asymptomatic bacteriuria. 2 Send MSU for M,C+S. If pyelonephritis suspected: blood cultures, FBC, U&E, CRP. Consider USS renal tract. Fetal well-being should be assessed. 3 Acute pyelonephritis Pyelonephritis is more common in the second half of pregnancy and is a signi \201 cant cause of fetal mortality and maternal morbidity. The increasing size of the uterus may cause ureteral obstruction and impaired urinary \202 ow (particularly on the right), encouraging stasis and sepsis. URINARY TRACT INFECTION 843 Recurrent UTIs in pregnancy 2 After more than one UTI (or a single episode in 5 with an abn ormal urinary tract), women should be offered prophylactic antibiotics for the duration of the pregnancy. Post-coital cefalexin 500mg PO stat or cefalexin 500mg nocte for 1 month, alternating with nitrofurantoin 100mg nocte, have proved safe and effective. Antimicrobial choice should ide ally re \202 ect sensitivities of organisms cultured. Post-partum investigation is recomme nded ( b p. 708). Treatment of UTI in pregnancy Asymptomatic bacteriuria or cystitis \200 First line, prior to sensitivities becoming available: \200 Nitrofurantoin 50mg PO qds x 7 days, or \200 Cefalexin 500mg PO bd (or 250mg qds) x 7 days. \200 Trimethoprim 200mg bd PO ( 1 but giv e a folic acid supplement during the 1st trimester, and avoid if patient is folate-de \201 cient or taking a folate antagonist, or if trimethoprim has been used in the preceding yea r). Amoxicillin 250mg qds PO x 7 days (often \201 rst choice if sensitivities known). Ampicillin 500mg PO qds x 7 \200\223 10 days for group B Streptococcus infections \200\224 and inform the patient s antenatal service, as prophylactic antibiotic s may be indicated during labor and delivery. Repeat MSU for M,C+S monthly to con \201 rm eradication. Pyelonephritis \200 Admit. \200 IV access and rehydration with 0.9% NaCl, as required. \200 Ceftriaxone 1g IV od or cefotaxime 1 \200\223 2g IV qds. \200 Alternative: ampicillin 1g IV qds + gentamicin 1. 5mg/kg tds. \200 If the patient is immunocompromised and/or has incomplete urinary drainage, then seek urgent microbiological advice. 1 Fluoroquinolones, such as cipro \202 oxacin, should be avoided, unless resistant organis ms are cultured. Co-trimoxazole needs to be used with caution (sulfonamides should not be u sed in the 3rd trimester). Safe antibiotics in pregnancy \200 Penicillins. \200 Cephalosporins. \200 Nitrofurant oin (a recent large Norwegian population study suggests low teratogenic potential but incre ased risk of neonatal jaundice if used within 30 days of delivery). Trimethoprim ( 1 safe after 1st trimester ( b p. 843)). CHAPTER 11 Pregnancy and the kidney 844 AKI during pregnancy Introduction AKI during pregnancy remains a signi \201 cant problem i n the developing world, accounting for up to 20% of all AKI (usually in circumstances where there is no access to safe and sterile termination). 2 In the developed world, pre-eclamps ia is the commonest pregnancy-related cause of AKI. Causes Pre-renal \200 Volume depletion: Esp. s to hyperemesis gravidarum during the 1st trimester. Placental abruption: Presents with abdominal pain and PV bleeding in 2nd or 3rd trimester. A classical cause of cortical necrosis ( b p. 845). \200 Post-partum hemorrhage (see also cortical necrosis, b p. 845). \200 Septic abortion ( b p. 845). Common in the developing world. Presents with abdominal pain, fever, and shock. Renal \200 Pre-eclampsia ( b p. 850). \200 Acute fatty liver of pregnancy: 3rd trimester. Presents with coagulopathy, abnormal LFTs, hypoglycaemia, and lactic acidosis. AKI common. HUS/TTP ( b p. 845): May present in either the antenatal or post-natal period. Exacerbation of existing renal disease, e.g. SLE: Renal biopsy may be required to con \201 rm diagnosis and is safe in early pregnancy in expert hands. \200 Acute interstitial nephritis ( b p. 580): Often drug-related, e.g. NSAIDs, antibiotics, proton pump inhibitors. Nephrotoxic drugs ( b p. 898). Post-renal \200 Acute urinary retention: 3rd trimester. Relates to bulk of expanding uterus. \200 Also occurs following combined k idney/pancreas transplantation where the transplanted kidney is placed in an intraperitonea l location (unusual in renal transplantation alone where the transplant is in the false pel vis). Investigations SCr ( 2 a SCr of >80 mol/L (0.9mg/dL) may indicate of renal impairment in p regnancy). FBC, U&E, LFTs, calcium, clotting, urate, haemolysis screen, G&S, infection scre en (MSU, blood cultures, vaginal swabs, as appropriate). Management Similar to non-pregnant patients. Careful assessment of \202 uid status, with correction of volume depletion. Treat underlying cause. AKI DURING PREGNANCY 845 Septic abortion Sudden onset (over hours) after attempted abortion. Fever (often >40 * C), rigors, myalgia, vomiting, and diarrhea (may be bloody). Abdominal pain is common, but vagi nal discharge is often absent. Progression to septic shock, with d BP, i HR, peripheral vas odilatation, oliguria, and DIC is rapid. Culpable organisms include E. coli and Clostridia . Investigations Blood cultures, Hb (haemolysis), d Plt (DIC) G&S, clotting, D-dimers, U&E, L FT. Perform VE for high vaginal swabs ( l M,C+S). Plain AXR may show intrauterine or intra \200\223 abdominal gas. Consider USS or CT to exclude pyometrium. Management Transfer to critical care. O 2 , resuscitate with IV \202 uids and blood prod- ucts ( b p. 168). 