiogenic factors, vascular endothelial growth factor (VEGF) and placental growth factor, which are scavenged by pathologically-elevated levels of a soluble VEGF receptor. It is clear that similar mechanisms take place in the setting of underlying DN and that measurement of (anti-)angiogenic factors may be useful in differential diagnosis or risk stratification of women with apparent preeclampsia diagnosed by clinical criteria, alone^86,87; by contrast, it is unclear how pathologic regulation of these angiogenic factors might interact with microvascular abnormalities, such as proliferative retinopathy, in women with diabetes. Similarly, vasoconstriction, hypertension, and oxidative stress in preeclampsia appear due to increased signaling at angiotensin (ATj) receptors due to autoantibodies which mimic the effects of angiotensin II.⁸⁸ Given the key role of the renin-angiotensin system in progression of DN, it will be crucial to define this mechanism in women with DN and to seek therapies which can reverse this pathophysiology without harming the fetus.

Few studies have examined the association of microalbuminuria and perinatal outcome. Combs et al.⁸⁹ found that even women with total protein excretion in the microalbuminuric range (<500 mg total protein per 24 hours) have an increased risk of developing preeclampsia. Risk increased dramatically (from 10%-40%) when proteinuria exceeded 190 mg/d, but preeclampsia did not appear more likely with further increases in proteinuria. Similarly, Ekbom et al.⁹⁰ found that the rate of prematurity among women with microalbuminuria was significantly increased, primarily due to an increased incidence of preeclampsia in this subpopulation. By contrast, another study failed to detect this increased risk of preeclampsia in women with 190-499 mg proteinuria, though it may have differed significantly in patient characteristics, case definitions for the diagnosis of preeclampsia, and laboratory methods.⁹¹ When DN progresses to overt nephropathy with macroproteinuria, there does not appear to be any further effect of the magnitude of proteinuria on pregnancy outcome, save for rare cases of refractory edema, hypoalbuminemia, and their morbid consequences. Khoury et al.⁵² reported that very-low-birth weight and neonatal hypoglycemia (in women with type 1 diabetes) were significantly associated with high baseline serum creatinine, independent of proteinuria and glycemic control. Decreased renal function also predicted a trend toward increased rates of perinatal death, growth restriction, and respiratory distress syndrome in that study.

Uncontrolled hypertension before conception or inadequately controlled hypertension early in pregnancy can predict maternal morbidity and poor pregnancy outcomes in women with nondiabetic renal disease. As discussed earlier, tight BP control is likely renoprotective in nonpregnant women with DN. There are few studies to determine whether we should similarly target tight BP control early in pregnancies complicated by DN. In a compelling preliminary report, Carr and colleagues⁹² followed 43 gravidas with DN comparing outcomes in those women who achieved a target MAP <100 mmHg before 20 weeks gestation with those who did not. The women with poorer BP control exhibited greater proteinuria, a fivefold increase in the likelihood of developing nephrotic syndrome, and a 13-fold increase in the likelihood of delivering before 32 weeks. This report may be viewed as complementary to the results of several studies which suggest that tight BP control with ACE inhibitors before conception limits proteinuria, improves pregnancy outcome, and may exert a persisting nephroprotective effect, even when these drugs are discontinued at the diagnosis of pregnancy.⁹³ Clinicians have been hesitant to treat women of childbearing age using ACE inhibitors following a 2006 report, which identified a 2.7-fold increase in congenital malformations, due entirely to increases in cardiovascular and central nervous system mal- formations⁹⁴ following ACE-inhibitor exposures limited to the first trimester. Subsequently, several much larger studies have failed to confirm concerns regarding first trimester exposure,^95-98 some suggesting that any increased risks of malformation may be related to maternal hypertension or to undiagnosed diabetes, rather than its treatment. Likewise, secondary analysis of 208 pregnancies which occurred during a randomized clinical trial of candesartan in type 1 diabetics suggested no excess risk due to first trimester ARB exposure.⁹⁹ So, although it seems prudent to discontinue their use when pregnancy is first confirmed, and many may argue against their use in women with prepregnancy essential hypertension, due to the high rates of unintended pregnancy and of delayed or limited antenatal care, these risks must be weighed against the significant potential benefits of their use in women of childbearing potential with compelling indications, such as those with underlying diabetic nephropathy. However, even these women should be counseled specifically to seek obstetric care early following conception and to discontinue these drugs to avoid the fetopathy which results from exposures following the first trimester.^100,101 Here we also note that many clinicians similarly deny ACE-inhibitor therapy to postpartum nursing mothers with DN out of a mistaken belief that neonatal drug exposure might prove damaging. In fact, captopril has been shown clearly not to be excreted in milk and infant exposure is undetectable.^102,103 with similarly reassuring data for enalapril and quinapril.^104,105

Fetal outcome is often affected by prematurity as a result of deteriorating maternal status requiring early delivery, and also due to an increased risk of fetal growth restriction and fetal hypoxia. Worsening nephropathy and superimposed preeclampsia appear to be the most significant risk factors associated with fetal distress, whereas hypertension and decreased creatinine clearance are the strongest predictors of fetal growth restriction. As shown in Table 35-4, perinatal survival of infants born to mothers with DN has been uniformly excellent in recent years. However, increased prematurity in pregnancies complicated by DN predicts an increased risk of developmental and functional problems in the children born of these pregnancies. Indeed, Kimmerle et al. followed 36 infants of mothers with DN for 0.5-11 years after delivery, and found that five had severe psychomotor impairment, and three had mild developmental impairment, primarily associated with prematurity.⁶¹ Thus, although women with DN may usually expect to deliver a viable fetus and take home a reasonably healthy infant, this group of patients is the one most likely to have a complicated course of pregnancy, requiring expert care and intensive management.

SUMMARY

The striking renal and cardiovascular adaptations that characterize normal pregnancy may interact with the pathophysiologic mechanisms which underlie nephropathy in women with diabetes. Although the literature includes excellent studies focusing on the relationship of glycemic control and microvascular complications in patients with the disease, there are shamefully few prospective studies addressing the effects of pregnancy or seeking to define optimal management before and during pregnancy on the course of DN and its complications. Research, which might directly impact care of women with DN, needs to include (1) clearer definitions of the duration of intensive preconception control of glucose, BP, and proteinuria required to improve pregnancy outcomes, (2) determining whether tight BP control during pregnancy will improve maternal and fetal outcomes without exacerbating fetal growth restriction, (3) assessing whether the choice of antihypertensive agents used in gravidas with DN should differ from those used in women with chronic hypertension, and, (4) determining how best to use (anti-) angiogenic biomarkers related to the pathophysiology of preeclampsia to allow early and accurate differentiation of superimposed preeclampsia from worsened hypertension and proteinuria due to DN alone.

Although it is difficult to determine with certainty the longterm effects of pregnancy on the progression of DN, it appears that pregnancy neither precipitates DN nor accelerates its progression in women with near-normal renal function and well- controlled BP. Tight BP control before and throughout pregnancy may improve both pregnancy outcomes and long-term renal prognosis in women with DN. Further, women would benefit if their glycemic and BP control were both optimized before pregnancy is contemplated, using ACE inhibitors up until pregnancy is confirmed.

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