Critical Care Obstetrics part 41 pdf

Martin Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Mississippi Medical Center, Jackson, MS, USA Introduction Sickle cell disease re

2 Ibdah JA Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications World J Gastroenterol 2006 ; 12 ( 46 ):

7397 – 7404

3 Reyes H , Sandoval L , Wainstein A , et al Acute fatty liver of

preg-nancy: a clinical study of 12 episodes in 11 patients Gut 1994 ; 35 :

101 – 106

4 Kaplan MM Acute fatty liver of pregnancy N Engl J Med 1985 ; 313 :

367

5 Usta IM , Barton JR , Amon EA , Gonzalez A , Sibai BM Acute fatty live

of pregnancy: an experience in the diagnosis and management of

fourteen cases Am J Obstet Gynecol 1994 ; 171 : 1342 – 1347

6 Pockros PJ , Peters RL , Reynolds TB Idiopathic fatty liver of

preg-nancy: fi ndings in ten cases Medicine 1984 ; 63 : 1

7 Bacq Y Acute fatty liver of pregnancy Semin Perinatol 1998 ; 22 ( 2 ):

134 – 140

8 Monga M , Katz AR Acute fatty liver in the second trimester Obstet Gynecol 1999 ; 93 ( 5 Pt 2 ): 811 – 813

9 Suzuki S , Watanabe S , Araki T Acute fatty liver of pregnancy at 23

weeks of gestation Br J Obstet Gynaecol 2001 ; 108 : 223 – 224

10 Barton JR , Sibai BM , Mabie WC , Shanklin DR Recurrent acute fatty

liver of pregnancy Am J Obstet Gynecol 1990 ; 163 : 534 – 538

11 Schoeman MN , Batey RG , Wilcken B Recurrent acute fatty liver of pregnancy associated with a fatty - acid oxidation defect in the

off-spring Gastroenterology 1991 ; 100 : 544 – 548

12 Wilcken B , Leung KC , Hammond J , Kamath R , Leonard JV Pregnancy and fetal long chain 3 hydroxyacyl coenzyme A dehydrogenase defi

-ciency Lancet 1993 ; 341 : 407 – 408

13 Burroughs AK , Seong NGJ , Dojcinov DM , et al Idiopathic acute fatty

liver of pregnancy in twelve patients Q J Med 1982 ; 204 : 481

14 Davidson KM , Simpson LL , Knox TA , d ’ Alton ME Acute fatty liver

of pregnancy in triplet gestation Obstet Gynecol 1998 ; 91 ( 5 Pt 2 ):

806 – 808

15 Ibdah JA , Bennett MJ , Rinaldo P , et al A fetal fatty - acid oxidation

disorder as a cause of liver disease in pregnant women N Engl J Med

1999 ; 340 ( 22 ): 1723 – 1731

16 Rinaldo P , Raymond K , al - Odaib A , Bennett MJ Clinical and

bio-chemical features of fatty acid oxidation disorders Curr Opin Pediatr

1998 ; 10 : 615 – 621

17 Pons R , Roig M , Riudor E , et al The clinical spectrum of long - chain

3 - hydroxyacyl - CoA dehydrogenase defi ciency Pediatr Neurol 1996 ;

14 : 236 – 243

18 Ibdah JA , Tein I , Dionisi - Vici C , et al Mild trifunctional protein defi ciency is associated with progressive neuropathy and myopathy

and suggests a novel genotype - phenotype correlation J Clin Invest

1998 ; 102 : 1193 – 1199

19 Treem WR , Rinaldo P , Hale DE , et al Acute fatty liver of pregnancy and long chain 3 hydroxyacyl coenzyme A dehydrogenase defi

-ciency Hepatology 1994 ; 19 : 339 – 345

20 Sims HF , Brackett JC , Powell CK , et al The molecular basis of pedi-atric long chain 3 - hydroxyacyl - CoA dehydrogenase defi ciency

associ-ated with maternal acute fatty liver of pregnancy Proc Natl Acad Sci USA 1995 ; 92 : 841 – 845

21 Isaacs JD Jr , Sims HF , Powell CK , et al Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein defi ciency:

molecular characterization of a novel maternal mutant allele Pediatr Res 1996 ; 40 : 393 – 398

22 Matern D , Hart P , Murtha AP , et al Acute fatty liver of pregnancy associated with short chain acyl coenzyme A dehydrogenase defi