2 Benzylpenicillin 1.2 \200\223 2.4g IVI qds, metronidazole 500mg IVI t ds + Gram \200\223ve cover (e.g. cefuroxime 1.5g stat, followed by 750mg IVI tds or cipro \202 oxacin 200mg IVI bd, adjusted for SCr). Acute fatty liver of pregnancy Occurs late in pregnancy or immediately post-partum. Part of a spectrum of pregnancy-related diseases characterized by endothelial dysfunction with end -organ damage (which also includes pre-eclampsia). Presents with nausea, vomiting, jaundice , encephalopathy, acute hepatitis, and DIC. AKI is common. Management is supportive. Expedi te delivery, if possible. Cortical necrosis Common historically, especially after placental abruption and post-partum hemorrhage. Sudden and profound renal vasospasm (often with marked d BP) causes patchy inf arction of the renal cortex. Causes severe AKI (often with persistent anuria) and often irr eversible renal failure. Contrast-enhanced CT scanning, Doppler USS or MAG-3 isotope scan- ning will demonstrate the perfusion defects. HUS/TTP ( b p. 574) Very rare ( 7 1 in 100,000 pregnancies). Presents with AKI (often requiring RRT), usually in the 3rd trimester or ear ly puerperium (up to 10 weeks post-partum), but can occur throughout pregnancy. Endothelial dysfunc- tion, with microangiopathic haemolytic anemia, thrombocytopenia (both typically s evere), and coagulopathy are present. i BP (>70%) and pro- teinuria (>80%) are common. May follow an otherwise unremarkable (normotensive and non-proteinuric) pregnancy. Easily (and 6 commonly) confused with other diagnoses, such as pre-eclampsia, HELLP, acute fatty liver of pregnancy, and antiphospho- lipid antibody syndrome. It is important to cons ider the diagnosis, as early treatment (FFP/plasmapheresis) is helping to improve historica lly poor outcomes for maternal morbidity and mortality. Pregnancy d ADAMTS13 levels (as doe s HELLP) \200\224 but they will be much lower in TTP and many cases of HUS (although usual ly not available to assist immediate manage- ment). Relapse may occur in subsequent pregnan cies. CHAPTER 11 Pregnancy and the kidney 846 Hypertension during pregnancy Introduction Blood pressure falls in the early stages of a no rmal pregnancy and returns to pre-pregnancy baseline by term. Hypertension is the most common medical problem encountered dur- ing pregnancy, affecting 7 5 \200\223 10% of women. Hypertensive disorders during pregnancy carry risks for the moth er and are among the leading causes of maternal death in the developed world. Hypertensive disorders also carry a risk for the fetus in terms of higher perinatal mortality rates, pre term birth, and low birthweight. De \201 nition (NICE) Diastolic blood pressure (DBP) of >90mmHg on two separate occasions, more than 4 hours apart, and/or a single DBP reading of >110mmHg. Degrees of hypertension \200 Mild: DBP 90 \200\223 99mmHg, SBP 140 \200\223 149mmHg. \200 Moderate: DBP 100 \200\223 109mmHg, SBP 150 \200\223 159mmHg. \200 Severe: DBP \211 110mmHg, SBP \211 160mmHg. Causes \200 Pre-existing essential hypertension ( \200\230 chronic hypertension \200 \231 ) ( b p. 847). Pregnancy-induced hypertension (PIH) ( \200\230 gestational hypertension \200\231 ) ( b p. 847). Pre-eclampsia ( b p. 850). \200 Hypertension complicating renal disease (either pre-exist ing or developing during pregnancy) ( b p. 856) or other causes of secondary i BP (e.g. hyperaldos teronism or phaeochromocytoma). Measuring blood pressure in pregnant women \200 Use a well-maintained mercury/aneroid sph ygmomanometer or validated automated device. Use the stethoscope bell for auscultation. \200 2 Always use the correct-sized cuff. \200 Measure with patient sitting after a period of rest, with the arm supported at heart level. Either arm, but use higher value if >10mmHg difference. \200 Record SBP when sounds are \201 rst heard (Korotkoff 1) and DBP at the point of disappearance of sounds (Korotkoff 5) . If the DBP is persistently below 40mmHg, use Korotkoff 4 (and make a note). HYPERTENSION DURING PREGNANCY 847 Pre-existing essential hypertension ( \200\230chronic hypertension \200\231) \200 Present s prior to conception or before 20 weeks \200\231 gestation (as BP tends to fall in the 1st and 2nd trimesters, a woman with i BP before 20 weeks can be assum ed to have pre-existing hypertension). X