Portal de Periódicos da CAPES

Blood Pressure Goals and Treatment in Pregnant Patients With Chronic Kidney Disease

2015; Elsevier BV; Volume: 22; Issue: 2 Linguagem: Inglês

10.1053/j.ackd.2014.08.002

1548-5609

Asher Hussain, Alan Karovitch, Michael Carson,

Pregnancy and Medication Impact

As the age of pregnant women and prevalence of obesity and diabetes are increasing, so is the prevalence of medical disorders during pregnancy, particularly hypertension and the associated CKD. Pregnancy can worsen kidney function in women with severe disease, and hypertension puts them at risk for pre-eclampsia and the associated complications. There are no specific guidelines for hypertension management in this population, and tight control will not prevent pre-eclampsia. Women with end-stage kidney disease should be placed on intense dialysis regimens to improve obstetric outcomes, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are best avoided. This article will review the rationale for a management plan that includes a multidisciplinary team to discuss risks and develop a plan before conception, antepartum monitoring for maternal and fetal morbidity, individualization of medical management using medications with established records during pregnancy, and balancing the level of blood pressure control proved to protect kidney function against the potential effects that aggressive blood pressure control could have on the fetal-placental unit. As the age of pregnant women and prevalence of obesity and diabetes are increasing, so is the prevalence of medical disorders during pregnancy, particularly hypertension and the associated CKD. Pregnancy can worsen kidney function in women with severe disease, and hypertension puts them at risk for pre-eclampsia and the associated complications. There are no specific guidelines for hypertension management in this population, and tight control will not prevent pre-eclampsia. Women with end-stage kidney disease should be placed on intense dialysis regimens to improve obstetric outcomes, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are best avoided. This article will review the rationale for a management plan that includes a multidisciplinary team to discuss risks and develop a plan before conception, antepartum monitoring for maternal and fetal morbidity, individualization of medical management using medications with established records during pregnancy, and balancing the level of blood pressure control proved to protect kidney function against the potential effects that aggressive blood pressure control could have on the fetal-placental unit. Clinical Summary•The prevalence of hypertension and CKD during pregnancy are increasing.•There are no specific guidelines for hypertension management in this population, and tight control will not prevent pre-eclampsia.•Planning should include pre-pregnancy consultations and discussions of risks and treatment.•Antepartum management should monitor for maternal and fetal morbidity, and use of medications with established records during pregnancy while balancing the level of blood pressure control proved to protect kidney function against the potential effects that aggressive blood pressure control could have on the fetal-placental unit. •The prevalence of hypertension and CKD during pregnancy are increasing.•There are no specific guidelines for hypertension management in this population, and tight control will not prevent pre-eclampsia.•Planning should include pre-pregnancy consultations and discussions of risks and treatment.•Antepartum management should monitor for maternal and fetal morbidity, and use of medications with established records during pregnancy while balancing the level of blood pressure control proved to protect kidney function against the potential effects that aggressive blood pressure control could have on the fetal-placental unit. New economic and domestic trends over the past 30 years have resulted in women waiting longer to have children. In 1970, the average age of a first-time mother was 21.4 years, compared with the average age of 25.0 years in 2008, and the number of women older than 40 having children increased by 65% between 1990 and 2005.1Mathews T.J. Hamilton B.E. Delayed childbearing: more women are having their first child later in life.in: Statistics NCfH NCHS Data Brief. No. 21. U.S. Department of Health and Human Services, Hyattsville, MD2009Google Scholar, 2CDC.gov. Overweight and obesity. 