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Pregnancy and Diabetic Nephropathy
E. Albert Reece and C.J. Homko*
Vice Chancellorand Dean, Professor, Departments of OB/GYN, Internal Medicine and
Biochemistry, The University of Arkansas College of Medicine
*Diabetes Nurse Specialist, Nurse Manager, General Clinical Research Center, Temple
University Hospital, U.S.A.
Diabetic nephropathy is a complication of diabetes occurring in 30 to 40% of patients
with type 1 diabetes and approximately 50% of individuals with type 2 diabetes. The
prevalence of diabetic nephropathy in pregnant patients with diabetes is estimated at 6%
[1]. Pregnancies complicated by diabetic nephropathy are considered to be at increased
risk for fetomaternal morbidity and perinatal mortality. The management and outcome of
pregnancy complicated by diabetic nephropathy will be reviewed here.
Definition and Diagnosis
Diabetic nephropathy refers to a progressive disease characterized by proteinuria,
hypertension, reduced glomerular filtration rate, and increasing renal failure. In
pregnancy, a diagnosis of diabetic nephropathy is made if there is persistent proteinuria
of greater than 300 mg/day or albuminuria greater than 300 mg/day in the first 20 weeks
of pregnancy in the absence of urinary tract infection. The normal rate of albumin
excretion is less than 20 mg/day (15 µg/min). Microalbuminuria refers to levels of
albuminuria too low to be detected by conventional dipstick methods, generally defined
as persistent albumin excretion of 30 to 300 mg/day (20 to 200 µg/min). It is usually
indicative of incipient diabetic nephropathy, unless there is coexistent renal disease, and
can be present for years before overt proteinuria is detected. Macroalbuminuria refers to
urinary albumin excretion greater than 300 mg/day.
Effect of nephropathy on pregnancy
Perinatal morbidity and mortality related to diabetic nephropathy have improved
significantly in parallel with efforts to achieve stringent glycemic control. Despite good
glycemic control, overt nephropathy is associated with a variety of pregnancy
complications, such as intrauterine growth restriction, fetal distress, and preeclampsia. As
a consequence, preterm delivery and cesarean birth are often required for maternal or
fetal indications.
Outcome of Pregnancy in Women with Diabetic Nephropathy: A compilation of
published trials
In Our review of the world literature from 1981 to 1996, we found that the overall
perinatal survival in pregnancy complicated by diabetic nephropathy was 95 percent [2].
Preterm delivery occurred in 22 percent of pregnancies and was associated with
significant neonatal morbidity (eg, respiratory distress syndrome and jaundice).
Intrauterine growth restriction occurred in 15 percent and the overall malformation rate
was 8 percent.
The degree of renal impairment correlates with the risk of pregnancy complications.
Mackie and colleagues found that infants of women with diabetic nephropathy and
normal serum creatinine concentration had better perinatal outcomes and reduced need
for neonatal intensive care than those born to mothers with moderate renal impairment
[3]. In another series of 45 women with diabetic nephropathy, women with either a high
degree of proteinuria (greater than 3 g/24 hours) or a markedly elevated serum creatinine
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(greater than 1.5 mg/dL) had an increased risk of preterm delivery, low birth weight, and
preeclampsia [4].
Preeclampsia is the most frequent complication of pregnancy in women with diabetic
nephropathy and appears to be related to their level of proteinuria in early pregnancy.
Combs and colleagues showed an increased risk of preeclampsia with early-pregnancy
proteinuria of 190 mg/day or more [5]. The rate of preeclampsia was 7 percent in women
with early-pregnancy proteinuria of less than 190 mg/day as compared with 31 percent if
proteinuria was between 190 to 499 mg/day, and 38 percent with proteinuria at levels of
of 500 mg/day or more. This relationship persisted after adjusting for the effects of parity,
chronic hypertension, retinopathy, and glycemic control. Microalbuminuria has also been
found to to be associated with adverse pregnancy outcomes including preterm birth,small
for gestational age infants and the development of preeclampsia[6].
Effect of pregnancy on diabetic nephropathy
Women with diabetic nephropathy are at increased risk for renal failure during or after
pregnancy and eventual morbidity or death from macrovascular disease. Whether
pregnancy causes a worsening of diabetic nephropathy or hastens the progression to endstage renal disease remains uncertain.