Treatment targets for hypertensive women without pre-eclampsia remain controversial. Alth ough treatment is likely to have maternal bene \201 ts, this must be balanced against pote ntial harm to the fetus (particularly IUGR). Goals: For uncomplicated i BP, aim <150/100mmHg (but DBP no less than 80mmHg). If evidence of target organ damage (e.g. renal disease), aim <140/90mmHg. Encourage to lower dietary salt intake. \200 Ensure antihypertensives are altered appropr iately, ideally, several months prior to conception (and that BP then stabilizes) or as soon as possible once pregna ncy occurs ( b p. 849). Treatment should be based on existing therapy, potential side effec t pro \201 les, and discussion with the patient. Seek specialist advice if known or suspected secondary i BP. \200 The majority of pregnan cies are uncomplicated, although outcomes are worse than for pregnancy in normotensive pati ents. There is: \200 An increased incidence of placental abruption, AKI, cardiac events, and stroke in the mother. Increased risk of growth retardation and unexplained mid-trimester fetal death. A pre-eclampsia risk of 7 20%. Warn about symptoms ( b p. 852). \200 These risks correlat e with maternal age, duration and degree of i BP, obesity, and presence of end-organ damage. Recommend aspirin 75mg od from 12 weeks \200\231 gestation onwards to reduce pre-eclampsia risk. Calcium supplementation may have a small role in preventing serious adverse events, such as fetal death, associated with pre-eclampsia in populations with a low calcium intake (<600m g/day). If proteinuria develops after 20 weeks \200\231 gestation, treat as for pre-eclampsia. Pregnancy-induced hypertension (PIH) ( \200\230gestational hypertension \200\231) \200 Oc curs after 20 weeks \200\231 gestation. \200 Not associated with proteinuria. \200 Usu ally no pre-existing diagnosis of i BP. \200 Risk factors include \201 rst pregnancy an d maternal age >40 years. \200 BP returns to normal post-partum (within 3 months). \200 Increased risk of progression to pre-eclampsia (15 \200\223 25%) \200\224 the earlier th e development of PIH, the greater the risk. Warn the mother about potential symptoms ( b p. 852). CHAPTER 11 Pregnancy and the kidney 848 Aspirin 75mg until delivery in those with one high risk factor or two moderate risk factors for pre-eclampsia. \200 High risk: hypertensive disease during a pr evious pregnancy, CKD, diabetes, thrombophilia, or relevant autoimmune disease (such as SLE or antiphospholipid antibody syndrome). Moderate risk: \201 rst pregnancy, age >40 years, pregnancy interval of 10 years, BMI >35 , +ve family history, twin or multiple pregnancy). \200 Calcium supplements may be bene \201 cial in certain groups ( b p. 852). \200 Increased risk of both PIH (16 \200\223 47 %) and pre-eclampsia (2 \200\223 7%) in subsequent pregnancies. Although the cause of gestational hypertension is unclear, it appears to identify women at risk of essential i BP later in life. Management BP lowering is not an end in itself \200\224 maternal and fetal well-being are also important indicators of the underlying condition. \200 Mild hypertension (BP 140/90 \200\223 149/99mmHg): Do not treat i BP. Measure BP no more than weekly. \200 Test for proteinuria at each visi t. \200 If <32 weeks or high risk of pre-eclampsia, test for proteinuria, and measure BP twice weekly. Moderate hypertension (BP 150/100 \200\223 159/109mmHg): Treat to keep BP <150/80 \200\223 100mmHg ( \201 rst-line agent: labetolol). \200 Measu re BP; test for proteinuria twice a week. \200 Check SCr, U&E, FBC, and LFTs at presentat ion. Severe hypertension (BP \211 160/110mmHg): \200 1 Admit until BP \211 159/109mmHg. \200 No role for \200\230 bed rest \200\231 . \200 Treat to keep BP <150/80 \200\223 100mmHg ( \201 rst-line agent: labetolol). \200 Measure BP at least 4 x per day. \200 Test for proteinuria daily. \200 Check SCr, U&E, FBC, and LFTs at presentation and then w eekly. Fetal assessment includes USS for fetal growth, amniotic \202 uid volume assessment, and umbilical artery Doppler velocimetry. Fetal cardiotocography should be performed if there is any change in condition, such as a decrease in fetal movements. Early delivery is not usually required, unless severe refractory i BP or other complications supervene. Guidelines The NICE guidelines for hypertension in pregnancy are a very useful resource. Th ey are available at M www.nice.org.uk HYPERTENSION DURING PREGNANCY 849 Drug treatment of hypertension in pregnancy 1 No drug is entirely \200\230 safe \200\231 in pregnancy. However, experience has allowed an inference of low fetal risk for many agent s (see Table 11.2). 1 ACE-I (and ARBs) are contraindicated during pregnancy: 1st trimester use is associated with an increased risk of cardiac and CNS malforma- tions, and 2nd trimes ter use is associated with fetal death, oligohydram- nios, growth restriction, and renal ag enesis. 