2012. Available at: http://www.cdc.gov/obesity/data/trends.html. Accessed July 24, 2012.Google Scholar During this time, medical societies modified criteria in an attempt to detect disease states and initiate early interventions that could prevent disease progression. The increase in the prevalence of obesity and diabetes has contributed to a growing population of people with CKD. Given these factors and the paucity of robust research data, clinicians are encountering more pregnant patients with baseline chronic illness, specifically the combination of CKD and hypertension, without clearly defined recommendations and guidelines. This article will review the information and guidelines and present the reader with a clinical approach to the management of hypertension during pregnancy for women with CKD. Earlier reported prevalence rates of pregnancies in CKD patients ranged from about 0.1% to 1%.3Williams D. Davison J. Chronic kidney disease in pregnancy.BMJ. 2008; 336: 211-215Crossref PubMed Scopus (212) Google Scholar However, with a new CKD staging and definition system developed by the Kidney Disease Outcomes Quality Initiative, more people are being identified, and the prevalence of CKD in pregnant women may be around 3%. According to the new guidelines, CKD is defined as kidney damage in terms of structural or functional abnormalities for greater than 3 months, with or without a decreased glomerular filtration rate (GFR) or estimated GFR.4National Kidney FK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar These abnormalities include pathologic evidence of damage or elevated markers of kidney damage including blood, urine, or imaging tests. CKD is also defined as a GFR less than 60 mL/min/1.73 m2 for greater than 3 months with or without kidney damage. The normal pattern of blood pressure values during pregnancy is a flat "U" shape. The systolic blood pressure (SBP) will often drop about 10 mm Hg and reach a nadir by 20 weeks gestation, after which it should increase to values seen in the first trimester but not higher than that. Higher values suggest the development of pre-eclampsia. Pregnancy is associated with normal anatomical and physiological changes in the kidneys. Because of the increases in the interstitial and vascular space, kidney length can increase by 1 to 1.5 cm and volume by 30%.5Hussein W. Lafayette R.A. Renal function in normal and disordered pregnancy.Curr Opin Nephrol Hypertens. 2014; 23: 46-53Crossref PubMed Scopus (50) Google Scholar The progesterone-induced physiological hydroureter/hydronephrosis of pregnancy begins as early as the fifth gestational week and increases the risk of pyelonephritis and preterm labor in pregnant women with asymptomatic bacteriuria. The degree of ureteral dilation is not necessarily proportional to the gestational week, and so, it is not possible to differentiate "normal" ureteral dilation to that caused by a clinical abnormality such as an obstructing stone. Because of an increase in kidney blood flow and a decrease in oncotic pressure, the GFR increases by 50%. This hyperfiltration appropriately decreases the blood urea nitrogen/urea and creatinine levels. Therefore, it is important to note that the top normal values in pregnancy are a creatinine of 0.9 mg/dL (79 μmol/L), and levels more than that should prompt further investigation.6Carson M.P. Pagan E.R. Effects of pregnancy on common laboratory tests.in: Powrie R.O. Greene M.F. Camann W. de Swiet's Medical Disorders in Obstetric Practice. 5th ed. Wiley-Blackwell, Hoboken, NJ2010: 661-670Crossref Scopus (1) Google Scholar In addition, there is a 6- to 8-L increase in total body water associated with a decrease in serum sodium by 4 to 5 mEq/L, although the sodium level should still be in the normal range.5Hussein W. Lafayette R.A. Renal function in normal and disordered pregnancy.Curr Opin Nephrol Hypertens. 2014; 23: 46-53Crossref PubMed Scopus (50) Google Scholar, 6Carson M.P. Pagan E.R. Effects of pregnancy on common laboratory tests.in: Powrie R.O. Greene M.F. Camann W. de Swiet's Medical Disorders in Obstetric Practice. 5th ed. Wiley-Blackwell, Hoboken, NJ2010: 661-670Crossref Scopus (1) Google Scholar There is a 10- to 20-fold increase in aldosterone, 8-fold increase in rennin, and a 4-fold increase in angiotensin, making the diagnosis of hyper-reninemia and hyperaldosteronism during pregnancy very challenging.7Vellanki K. Hou S. The kidney in pregnancy.in: Gilbert S. Weiner D. National Kidney Foundation Primer on Kidney Diseases. 