-ciency J Pediatr 2001 ; 138 ( 4 ): 585 – 588

gastric tube Nitrogenous waste production can be reduced

further by exclusion of protein intake during the acute phase of

the illness Once clinical improvement is evident, protein intake

should gradually be restored With rare exceptions, any drug that

requires hepatic metabolism should be withheld from the patient

Colonic emptying should be facilitated through the use of enemas

and/or magnesium citrate; ammonia production by intestinal

bacteria may be diminished by the administration of neomycin,

6 – 12 g orally per day

Exchange transfusion, hemodialysis, plasmapheresis,

extracor-poreal perfusion, and corticosteroids have all been used to treat

fulminant hepatic failure [39] and should be considered in cases

unresponsive to traditional management Successful liver

trans-plantation has also been reported in women with AFLP who

continue to deteriorate in spite of delivery and appropriate

sup-portive care [40 – 42] However, because the pathophysiologic

changes associated with AFLP are reversible, transplantation is

inappropriate in all but the most extreme cases [1,43] Successful

temporary auxiliary liver transplant has also been reported [41]

Mild coagulation abnormalities need not be corrected if

deliv-ery can be accomplished atraumatically and there is no evidence

of clinical bleeding However, in the presence of hemorrhagic

complications or if surgery is contemplated, the coagulation

abnormalities should be corrected with platelet, fresh frozen

plasma, or cryoprecipitate transfusion based on the results of

laboratory evaluation The successful use of antithrombin [1,43]

and factor VII [44] concentrations have also been reported

Morbidity from other potential complications may be

pre-vented by prophylactic treatment and careful surveillance The

liberal use of broad - spectrum antibiotics may decrease the

inci-dence of concomitant infection [1] Prophylactic administration

of antacid solutions and H 2 blocking agents may decrease the risk

of gastrointestinal bleeding

Summary

Acute fatty liver of pregnancy is fortunately uncommon but when

it occurs, results in serious morbidity and even mortality in the

worst cases Early diagnosis and prompt treatment remain the

best strategy for managing patients with AFLP Defects in long

chain fatty acid oxidation play a role in the development of AFLP

and genetic testing may useful in preventing neonatal morbidity

as well as future pregnancy morbidity Delivery is the treatment

of choice and supportive care and treatment of systemic

manifes-tations of AFLP improve both maternal and perinatal survival

References

1 Castro MA , Fassett MJ , Reynolds TB , Shaw KJ , Goodwin TM

Reversible peripartum liver failure: a new perspective on the

diagno-sis, treatment, and cause of acute fatty liver of pregnancy, based on

28 consecutive cases Am J Obstet Gynecol 1999 ; 181 ( 2 ): 389 – 395

Chapter 29

34 Clements D , Young WT , Thornton JG , Rhodes J , Howard C , Hibbard

B Imaging in acute fatty liver of pregnancy Case report Br J Obstet Gynaecol 1990 ; 97 : 631 – 633

35 Farine D , Newhouse J , Owen J , Fox HE Magnetic resonance imaging and computed tomography scan for the diagnosis of acute fatty liver

of pregnancy Am J Perinatol 1990 ; 7 : 316 – 318

36 Goldfarb G , Debaene B , Ang ET , Roulot D , Jolis P , Lebrec D Hepatic blood fl ow in humans during isofl urane N 2 O and halothane - N 2 O

anesthesia Anesth Analg 1990 ; 71 : 349 – 353

37 Holzman RS , Riley LE , Aron E , Fetherston J Perioperative care of a

patient with acute fatty liver of pregnancy Anesth Analg 2001 ; 92 ( 5 ):

1268 – 1270

38 Antognini JF , Andrews S Anaesthesia for caesarean section in a

patient with acute fatty liver of pregnancy Can J Anaesth 1991 ; 38 :

904 – 907

39 Katelaris PH , Jones DB Fulminant hepatic failure Med Clin North

Am 1989 ; 73 : 955 – 970

40 Amon E , Allen SR , Petrie RH , Belew JE Acute fatty liver or pregnancy associated with pre - eclampsia: management of hepatic failure with

postpartum live transplantation Am J Perinatol 1991 ; 8 : 278 – 279

41 Franco J , Newcomer J , Adams M , Saeian K Auxiliary liver transplant

in acute fatty liver of pregnancy Obstet Gynecol 2000 ; 95 ( 6 Pt 2 ):