1 Diuretics should be avoided in pregnancy, as hypovolaemia may com- promise placen tal blood \202 ow. Occasionally, severe oedema, e.g. in the context of nephrotic syndrome , necessitates their use, but this should under close specialist supervision. Breastfeeding Antihypertensive agents safe for breastfeeding in the post-natal period inclu de enalapril, captopril, labetalol, nifedipine, atenolol, and metopro- lol. 1 There is insu f \201 cient evidence to recommend other ACE-I, ARBs, or amlodipine. Table 11.2 Antihypertensives in pregnancy Drug Dose Comment Labetalol 200mg bd \200\223 500mg tds Low risk to fetus First line for PIH and pre-eclampsia Atenolol is no longer recommended, a s low birthweights have been reported Methyldopa 250mg bd \200\223 1g tds Low risk to fetus SE: drowsiness, depression Nifedipine 10mg bd \200\223 30mg bd Low risk to fetus Limited data on other dihydropyridine CCBs, including amlodipine Non-dihy dropyridine: limited data suggest verapamil is low risk, but diltiazem should be avoided Prazosin 0.5mg tds \200\223 4mg tds Limited data suggest low risk Limited data on other alpha-blockers, including doxazosin, bu t many authorities are happy to use in pregnancy Hydralazine 25mg tds \200\223 75mg tds Low risk to fetus Maternal SEs (including headaches, tachycardia, and palpitations) are com mon and may mimic the onset of pre-eclampsia CHAPTER 11 Pregnancy and the kidney 850 Pre-eclampsia: pathophysiology Introduction Pre-eclampsia (from the Greek eclampsus or ligh tning) is a pregnancy spe- ci \201 c multisystem disorder, characterized by the developmen t of i BP and proteinuria, usually, but not always, after 20 weeks \200\231 gestation. It affects 3 \200\223 5% of pregnant women and is a leading cause of maternal and neonatal mo rbidity and mortality. The only cure is delivery, hence an association with prematurity. It is also associated with fetal growth restriction and oligohydramnios. Maternal complicatio ns include pulmonary oedema, cer- ebral hemorrhage, hepatic failure, AKI, and death. Seizur es (2% of cases) herald the development of eclampsia. Pathogenesis The placenta plays a critical role in the pathophysiology of pre-eclampsia and the related conditions of PIH, acute fatty liver of pregnancy, HELLP syndrome, and pregnan cy-induced HUS/TTP. All are associated with inadequate placental cytotrophoblast invasion a nd widespread maternal endothelial dysfunction (see Fig. 11.1). Pre-eclampsia and the placenta During normal placental development, cytotrophoblasts of fet al ori- gin invade the uterine spiral arteries and remodel them from small, high-resistance vessels into larger, more dilated vessels able to provide an adequate blood supply to the developing fetus. In pre-eclampsia, this remodeling is defective, with dysregulation of several angiogenic fa ctors, including soluble Fms-like tyrosine kinase 1 (sFlt-1) (itself a receptor for placent al growth factor (PlGF) and VEGF) and endoglin (sEng) (which impairs binding of TGF-1 to en dothelial receptors and leads to d endothelial NO-dependent vasodilatation). High concentra tions of sFlt-1 are present in in the blood of women with pre-eclampsia, and the administra tion of sFlt-1 to animals pro- duces a similar syndrome. Several studies of the utility of biomarkers, including sFlt-1, sEng, and PlGF, for the prediction and early diagnosis of pre -eclampsia are in progress. Low placental L-arginine activity also reduces NO activity, thereby stimulating endothelial NO synthase to generate reactive oxygen spe- cies (e.g. peroxynitrite and OH radical) and worsen oxidative stress. Subsequent release of vasopressive factors from the diseased placenta affects maternal endo thelium, with increased sensitivity to vasopressors, such as angiotensin II and noradrenali ne. This results in the widespread vasoconstriction, hypoperfusion, ischaemia, and vascular dysfunction, characteristic of the clinical syndrome. Abnormalities of RAS, in \202 ammation, immune maladaptation, and genetic susceptibility also appear to play a role. PRE-ECLAMPSIA: PATHOPHYSIOLOGY 851 Placenta Maternal circulation/organs Free VEGF VEGF sFlt1 sFlt1 Permeability of fenestrated endothelium Oxidative stress Arginase II expression Oxidative stress L-Arg eNOS \200\223 O2 NO NO activity/ half-life On endothelial cells Brain Liver Kidney Peroxynitrite TxA2 PGI2 Adhesion molecules Cytokines Oedema OH Proteinuria Angiogenic/ vasculogenic activity MMP2/ MMP9 activity Placental vasculature constriction Endothelial dysfunction Hypoperfusion Signals to increase perfusion Hypertension B2 receptor Oxidative stress Abnormal cytotrophoblast invasion Hypoxia AT1 \200\223B2 receptor heterodimers Vascular responsiveness Ang II Agonistic AT1 Abs Fig. 11.1 The pathophysiology of pre-eclampsia. Abs, antibodies; Ang