6th ed. Elsevier Saunders, Philadelphia, PA2014: 427-436Crossref Scopus (2) Google Scholar The issues to consider during pregnancy are how the pregnancy could affect the kidneys, how the kidney disease could affect the pregnancy/risk of obstetric complications, and how treatment of maternal disease could affect fetal well-being. The overarching principle is that a healthy fetus depends on a healthy mother. The most serious concern for a woman with CKD who becomes pregnant is the potential that the increased GFR/stress of pregnancy could accelerate the decline in kidney function. This risk increases with the severity of baseline kidney insufficiency. In women with pre-pregnancy creatinine levels greater than 2 mg/dL (177 μmol/L), pregnancy can be associated with irreversible loss of kidney function in up to 50%, especially if they have uncontrolled hypertension, and any loss of function may not be reversed even with the termination of the pregnancy (Fig 1).8Hayslett J.P. Interaction of renal disease and pregnancy.Kidney Int. 1984; 25: 579-587Crossref PubMed Scopus (39) Google Scholar, 9Bili E. Tsolakidis D. Stangou S. Tarlatzis B. Pregnancy management and outcome in women with chronic kidney disease.Hippokratia. 2013; 17: 163-168PubMed Google Scholar In a study that looked at 67 women with an initial creatinine of 1.4 mg/dL (124 μmol/L), pregnancy-related loss of maternal kidney function occurred in 43 women and about 10% progressed to end-stage kidney failure.10Jones D.C. Hayslett J.P. Outcome of pregnancy in women with moderate or severe renal insufficiency.N Engl J Med. 1996; 335: 226-232Crossref PubMed Scopus (326) Google Scholar In women with baseline proteinuria, expect that the normal changes of pregnancy will cause an increase, often to severe levels, but it can resolve after delivery. Despite the maternal risk, fetal outcomes are generally good. The rate of live births is around 90% for women with CKD Stage 1 or 2.11Jungers P. Houillier P. Forget D. Henry-Amar M. Specific controversies concerning the natural history of renal disease in pregnancy.Am J Kidney Dis. 1991; 17: 116-122Abstract Full Text PDF PubMed Scopus (60) Google Scholar, 12Fischer M.J. Lehnerz S.D. Hebert J.R. Parikh C.R. Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy.Am J Kidney Dis. 2004; 43: 415-423Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar However, the frequency of premature birth was 13% in women with CKD and uncontrolled hypertension, compared with 6% in women without kidney disease.13Nevis I.F. Reitsma A. Dominic A. et al.Pregnancy outcomes in women with chronic kidney disease: a systematic review.Clin J Am Soc Nephrol. 2011; 6: 2587-2598Crossref PubMed Scopus (178) Google Scholar There is also an increased risk of intrauterine growth restriction and placental abruption. It is estimated that the risk of fetal death is about 10-fold higher in women with a mean arterial pressure greater than 105 mm Hg at conception compared with those who are normotensive.14Jungers P. Chauveau D. Pregnancy in renal disease.Kidney Int. 1997; 52: 871-885Crossref PubMed Scopus (132) Google Scholar Chronic hypertension in pregnancy has been associated with a number of adverse pregnancy outcomes including premature delivery, fetal growth restriction, fetal demise, placental abruption, and Cesarean delivery. The incidence of these complications appears related to the duration of pre-existing disease, severity of the hypertension, and the presence of superimposed pre-eclampsia.1Mathews T.J. Hamilton B.E. Delayed childbearing: more women are having their first child later in life.in: Statistics NCfH NCHS Data Brief. No. 21. U.S. Department of Health and Human Services, Hyattsville, MD2009Google Scholar Women with mild hypertension (current measurements: SBP 140-159 mm Hg or diastolic blood pressure [DBP] 90-109 mm Hg) should be counseled that their risk of pre-eclampsia is about 20%, those with severe hypertension (current measurements: SBP >160 mm Hg or DBP >110 mm Hg) is about 50%, and those with target organ damage or secondary hypertension as high as 75%.4National Kidney FK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar, 5Hussein W. Lafayette R.A. Renal function in normal and disordered pregnancy.Curr Opin Nephrol Hypertens. 2014; 23: 46-53Crossref PubMed Scopus (50) Google Scholar Other than these gross numbers, there is no way to further stratify a specific patient's risk of pre-eclampsia. Pregnancy can unmask unidentified hypertension in women with mild kidney insufficiency. The consensus definition of chronic hypertension in pregnancy is the use of antihypertensive medications before pregnancy, onset of hypertension before the 20th week of pregnancy, or hypertension that persists for over 12 weeks after delivery.1Mathews T.J. Hamilton B.E. Delayed childbearing: more women are having their first child later in life.in: Statistics NCfH NCHS Data Brief. No. 21. U.S. Department of Health and Human Services, Hyattsville, MD2009Google Scholar, 2CDC.gov. Overweight and obesity. 