1042

42 Ockner SA , Brunt E , Cohn SM , Krul ES , Hanto DW , Peters MG Fulminant hepatic failure caused by acute fatty liver of pregnancy by

orthotopic liver transplantation Hepatology 1990 ; 11 : 59 – 64

43 Doepel M , Backas HN , Taskinen EI , Isoniemi HM , Hockerstedt KA Spontaneous recovery of post partus liver necrosis in a patient listed for transplantation Hepatogastroenterology 1996 ; 43 ( 10 ):

1084 – 1087

44 Gowers CJ , Parr MJ Recombinant activated factor VIIa use in massive transfusion and coagulopathy unresponsive to conventional therapy

Anaesth Intens Care 2005 ; 33 ( 2 ): 196 – 120

23 Treem WR Mitochondrial fatty acid oxidation and acute fatty liver

of pregnancy Semin Gastrointest Dis 2002 ; 13 : 55 – 66

24 Yang Z , Zhao Y , Bennett MJ , Strauss AW , Ibdah JA Fetal genotypes

and pregnancy outcomes in 35 families with mitochondrial

trifunc-tional protein mutations Am J Obstet Gynecol 2002 ; 187 : 715 – 720

25 Yang Z , Yamada J , Zhao Y , Strauss AW , Ibdah JA Prospective

screen-ing for pediatric mitochondrial trifunctional protein defects in

preg-nancies complicated by liver disease JAMA 2002 ; 288 : 2163 – 2166

26 Ibdah JA , Zhao Y , Viola J , Gibson B , Bennett MJ , Strauss AW

Molecular prenatal diagnosis in families with fetal mitochondrial

tri-functional protein mutations J Pediatr 2001 ; 138 : 396 – 399

27 Kennedy SK , Hall PM , Seymore AE , Hague WM Transient diabetes

insipidus and acute fatty liver of pregnancy Br J Obstet Gynaecol 1994 ;

101 : 387 – 391

28 Tucker ED , Calhoun BC , Thorneycroft IH , Edwards MS Diabetes

insipidus and acute fatty liver: a case report J Reprod Med 1993 ; 38 :

835 – 838

29 Purdie JM , Waters BNJ Acute fatty liver of pregnancy Clinical

fea-tures and diagnosis Aust NZ J Obstet Gynaecol 1988 ; 28 : 62 – 67

30 Castro MA , Ouzounian JG , Colletti PM , Shaw KJ , Stein SM , Goodwin

TM Radiologic studies in acute fatty liver of pregnancy A review of

the literature and 19 new cases J Reprod Med 1996 ; 41 ( 11 ):

839 – 843

31 Liebman HA , McGhee WG , Patch MJ , Feinstein DI Severe

depres-sion of antithrombin III associated with disseminated intravascular

coagulation in women with fatty liver of pregnancy Ann Intern Med

1983 ; 98 : 330 – 333

32 Lauersen B , Frost B , Mortensen JZ Acute fatty liver of pregnancy with

complicating disseminated intravascular coagulation Acta Obstet

Gynecol Scand 1983 ; 62 : 403

33 Duma RJ , Dowling EA , Alexander HC , et al Acute fatty liver of

preg-nancy: report of a surviving patient with serial liver biopsies Ann

Intern Med 1965 ; 63 : 851

Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,

M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd.

Michelle Y Owens & James N Martin

Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, University of Mississippi Medical Center, Jackson, MS, USA

Introduction

Sickle cell disease represents a spectrum of heritable disorders of

hemoglobin synthesis that result in the production of abnormal

hemoglobin molecules (hemoglobin S) Included in this group

are sickle cell anemia (Hgb β S β S ), SC disease (Hgb β S β C ), and

sickle β - thalassemia (Hgb β + β 0 ) In sickle cell trait (Hgb β A β S )

only one β - chain is abnormal As such, sickle trait is considered

to be an essentially benign disease, except under extremely

stress-ful physiologic conditions In sickle cell disease, the production

of abnormal hemoglobin causes deformities of the red cell

mem-brane which result in hemolytic anemia, tissue ischemia, organ

failure, and episodic vaso - occlusive pain crises Other sequelae

include chronic pain from long - term or repeated ischemic events,

and altered immunity leading to an increased susceptibility to

infections When compared with unaffected pregnancies, sickle

cell disease in pregnancy is associated with an increased incidence

of pre - eclampsia, preterm labor, spontaneous abortion, and

still-birth compared to unaffected pregnancies [1,2]