II, angiotensin II; AT 1, angiotensin II type 1 receptor; eNOS, endothelial nitric oxide synthase; L-Arg, L-argini ne; MMP2, matrix metalloproteinase 2; MMP9, matrix metalloproteinase 9; NO, nitric oxide; O 2 \200\223 , superoxide anion; OH*, hydroxyl radical; PGI 2 , prostacyclin; sFlt1, solubl e Fms-like tyrosine kinase 1; TxA 2 , thromboxane A 2 ; VEGF, vascular endothelial growth f actor. Reproduced from from Noris M et al. (2005). Nat Clin Pract Neprol, 1: 98 \200\223 1 14 with permission from Nature Publishing Group. Organs affected \200 Circulation: vasoconstriction l i BP; capillary leak l oedema. \200 Lungs: pulmonary oedema. \200 Kidney: Proteinuria. \200 AKI. \200 Glomerular endotheliosis is the term used to describe the ultrastructural changes seen in the kidney. d Renal blood \202 ow l impaired tubular function l d urate clearance l i serum urate. Pre-eclampsia increases the relative risk of developing ESRD. Liver: ischaemia l i LFTs. \200 Brain: ischaemia and oedema lead to seizures (eclampsia). Severe uncontrolled i BP can lead to cerebral hemorrhage. Coagulation: Platelet activation occurs early and may be associated with thrombocytopenia. Several clotting factors are elevated beyond the raised levels already characteristic of pregnancy. CHAPTER 11 Pregnancy and the kidney 852 Pre-eclampsia: management Introduction 2 Pre-eclampsia has the potential to deteriorate rap idly. Seek special- ist help. Near term, induction of labor is usually the therapy of choic e, whereas a trial of stabilizing, or expectant, treatment may be more appro- priate if the pregnancy is at an earlier stage. Maternal risk factors for pre-eclampsia \200 High risk: hypertensive disease during a pre vious pregnancy, CKD, diabetes, thrombophilia, or relevant autoimmune disease (e.g. SLE or antiphospholipid antib ody syndrome). Moderate risk: \201 rst pregnancy, age >40 years, pregnancy interval of \211 10 years, BMI >35, +ve family history, twin or multiple pregnancy. Prevention \200 5 with one high-risk factor or two or more moderate risk factors should take aspirin 75mg od after 12 weeks \200\231 gestation (reduces risk by 7 15%). X Calcium supplementation may have a role in preventing serious adverse events, such as fet al death, associated with pre-eclampsia in populations with a low calcium intake (<600mg/da y). Diagnosis \200 New onset i BP (SBP >140 or DBP >90mmHg), presenting after 20 weeks \200 \231 gestation, with signi \201 cant proteinuria (generally >300mg/24h; equivalent to uPCR >30mg/mmol). 2 Classi \201 ed as severe when there is signi \201 cant i BP ( \211 160/110mmHg) 9 symptoms 9 biochemical or hematological derangement. Symptoms 2 An explanation of the potential symptoms of pre-eclampsia should be given to all women at risk. Advise them to seek immediate medical attention if they develop: Severe headaches. \200 Visual disturbances (e.g. blurred vision, \202 ashing lights, do uble vision, \202 oating spots). New epigastric pain (or pain in the right upper quadrant). \200 Vomiting. \200 Breathle ssness. \200 Sudden swelling of the hands, feet, or face ( 1 although oedema is a feature of pre-eclampsia, it also occurs in 60% of normal pregnancies). PRE-ECLAMPSIA: MANAGEMENT 853 Management 3 Admit to hospital, and undertake fetal monitoring. BP reduction is not the sol e endpoint of management \200\224 additional assessments of maternal and fetal well-being are equally important. Fetal assessment \200 USS for fetal growth, amniotic \202 uid volume assessment, and umbilical artery Doppler velocimetry. Fetal cardiotocography should be performed if there is any change in maternal condition (e. g. decrease in fetal movements, vaginal bleeding, or abdominal pain). Mild hypertension (BP 140/90 \200\223 149/99mmHg): Do not treat i BP. \200 Measure BP at least 4 x /day. \200 SCr, U&E, LFTs, and FBC x 2/ week. Moderate hypertension (BP 150/100 \200\223 159/109mmHg): Treat to keep BP <150/80 \200\223 100mmHg ( \201 rst-line agent: labetalol, b p. 849). Measure BP at least 4x/day. \200 SCr, U&E, LFTs, and FBC x 2/week. \200 Severe hyperten sion (BP \211 160/110mmHg): Consider admission to high dependency environment. \200 Treat to keep BP <150/80 \200 \223 100mmHg ( \201 rst-line agent: labetalol). \200 Measure BP at least 4 x per day. \200 SCr, U&E, LFTs, and FBC at least x 3/week. Delivery \200 Before 34 weeks: the decision to deliver can be very dif \201 cult. The rationale for delay is to improve neonatal outcome through delivery of a more mature fetus. It also affords the opportunity to administer corticosteroids to accelerate fetal lung mat urity. However, it risks worsening organ damage in the mother. Delivery is generally recomm ended if any of the indications shown in Table 11.3 are present. After 34 weeks: delivery is generally recommended once BP has been controlled and a course of