2012. Available at: http://www.cdc.gov/obesity/data/trends.html. Accessed July 24, 2012.Google Scholar, 15Palma-Reis I. Vais A. Nelson-Piercy C. Banerjee A. Renal disease and hypertension in pregnancy.Clin Med. 2013; 13: 57-62Crossref PubMed Scopus (13) Google Scholar Because there is no evidence that maternal blood pressure control can decrease the risk of pre-eclampsia, the purpose of treatment is to decrease the short-term risks of severely elevated pressures, especially in the setting of superimposed pre-eclampsia. Consensus guidelines suggest maintaining SBP <160 and DBP <110 mm Hg, regardless of the presence of target organ damage.16Task Force on Hypertension in PregnancyHypertension in pregnancy.Obstet Gynecol. 2013; 122: 1122-1131Crossref PubMed Scopus (808) Google Scholar However, although we would aggressively treat hypertension in an effort to prevent worsening of CKD in nonpregnant women, there is little data to define our treatment goals for these patients when they become pregnant. It has been suggested that mild hypertension should be treated, essentially taking the approach to optimize long-term maternal health and address maternal disease during pregnancy as we would if she were not pregnant. To prevent further renovascular damage, treatment should aim to keep the blood pressure less than 140/90 mm Hg. On the other hand, very tight blood pressure control increases the risk of hypotension, will not decrease the risk of pre-eclampsia, and may be associated with decreases in fetal birth weight and fetal growth.17von Dadelszen P. Magee L.A. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: an updated metaregression analysis.J Obstet Gynaecol Can. 2002; 24: 941-945Abstract Full Text PDF PubMed Scopus (110) Google Scholar The lack of consensus guidelines and studies focusing on this subset of patients with hypertension makes it difficult to define absolute blood pressure cutoffs that require treatment. Therapy should be individualized, but the best approach will consider maternal comorbidities and symptoms and understand that the maternal and fetal benefits are not at odds with each other. Risks and benefits of antihypertensive therapy should be assessed for both mother and fetus, not only initially but rather throughout the pregnancy focusing on any signs of worsening kidney function or adverse fetal effects. Despite the fact that conception is rare in dialysis patients, there have been an increasing number of pregnancies in these women. Patients receiving dialysis have frequent menstrual irregularities including amenorrhea, early menopause, and anovulatory cycles. The first successful pregnancy in a dialysis patient was reported in 1971 and was considered a medical miracle. Since then, pregnancy outcomes have significantly improved related to data associating longer dialysis times with better fetal outcomes. A retrospective study reported live birth rates of 48% in women dialyzed for 20 hours or less per week vs 85% in those dialyzed more than 36 hours per week (P = .02), in addition to a later gestational age and greater infant birth weight for women dialyzed more intensively.18Hladunewich M.A. Hou S. Odutayo A. et al.Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States Cohort Comparison.J Am Soc Nephrol. 2014; 25: 1103-1109Crossref PubMed Scopus (194) Google Scholar Better outcomes are reported with patients receiving nocturnal dialysis for an average of 48 hours per week.19Hou S. Pregnancy in women on dialysis: is success a matter of time?.Clin J Am Soc Nephrol. 2008; 3: 312-313Crossref PubMed Scopus (16) Google Scholar, 20Barua M. Hladunewich M. Keunen J. et al.Successful pregnancies on nocturnal home hemodialysis.Clin J Am Soc Nephrol. 2008; 3: 392-396Crossref PubMed Scopus (176) Google Scholar However, the rate of premature delivery is still higher among dialysis patients. As mentioned earlier, hypertension is associated with maternal and fetal morbidity, primarily through the association with pre-eclampsia and other placental syndromes such as fetal growth restriction and placental abruption. Although the management of chronic hypertension in pregnancy has been well studied, the same is not true for hypertension in pregnant patients with CKD. Rather than discussing pre-eclampsia or gestational hypertension, we will focus on chronic hypertension. Pregnancy planning and management for women with CKD and its associated hypertension requires a multidisciplinary team consisting of the