Over the past few decades, much has been learned about this

particular class of hemoglobinopathies In one generation,

sur-vival for individuals with sickle cell disease has increased from 14

years to almost 50 years, and 50% survive beyond the fourth

decade [3] With the advent of widespread screening,

prophylac-tic antibioprophylac-tic therapy, vaccine use, and the application of novel

technologies such as transcranial Doppler, morbidity and

mortal-ity from sickle cell disease have diminished greatly and signifi cant

increases in quality of life have occurred

Epidemiology

The sickle cell mutation arose, independently, in fi ve geographic

locations worldwide [4] The mutations are identifi ed by their

association with different β - globin gene haplotypes (Tables 30.1 & 30.2 ) Four occurred in Africa (Senegal, Bantu, Benin, and Cameroon types), and one originated in Southern India (Indian/ Saudi Arabian type) The high prevalence of such a deleterious gene among some ethnic groups has been attributed to selective pressure from falciparum malaria Heterozygotes (sickle cell trait) are usually asymptomatic and have partial protection against the malarial parasite

Sickle cell anemia is the most common heritable hemoglobin-opathy It is the most common single gene disorder in the United States, with 1 in 400 African Americans affected and 1 in 12 being carriers of the trait The disorder is also common among other ethnic groups around the world, including Asian Indians, those

of Mediterranean descent, and inhabitants of the Arabian Peninsula Hemoglobin SC disease has an approximate frequency

of 1 in 1250 and the sickle β - thalassemias occur in approximately

1 in 24 000 African Americans [5] However, because American society is made up of immigrants from many countries, it is useful

to be aware that the sickle hemoglobin gene has a prevalence of 25% in some parts of Saudi Arabia and 30% among some Indian populations The gene has also been identifi ed in parts of the former Soviet Union, in Arabs living in Israel, in Central and South America, and in the Mediterranean countries of Greece, Italy, and Spain [4,6]

Similarly, the β - thalassemia mutations are common in Africa, some parts of India and around the Mediterranean and in Southeast Asia

Fertility is not impaired in women with sickle cell disease Although no statistics are available on the number of births to affected women, the high prevalence of the disease makes it very likely that a clinician will at some time be responsible for the care

of a pregnant sickle cell patient

Molecular b asis of the s ickle

h emoglobinopathies

The sickle hemoglobinopathies are inherited as autosomal reces-sive traits Individuals with sickle cell disease possess at least one

Chapter 30

gene which precludes any production of β - chains Sickle β + thalassemia is the mildest variant of sickle cell disease, followed

in order of increasing severity by doubly heterozygous sickle hemoglobin C (SC), sickle β 0 - thalassemia, and homozygous sickle cell disease

Diagnosis

The diagnosis of sickle cell disease cannot and must not be made from either a sickle cell preparation or a solubility test While these are adequate screening tools, neither of these tests will reliably distinguish sickle cell trait from sickle cell disease Cellulose acetate electrophoresis or an isoelectric focusing test can be used for diagnostic purposes [9] Preimplantation genetic diagnosis is also available for use with assisted reproductive technologies

Pathophysiology

Under conditions of normal oxygenation, sickle hemoglobin has normal form and function Under conditions that cause reduced oxygen concentrations, the sickle β - globin demonstrates a high affi nity for other Hgb S chains This process is facilitated by the neutrally charged valine which is substituted for glutamic acid Tetramers of deoxyhemoglobin polymerize to form longer deoxyhemoglobin strands within the erythrocyte [10,11] These rigid polymers deform the erythrocyte membrane, causing occlu-sion of the smaller - caliber blood vessels Fully oxygenated hemo-globin is sterically prevented from polymerization Additionally, sickled cells adhere to the vascular endothelium and precipitate intimal hyperplasia and the release of infl ammatory cytokines which accelerate endothelial injury Most importantly, there is a delay between the deoxygenation and the formation of the hemo-globin polymer that is inversely dependent upon the concentra-tion of sickle hemoglobin [12] Thus, the higher the intracellular hemoglobin concentration, the more readily polymerization will occur It is this polymerization that is responsible for the distor-tion of the red cell membrane This process remains cyclical throughout the life of the red blood cell, and is also responsible for alterations in cellular membrane permeability leading to the overall egress of water from the erythrocyte [13] While polym-erization is a reversible process, the dehydration process is not Over time, the net effect of multiple episodes of polymerization and dehydration is an irreversibly sickled cell