corticosteroids administered, depending on maternal and fetal co ndition. After 37 weeks, delivery within 24 \200\223 48h is advocated. The choice between Cesarean or vaginal birth will need to be determined in each individual case. Table 11.3 Indications for delivery in pre-eclampsia Fetal Maternal Severe i BP despite treatment AKI Worsening liver function Thrombocytopenia Albumi n <20g/L No growth Abnormal CTG Abnormal umbilical artery Doppler signal CHAPTER 11 Pregnancy and the kidney 854 Severe pre-eclampsia 3 Characterized by severe i BP ( \211 160/110mmHg) 9 symptoms 9 bioc hemical or hematological derangement. \200 2 Features: Severe i BP and proteinuria (can be heavy). \200 Mild to moderate i BP with one of: sever e headache, visual disturbance, vomiting, epigastric or hypochondrial pain, liver tendernes s, papilloedema, clonus, HELLP, platelet count <100 x 10 9 /L, abnormal LFTs. 2 Transfer to critical care if: eclampsia, HELLP, hemorrhage, AKI, electrolyte disturbances , coagulopathy, unstable or refractory i BP (including need for parenteral therapy), cardia c failure, or abnormal neurology. Continuous BP monitoring. Consider invasive monitoring. \200 Careful \202 uid managemen t: Chart input/output. Catheterize, and monitor UO. \200 Limit maintenance \202 uids to 80 mL/h, unless there are ongoing \202 uid losses (e.g. bleeding). Avoid volume expansion, unless hydralazine is used as antihypertensive therapy ( b see below). BP management \200 2 Consult local guidelines. \200 Aim to keep BP <150/80 \200\223 10 0mmHg. \200 Monitor maternal and fetal response, in addition to BP response. \200 Conti nue antenatal antihypertensive therapy. \200 If parenteral therapy is required: Labetalol 20mg IV ( 1 contraindications: asthma, heart block); double the dose at 10min intervals to maximum cumulative dose of 200mg (or continuous infus ion of 1 \200\223 2mg/min). If inadequate response, give hydralazine 5mg IV, repeated every 15min, to a maximum cumulat ive dose of 20mg (or continuous infusion 0.5 \200\223 10mg/h). Consider administration of 500mL crystalloid before, or at the same time as, the \201 rst dose of hydralazine. Anticonvulsants \200 Give IV magnesium sulfate (superior to phenytoin and benzodiazepines) if a mother with severe i BP or severe pre-eclampsia has a seizure (or has previously had an eclamptic seizure). Consider magnesium sulfate if delivery is planned within 24h in those with severe pre-eclampsia. Regimen: Loading dose of 4g IV over 5min. \200 Further dose of 2 \200\223 4g over 5min if recurre nt seizures. \200 Follow with an infusion of 1g/h for 24h. \200 Monitor UO, respiratory rate, O 2 saturation, and re \202 exes. Measure serum magnesium level if toxicity is suspected (treatment for toxicity is 10% calcium gluco nate). PRE-ECLAMPSIA: MANAGEMENT 855 Pre-eclampsia: follow-up and prognosis Follow-up \200 Do not discharge until all symptoms of pre-eclampsia have resolved, BP is <149/99mmHg, and biochemical and hematological parameters are improving. Post-discharge, measure BP every 1 \200\223 2 days for 2 weeks. \200 Those with persiste nt i BP should be referred for specialist advice. \200 Aim to keep BP <140/90mmHg. Reduce treatment if <130/80mmHg. \200 If methyldopa has been used antenatally, withdrawal is recommended post-partum ( 1 risk of depression). The choice of alternative antihypertensive therapy, if required, will need to re \202 ect the mother s desire to breastfeed. Repeat blood tests, as clinically indicated. \200 If proteinuria persists at 3 months, se ek nephrology advice. \200 Women should be advised to keep their BMI in the healthy range prior to future pregnancies. Prognosis Women with pre-eclampsia have: \200 An increased risk of gestational hypertensi on in future pregnancies (13 \200\223 53%). An increased risk of pre-eclampsia in future pregnancies (16 \200\223 25%) ( 1 >50% if pre-eclampsia led to delivery before 28 weeks). \200 An increased risk of dev eloping i BP and CV disease in later life. \200 An increased relative risk of CKD and ESR D (even if normotensive with no proteinuria at post-natal review), although this risk is lo w. HELLP syndrome \200 Refers to a syndrome of haemolysis, elevated liver enzymes, and low platelet count. Occurs in 0.1 \200\223 0.2% pregnancies. \200 Probably represents a severe form of pre-e clampsia. \200 15 \200\223 20% of patients do not have i BP or proteinuria. \200 Often presents with nausea, vomiting, abdominal pain, and malaise. \200 About 70% of cases dev elop prior to delivery (usually 27 \200\223 37 weeks) and most of the remainder within 48 hours of delivery. The Martin/Mississippi classi \201 cation grades severity as class I (most severe) to III, based on nadir platelet count, LDH, and liver function. This helps estimate the maternal morbidity risk (intracerebral hemorrhage is the principal cause of death). Management