nephrologist or internist, obstetrician, perinatologist, and nutritionist. Counseling should include the implications of pregnancy regarding the risk of pre-eclampsia and the potential effect on the fetus and the potential risk to maternal kidney function. It is best to optimize blood pressure before conception, so that the patient is stable and baseline clinical status can be determined. This way, when the blood pressure normally increases after 20 weeks gestation, the clinical team is less likely to speculate that increasing values are related to recent changes in medication doses. If the cause of CKD is not clear, then biopsies should be performed before conception to delineate the treatment plan and how the kidney disease and its treatment could affect the pregnancy. For example, patients with lupus nephritis should have their disease stabilized before conception as active lupus puts patients at very high risk of pre-eclampsia and lupus flare.21Liu J. Zhao Y. Song Y. et al.Pregnancy in women with systemic lupus erythematosus: a retrospective study of 111 pregnancies in Chinese women.J Matern Fetal Neonatal Med. 2012; 25: 261-266Crossref PubMed Scopus (65) Google Scholar Although not absolutely contraindicated in pregnancy, kidney biopsies are safely obtained in women with normal coagulation indices and controlled hypertension and are indicated for all with a sudden unexplained deterioration in kidney function.22Kuller J.A. D'Andrea N.M. McMahon M.J. Renal biopsy and pregnancy.Am J Obstet Gynecol. 2001; 184: 1093-1096Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 23Piccoli G.B. Daidola G. Attini R. et al.Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review.BJOG. 2013; 120: 412-427Crossref PubMed Scopus (85) Google Scholar It is important to remember that the GFR in pregnancy normally increases by 50% over the nonpregnant baseline, and the maximum normal serum creatinine is 0.9 mg/dL; therefore, clinicians should not be reassured by a "normal" estimated GFR value that is more than 60.6Carson M.P. Pagan E.R. Effects of pregnancy on common laboratory tests.in: Powrie R.O. Greene M.F. Camann W. de Swiet's Medical Disorders in Obstetric Practice. 5th ed. Wiley-Blackwell, Hoboken, NJ2010: 661-670Crossref Scopus (1) Google Scholar When indicated, biopsies are preferably performed by experienced operators under ultrasound guidance before 32 weeks gestation.24Packham D. Fairley K.F. Renal biopsy: indications and complications in pregnancy.Br J Obstet Gynaecol. 1987; 94: 935-939Crossref PubMed Scopus (69) Google Scholar Consider increased antenatal visits with the obstetrician to monitor for blood pressure changes and new proteinuria, co-ordinate with a perinatologist regarding the timing of fetal growth scans to assess placental well-being (once a trimester), and the nephrologist/internist should co-ordinate serial monitoring of maternal kidney function. The patient should be taught to monitor home blood pressures frequently, bring the cuff to the office to be sure it correlates with the office equipment, and counsel her regarding the symptoms/signs of pre-eclampsia including new and persistent headaches, visual changes, abdominal pain suggestive of hepatic involvement, edema of the hands or face, or rapidly developing leg edema. The initial cornerstone of hypertension management begins with lifestyle modifications, namely diet and exercise. In pregnant women, however, aggressive salt restriction may decrease intravascular volumes.25European Society of GynecologyAssociation for European Paediatric CardiologyGerman Society for Gender Medicineet alESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC).Eur Heart J. 2011; 32: 3147-3197Crossref PubMed Scopus (1325) Google Scholar Normally, patients with advanced CKD and ESRD are on restrictive diets; however, given the increased nutritional requirements during pregnancy and the intensified hemodialysis for pregnant women, a normal diet without a protein restriction is advised. Here, a nutritionist's role is helpful ensuring appropriate nutrition, and it should be tailored to those who are obese. Exercise is reasonable for women with chronic hypertension and no other complications, but the regimen may need to be put on hold should she develop labile blood pressures and/or pre-eclampsia.26Maloni J.A. Lack of evidence for prescription of antepartum bed rest.Expert Rev Obstet Gynecol. 