Proteinuria — The amount of proteinuria in women with diabetic nephropathy typically
increases as pregnancy progresses and regresses to near prepregnancy levels after
delivery [2,7]. Increased protein excretion also occurs in women with microalbuminuria.
In a series of 12 women with microalbuminuria at baseline, urinary protein excretion
during pregnancy increased almost seven-fold to a mean of 492 µg/min (equivalent to
708 mg/day), exceeding 3 g/day in four of the women, but returning to baseline in all
within 12 weeks after delivery [8].
Renal function — Although many women experience a temporary decline in renal
function during gestation, pregnancy per se does not appear to hasten the natural
progression to end-stage renal disease for most women; however, this depends upon the
initial degree of renal impairment. Women with mild renal dysfunction (serum creatinine
concentration less than 1.4 mg/dL, creatinine clearance greater than 80 mL/min) prior to
pregnancy are likely to maintain stable renal function throughout pregnancy. However
women with moderate to severe renal insufficiency typically show rising creatinine
concentrations by the third trimester that may persist postpartum [2,3]. The risk of
acceleration is highest among those with an initial plasma creatinine concentration above
2.0 mg/dL (177 µmol/L) [9].
The impact of pregnancy on the long-term progression of renal disease is unclear. There
is a concern that worsening hypertension, proteinuria, and glomerular filtration rate
during pregnancy might accelerate the progression of nephropathy to end-stage renal
disease (ESRD) [10,11]. Women with mild to moderate renal insufficiency generally
experience no permanent acceleration in the rate of decline of renal function postpartum
[12]. However, permanent renal damage, including renal failure, may be more common
among women with poorly controlled hypertension or moderate to severe renal
insufficiency at the onset of pregnancy [11,13].
Management Principles
Ideally, women with diabetes mellitus should be evaluated for stage of disease, receive
counseling, and achieve good glycemic control prior to pregnancy. Informed women are
more motivated to adhere to intensive treatment regimens. Preconceptional care of
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women with diabetic nephropathy should include evaluation of renal function and staging
of nephropathy, if present. A 24-hour urine specimen should be collected for
determination of total urine protein excretion and creatinine clearance. Women with
incipient or overt diabetic nephropathy who are receiving angiotensin converting enzyme
(ACE) inhibitors should be changed to other agents to control hypertension before
conceptionif pregnancy is planned or considered.
Progression of nephropathy and development of proteinuria increases when blood
pressure is poorly controlled. For these reasons, elevated blood pressure in women with
nephropathy should be aggressively treated. In addition, interventions aimed at reducing
microalbuminuria, and improving glycemic control have a protective effect on the
glomeruli and decrease the rate of decline of glomerular filtration rate (GFR) [14, 15].
Angiotensin converting enzyme inhibitors (ACE) and angiotensin II receptor antagonists
are commonly used in nonpregnant diabetics for renoprotection. The effectiveness of
these agents is of crucial importance for the obstetrician since they are contraindicated in
pregnancy. However, studies have shown that women treated with ACE inhibitors and
intensive metabolic control for three to six months prior to conception maintained a
renoprotective effect throughout pregnancy [16, 17]. In addition, prepregnancy treatment
was associated with favorable perinatal outcomes.
Calcium channel blockers seem to have similar renal protective effects as ACE inhibitors
and do not appear to be associated with an increased risk for congenital malformations
when compared to controls [15]. Therefore, these agents are a reasonable option for the
treatment of hypertension in pregnant women with diabetic nephropathy,
microalbuminuria, or microvascular disease. Additional alternatives include methyldopa
and beta blockers.
An intensive program of fetal evaluation is required in women with diabetic nephropathy.
Serial ultrasound evaluations for estimated fetal weight are important in detecting
intrauterine growth restriction. Fetal surveillance, may be indicated as early as 26 weeks
of gestation but should always be initiated by 32 weeks. Daily fetal movement counts are
supplemented by biweekly evaluation with nonstress tests or biophysical profile or a
combination of these tests.