is similar to pre-eclampsia. X In addition, corticosteroids (dexamethasone, betamethasone, or prednisolone) are commonly used to increa se platelet counts, although it remains unclear if this strategy improves overall outcomes. CHAPTER 11 Pregnancy and the kidney 856 Pre-existing renal disease Introduction The ability to conceive falls with d GFR. 2 However , once pregnant, the key determinant of pregnancy outcome in women with pre-existing renal disease is the degree of renal impairment. Other factors that in \202 uence outcome include: Hypertension. \200 Degree of proteinuria. \200 Type of renal disease. Obstetric complications include miscarriage, pre-eclampsia, preterm deliv- ery, and low bir thweight. Pregnancy can also result in a deterioration in renal function (see Table 11.4). This may be permanent and associated with progression to end-stage kidney disease. 1 Even w ith normal renal function, normal BP, and non-signi \201 cant pro- teinuria, women with a history of renal disease have an increased risk of pre-eclampsia ( 7 10%, compared to a bac kground rate of 3 \200\223 5% in the general population). General rules The following are helpful to remember when counseling women with renal diseas e that: \200 Pre-pregnancy SCr <200 mol/L: (2.25mg/dL) although there is an increased ri sk of complications (see Table 11.4), the chances of a successful outcome and healthy baby are relatively good. Pre-pregnancy SCr >250 mol/L: (2.8mg/dL) high risk of a poor fetal outcome (including prematurity and signi \201 cant developmental problems), together with a high risk of developing ESRD during (or soon after) pregnancy. The presence and degree of maternal i BP and proteinuria are also important considerations. Table 11.4 Approximate risks of obstetric complications and deterioration in renal function , based on pre-pregnancy renal function Degree of renal impairment Mild i SCr <125 mol/L (1.4mg/dL) Moderate i SCr 125 \200\223 180 mol/L (1.4 \200\2232.0mg/dL) Severe i SCr >180 mol/L (>2.0mg/dL) Pre-eclampsia 10 \200\223 20% 30 \200\223 50% 60% Preterm delivery 20 \200\223 30% 60% 80 \200\223 90% Permanent deterioration in renal function 0% 20% 50% PRE-EXISTING RENAL DISEASE 857 Speci \201 c renal diseases Diabetic nephropathy Now the commonest renal condition encount ered in pregnancy. It is essential that women with diabetes are educated about the importan ce of good pre-conception diabetic control for reducing the risk of congenital malformation (aim HbA1C \211 6.1% (43mmol/mol)). There is an increased incidence of babies of higher b irthweight. Otherwise, risks relate to both the degree of renal impairment and the degree o f proteinuria, as shown in Table 11.4. Re \202 ux nephropathy Women with re \202 ux nephropathy should be screened for UTI durin g preg- nancy, and, if present, infection should be treated promptly. Acute pyelo- nephriti s is more common. Mothers should also be counseled regarding the potential risk of inherita nce ( 7 25 \200\223 30%) and offered post-natal screen- ing for their children ( b p. 712) . Autosomal dominant polycystic kidney disease (ADPKD) Cyst complications in pregnancy, suc h as hemorrhage or infection, may masquerade as obstetric complications. Patients with a fa mily history of intracranial aneurysms should ideally be screened for aneurysms them- selve s prior to pregnancy. Primary glomerular disease The exact type of glomerular disease does not impact on pregnanc y out- come, but renal impairment, proteinuria, and maternal i BP all can. Relapse of a stable pre-existing glomerular lesion is generally unlikely (and usually very dif \201 cult to differentiate from pre-eclampsia when it occurs) ( b p. 859). Wait until disease is in remission (ideally >6 months) before trying to conceive. The form of treatmen t is also a consideration. If relevant, wait until off cytotoxic agents and on lowest possi ble effec- tive doses of corticosteroids. For other immunosuppressant drugs, see b p. 866. Proteinuria is likely to double during pregnancy. If >3g/24h (PCR >300mg/ mmol), then antic oagulation with low molecular weight heparin (LMWH) should be recommended, as there is an i ncreased thrombotic risk. In addition, signi \201 cant proteinuria (>3g/day) is associated with 7 x 2 increased risk of perinatal loss and preterm delivery, compared to no proteinuria. Lupus nephritis Renal impairment, proteinuria, and maternal i BP can all impact on preg- na ncy outcome. The risk of a disease \202 are increases in pregnancy (30%). Active lupus is associated with increased fetal loss, prematurity, and IUGR. In addition, there is a risk of a transient rash and fetal heart block (requiring pacing) in babies born to anti-Ro posi tive mothers. Those with antiphospholipid antibodies are at increased risk of spontaneous a bortion and should be considered for LMWH from conception. CHAPTER 