2011; 6: 385-393Crossref PubMed Scopus (26) Google Scholar Pharmacologic therapy to control blood pressure in pregnant women with CKD should mirror therapy in women without CKD. For mild-to-moderate hypertension, there are many oral medication options. A healthy fetus depends on a healthy mother, and the Food and Drug Administration system to categorize medication use during pregnancy is oversimplified. Perhaps with the exception of category X, the single-letter system does not provide the clinician with information to reach a balanced decision regarding the safety or benefit of a medication in terms of the dose to which the fetus was exposed, the duration of exposure, the trimester of exposure, or the risk to the mother of not taking the medication. Medication use should be considered indicated or not, rather than simply "safe" or not. Although almost all antihypertensive medications cross the placenta, the following are considered appropriate when indicated: alpha methyldopa has been used for blood pressure control in pregnant women since the 1960s. Because of its long-term use, it is initiated as a first-line agent, has been demonstrated to be safe for both mother and fetus, and in utero exposure had no effect on childhood development.27Cockburn J. Moar V.A. Ounsted M. Redman C.W. Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children.Lancet. 1982; 1: 647-649Abstract PubMed Scopus (222) Google Scholar However, in pregnant women with CKD who have hard to manage hypertension, this mild agent may not be effective because of its slow onset of action. Many women are affected by its side effects, most notably somnolence. A more widely used agent has been labetalol. Its more rapid onset of action, oral and parenteral administration, and tolerability contribute to its use. Labetalol has both alpha and beta-adrenergic blockade and has been shown to be safe in pregnancy.28Molvi S.N. Mir S. Rana V.S. Jabeen F. Malik A.R. Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa.Arch Gynecol Obstet. 2012; 285: 1553-1562Crossref PubMed Scopus (42) Google Scholar Case reports have associated beta-adrenergic blocking agents, such as atenolol and propranolol, with neonatal bradycardia, intrauterine growth restriction, hypoglycemia, and respiratory depression and therefore are typically avoided.29Lydakis C. Lip G.Y. Beevers M. Beevers D.G. Atenolol and fetal growth in pregnancies complicated by hypertension.Am J Hypertens. 1999; 12: 541-547Crossref PubMed Scopus (212) Google Scholar Among calcium channel blockers, long-acting nifedipine has been studied and most widely used because of its minimal effect on uteroplacental blood flow. Of note is the synergistic activity of nifedipine with magnesium in lowering blood pressure.30Smith P. Anthony J. Johanson R. Nifedipine in pregnancy.BJOG. 2000; 107: 299-307Crossref PubMed Scopus (74) Google Scholar Nondihydropyridine calcium channel blockers (diltiazem and verapamil) and amlodipine have been efficacious and safe; however, there is sparse data concerning their use in pregnancy. The next few classes of antihypertensive agents are less frequently used either because of insufficient data or their adverse side effect profile. Hydralazine is used to control blood pressure as an adjunct because as a single agent it is not as effective. In 1 meta-analysis, hydralazine did show a slightly increased rate of adverse outcomes as compared with labetalol; however, it is still used, especially for acute hypertensive treatment.31American College of Obstetricians and GynecologistsACOG practice bulletin Number 33. Diagnosis and management of preeclampsia and eclampsia.Obstet Gynecol. 2002; 99: 159-167Crossref PubMed Google Scholar Orally, however, it has the potential to cause reflex tachycardia and fluid retention that make its use less favorable. Diuretic use in pregnancy is controversial. Many clinicians avoid diuretics because they potentiate intravascular volume depletion. However, loop diuretics are reasonable during pregnancy when used to manage volume overload related to conditions, such as CKD and congestive heart failure, or to mitigate edema related to severe proteinuria. Clonidine is reserved for patients who cannot achieve blood pressure control with other agents or cannot tolerate oral agents because clonidine is available as a transdermal patch. Because of its limited data and risk of rebound hypertension, it is not frequently used. When pressures are acutely and severely elevated in women with pre-eclampsia, intravenous hydralazine is the drug of choice for hypertensive crisis in pregnancy, followed by labetalol because of their rapid onset and ability to be titrated easily. With higher doses, fetal heart rate should be monitored for bradycardia. Short-acting nifedipine, oral or sublingual, should be avoided because of the risk of