There is little benefit in continuing pregnancy beyond 38 completed weeks of gestation if
fetal pulmonary maturity can be demonstrated and the cervix is favorable. If the cervix is
not favorable, cervical ripening agents may be used or pregnancy may be continued until
39 to 40 weeks if there are no additional complications, such as poor glycemic control,
noncompliance, preeclampsia, abnormal fetal growth, history of stillbirth, poorly
controlled hypertension, or significantly deteriorating renal function.
In summary, maternal and perinatal outcomes are generally good with tight control of
glycemia and blood pressure. Although mortality is low, maternal and neonatal morbidity
are increased compared to nondiabetics and diabetic women without nephropathy. The
major obstetrical complications are preeclampsia, fetal growth restriction, and preterm
birth.
References
1. Reece, EA, Coustan, DR. Diabetes mellitus in pregnancy. New York: Churchill
Livingston, 1995.
2. Reece, EA, Leguizamon, G, Homko, C. Pregnancy performance and outcomes
associated with diabetic nephropathy. Am J Perinatol 1998; 15:413.
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3. Mackie, AD, Doddridge, MC, Gamsu, HR, Brudenell, JM. Outcome of pregnancy in
patients with insulin-dependent diabetes mellitus and nephropathy with moderate renal
impairment. Diabet Med 1996; 13:90.
4. Gordon, M, Landon, MB, Samuels, P, Hissrich, S. Perinatal outcome and long-term
follow-up associated with modern management of diabetic nephropathy. Obstet Gynecol
1996; 87:401.
5. Combs, CA, Rosenn, B, Kitzmiller, JL, Khoury, JC. Early-pregnancy proteinuria in
diabetes related to preeclampsia. Obstet Gynecol 1993; 82:802.
6. Ekbom, P, Damm, P, Feldt-Rasmussen, B, et al. Pregnancy outcome in type 1 diabetic
women with microalbuminuria. Diabetes Care 2001; 24:1739.
7. Kitzmiller, JL, Brown, ER, Phillippe, M, Stark, AR. Diabetic nephropathy and
perinatal outcome. Am J Obstet Gynecol 1981; 141:741.
8. Biesenbach, G, Zazgornik, J, Stoger, H, et al. Abnormal increases in albumin excretion
during pregnancy in IDDM women with pre-existing microalbuminuria. Diabetologia
1994; 37:905.
9. Jones, DC, Hayslett, JP. Outcome of pregnancy in women with moderate or severe
renal insufficiency. N Engl J Med 1996; 335:226.
10. Biesenbach, G, Grafinger, P, Stoger, H, Zazgornik, J. How pregnancy influences
renal function in nephropathic type 1 diabetic women depends on their pre-conceptional
creatinine clearance. J Nephrol 1999; 12:41.
11. Biesenbach, G, Stoger, H, Zazgornik, J. Influence of pregnancy on progression of
diabetic nephropathy and subsequent requirement of renal replacement therapy in female
type I diabetic patients with impaired renal function. Nephrol Dial Transplant 1992;
7:105.
12. Reece, EA, Winn, HN, Hayslett, JP, Coulehan, J. Does pregnancy alter the rate of
progression of diabetic nephropathy?. Am J Perinatol 1990; 7:193.
13. Purdy, LP, Hantsch, CE, Molitch, ME, Metzger, BE, Phelps, RL, Dooley, SL, Hou,
SH. Effect of pregnancy on renal function in patients with moderate-to-severe diabetic
renal insufficiency. Diabetes Care 1996; 19:1067.
14. Reece, EA, Leguizamon, G, Homko, C. Stringent controls in diabetic nephropathy
associated with optimization of pregnancy outcomes. J Matern Fetal Med 1998; 7:213.
15. Leguizamon, G, Reece, EA. Effect of medical therapy on progressive nephropathy:
influence of pregnancy, diabetes and hypertension. J Matern Fetal Med 2000; 9:70.
16. Hod, M, van Dijk, DJ, Karp, M, Weintraub, N. Diabetic nephropathy and pregnancy:
the effect of ACE inhibitors prior to pregnancy on fetomaternal outcome. Nephrol Dial
Transplant 1995; 10:2328.
17. Bar, J, Chen, R, Schoenfeld, A, Orvieto, R. Pregnancy outcome in patients with
insulin dependent diabetes mellitus and diabetic nephropathy treated with ACE inhibitors
before pregnancy. J Pediatr Endocrinol Metab 1999; 12:659.