11 Pregnancy and the kidney 858 Management of renal disease in pregnancy \200 Requires a multidisciplinary approach, incl uding an obstetrician, a nephrologist, and, ideally, an obstetric physician. Pre-pregnancy counseling (including genetic counseling, if relevant) is extremely important. Folic acid 400 micrograms od 3 months before trying to conceive. \200 Alter medications, including antihypertensives, to drugs that are safe in pregnancy ( b p. 849). Recommend aspirin 75mg, particularly from 12 weeks onwards, to reduce the risk of pre-eclampsia. Patients should be booked early to antenatal clinic. \200 Aim to see every 2 \200\223 3 weeks until 28th week, thereafter weekly. \200 BP every visit. Home BP monitoring may be helpful. \200 Urinalysis every visit (MSU for M,C+S in those at particular risk of infection). SCr, U&E, Ca 2+ , LFT, urate, and uPCR or uACR every 2 \200\223 4 weeks. \200 FBC every 4 weeks (IV iron and ESAs are safe). \200 If proteinuria >3g/24h (uPCR >300mg/mmol), then anticoagulation with LMWH should be considered. Monitor disease activity, where possible, e.g. SLE. \200 Serial obstetric scans for those at higher risk ( b p. 853). PRE-EXISTING RENAL DISEASE 859 Case study A 27-year-old primigravid Chinese woman presents to antenatal clinic at 18 weeks \200\231 gestation with progressive oedema. She is found to be nor- motensive, but urinal ysis reveals 3+ proteinuria. Her SCr is 54 mol/L (0.6mg/dL), uPCR 524mg/mmol, and serum al bumin 26g/L. Further investigations included: low C3 and C4, +ve ANA, +ve dsDNA, and +ve antiphospholipid antibody. Renal USS was normal. After discussion, a renal biopsy was undertaken and revealed class V lupus nephritis ( b p. 659). Treatment options Lupus nephritis ( b p. 658) can be treated w ith corticosteroids. Azathioprine is also safe in pregnancy, as is tacrolimus ( b p. 866). However, MMF ( b p. 866) and cyclophosphamide are contraindi- cated. Rituximab may also be considered ( X ) but ideally not in the last 6 months of pregnancy so that fetal B cells ha ve time to reconstitute prior to delivery. This patient should also be offered LMWH treatme nt in view of her proteinuria and antiphospholipid antibody status. If pos- sible, diuretic s should be avoided despite her oedema ( b p. 849). Learning point If new-onset proteinuria ( 9 renal impairment) occurs in early pregnancy (<20 weeks), it is important to attempt to diagnose the underlying renal lesion. Investigation will include immunological and serolog ical test- ing ( b p. 40) and potentially a renal biopsy. A histological diagnosis is likel y to assist management in later pregnancy easier, as differentiating primary renal disease from pre-eclampsia becomes very dif \201 cult (see Table 11.5). Table 11.5 Pre-eclampsia or active lupus nephritis? Pre-eclampsia i i +++ 9 \200\223 i Normal Lupus nephritis i i +++ BP Proteinuria Haematuria +++ Red cell casts ++ ALT Normal d i ++ Complement dsDNA titres Normal Symptoms of lupus \200\223 Response to steroids \200\223 + CHAPTER 11 Pregnancy and the kidney 860 Disorders of the urinary tract in pregnancy Changes to the anatomy of the renal tract durin g pregnancy, particularly dilatation of the collecting system ( b p. 840), need to be consi dered dur- ing the assessment of urinary tract symptoms and signs. Haematuria In the absence of proteinuria, haematuria is usually due to anatomi- cal changes (bleeding from small venules in dilated collecting systems). On microscopy, 2 \200\223 3 RBC/hpf is normal in pregnancy (unlike 1 \200\223 2 in the non-pregnant population). If SC r is normal and no proteinuria, wait until 12 weeks after delivery for further assessment ( b p. 66). Obstruction May occur s to mechanical pressure exerted by the uterus (usually on the right ureter, often where the ureter crosses the iliac artery) or s to pelvic or ureteric stone i mpaction. Renal stones Renal stones are uncommon in pregnancy and usually occur in women known to hav e pre-existing nephrolithiasis. However, collecting system dilatation, coupled with stasis and a 2 \200\223 3-fold increase in urinary calcium excretion, may precipitate new stone f ormation in pregnancy. Ureteric stones are more common than stones in the renal pelvis, and most occur after the \201 rst trimester. The majority will pass spontaneously, but impac ted stones may remain painful, and s urinary infection is a concern. Women with cystinuria should be offered genetic counseling prior to conception, and proactive management of their stone disease should start pre-pregnancy ( b p. 719). 1 The differential diagnosis of ston e-induced colic must include obstetric problems, such as placental abruption Investigation Urine dipstick for haematuria and proteinuria. Microscopy: red cells (+ morph ology), casts, pus cells, and organisms. Urine culture 9 stone analy- sis. FBC, U&E, serum calcium, PTH.