significant, rapid decreases in blood pressure. Also short acting nifedipine was shown in a retrospective study to be associated with stroke and myocardial infarction in nonpregnant patients.32Gillman M.W. Ross-Degnan D. McLaughlin T.J. et al.Effects of long-acting versus short-acting calcium channel blockers among older survivors of acute myocardial infarction.J Am Geriatr Soc. 1999; 47: 512-517PubMed Google Scholar Nonpregnant women with CKD, especially when it is associated with diabetic nephropathy and/or proteinuria, are often prescribed angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) to control blood pressure as they confer kidney protection by reducing the progression of nephropathy and decreasing proteinuria.33Gansevoort R.T. de Zeeuw D. de Jong P.E. ACE inhibitors and proteinuria.Pharm World Sci. 1996; 18: 204-210Crossref PubMed Scopus (12) Google Scholar, 34Galle J. Reduction of proteinuria with angiotensin receptor blockers.Nat Clin Pract Cardiovasc Med. 2008; 5: S36-S43Crossref PubMed Scopus (40) Google Scholar ACE inhibitors and ARBs are avoided during pregnancy because of the known risk of oligohydramnios, fetal kidney dysplasia, and fetal pulmonary hypoplasia in the second and third trimesters. Additionally, first trimester exposure to either ACE inhibitors or ARBs might increase the risk of congenital cardiovascular and neurologic anomalies.35Cooper W.O. Hernandez-Diaz S. Arbogast P.G. et al.Major congenital malformations after first-trimester exposure to ACE inhibitors.N Engl J Med. 2006; 354: 2443-2451Crossref PubMed Scopus (881) Google Scholar Therefore, because of the benefits of ACE inhibitors and ARBs, nonpregnant women should be counseled about appropriate birth control and, then before pregnancy, be transitioned to the medications listed earlier. A literature search did not identify any objective data quantifying the effect that removal of an ACE/ARB for 10 to 12 months can have regarding proteinuria and kidney function, but given the known adverse fetal effects, it seems clear that the risk:benefit ratio favors avoidance of these medications. Subsequent studies have questioned the link between first-trimester ACE inhibitor exposure and congenital malformations. Based on more recent data, it is suggested that hypertension rather than ACE inhibitor exposure is associated with congenital malformations.36Li D.K. Yang C. Andrade S. Tavares V. Ferber J.R. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study.BMJ. 2011; 343: d5931Crossref PubMed Scopus (144) Google Scholar In women with diabetic nephropathy, adverse outcomes are increased when blood pressure, glucose levels, and proteinuria are uncontrolled. Tighter control of these parameters is associated with better outcomes. Given recent evidence, the question arises, would pregnant women with CKD benefit from continued use of ACE inhibitors for hypertension control in the first trimester? Some have suggested that such women continue their ACE inhibitor or ARB up until the first positive pregnancy test and once pregnancy is confirmed discontinue these medications and restart them immediately postpartum.37Lewis G. Maxwell A.P. Should women with diabetic nephropathy considering pregnancy continue ACE inhibitor or angiotensin II receptor blocker therapy until pregnancy is confirmed?.Diabetologia. 2014; 57: 1082-1083Crossref PubMed Scopus (8) Google Scholar However, there is no data that an extra 1 to 2 months of exposure to these medications can impart long-term protection for kidney function; therefore, it seems reasonable to minimize the risk of pregnancy complications by an appropriate pre-pregnancy plan and transition to a medication with reassuring data. The increase in maternal age and obesity are related to an increase in the number of pregnancies complicated by the maternal medical issues, including CKD, hypertension, proteinuria, and even ESRD. Early detection of complications and optimizing hypertension has favorable outcomes for both mother and fetus. Research in this area is still ongoing concerning the effects of ACE inhibitor use in the first trimester along with other recommendations for when to initiate antihypertensive therapy. The astute clinician needs to be cognizant of this and appropriately manage such pregnant women using a multidisciplinary team approach for pre-eclampsia, fetal well-being, and the need to adjust medication doses. The optimal blood maternal pressure values are not clear; therefore, care must be individualized to each patient keeping in mind the cause and degree of CKD, patient symptoms, and risk-benefit assessment for both mother and fetus.