It has been shown that the presence of fetal hemoglobin (Hgb F) decreases the severity of sickle cell anemia Fetal hemoglobin has a higher affi nity for oxygen and does not polymerize Individuals with higher percentages (20 – 30%) of hemoglobin F rarely experience crises because the speed of the sickling is reduced and the presence of the alternate globin chain inhibits the polymerization process [6]

gene for sickle hemoglobin in addition to another abnormal

hemoglobin gene Those with sickle cell trait possess one gene for

sickle hemoglobin and another for normal adult hemoglobin

The offspring of parents with sickle cell trait have a 25% chance

of being homozygous for sickle cell anemia, a 25% chance of

having normal hemoglobin, and a 50% chance of being a carrier

Clinical manifestations of sickle cell disease vary according to the

type of abnormal hemoglobin produced as well as the amount of

abnormal hemoglobin present

The β - globin chain is coded on the short arm of chromosome

11 Sickle cell anemia was the fi rst disease determined to have a

molecular basis [7] Though the fi rst clinical description of sickle

cell anemia was published by Herrick in 1910 [8] , it was not until

1949 that Pauling and colleagues [7] discovered the underlying

mechanism of disease They determined that sickle cell anemia

was the result of a point mutation in the gene coding for the β

chain of the hemoglobin molecule which resulted in the

substitu-tion of a single amino acid (valine for glutamic acid) in the sixth

position of the β - globin chain When present on both

chromo-somes in a patient, the result was sickle cell hemoglobin (Hgb S)

[7] It was later discovered that another abnormal hemoglobin,

hemoglobin C, was also the result of a missense mutation at the

sixth position causing lysine to replace glutamic acid

In addition to the more common point mutations, double

mutations also sometimes occur These resultant hemoglobin

variants still exhibit the characteristic sickling tendencies, but

when electrophoresed, they demonstrate different migration

pat-terns There are six known double mutation variants, which result

in abnormalities of the tertiary structure of the resulting globin

chain [4]

Unlike the sickle gene which is responsible for the production

of a dysfunctional globin chain, the thalassemia genes result in an

abnormal amount of globin produced The β - thalassemia

muta-tions are subdivided into two categories, β + and β 0 , based on

globin gene production In β + , there is reduced production of

β - chains, while β 0 is the result of a gene deletion or abnormal

Table 30.1 Mutations that cause sickle cell disease

β 6glu → val

β 0

or β +

Table 30.2 Known double mutations

β 6glu → val 121glu → lys

β 6glu → val 73asp → asn

β 6glu → val 142ala → val

β 6glu → val 23val → ile

β 6glu → val 82lys → asn

β 6glu → val 58pro → arg

Additionally, parturients with sickle cell disease are at increased risk for gestational hypertension, pre - eclampsia, and growth restriction The reasons why this occurs is unknown The authors recommend screening for hypertensive disorders at the time of registration which includes a 24 - or 12 - hour urine collection for urine protein and creatinine, liver function tests, uric acid, and a complete blood count to establish a baseline from which to evalu-ate these patients if and when symptoms occur Furthermore, close monitoring of maternal weight, blood pressure, clinical symptoms, and urine protein is essential In sickle cell disease, blood pressures tend to be lower than that with normal hemo-globin Part of our routine care also includes serial ultrasonogra-phy to evaluate the fetal rate of growth The authors typically follow these patients serially (4 – 6 weeks) if fetal growth rate is normal and every 3 weeks in the presence of growth restriction However, alterations in the timing of such examinations may be necessary as clinical indications arise

Respiratory

Another common site for sickle cell involvement is the lung The degree of involvement is variable, and comprises both acute and chronic processes Pulmonary complications are the second leading cause of hospitalization, and represent the leading cause

of death in the patient with sickle cell disease [18] Pulmonary mortality has declined with the initiation of penicillin prophylaxis and widespread vaccination protocols in childhood sicklers, but pneumonia remains a serious complication of sickle cell anemia Pneumonia is the third leading cause of death in pregnancy

com-plicated by sickle cell disease Though Streptococcus pneumoniae

is most common, atypical organisms such as Chlamydia species

should also be considered in this population [9] It is also recom-mended that these patients receive the infl uenza vaccine annually and the polyvalent pneumococcal vaccine In cases of asplenia, vaccination against Haemophilus infl uenzae type B and the meningococcus is also recommended [19]

Acute chest syndrome (ACS) is an acute life - threatening illness that can occur in sickle cell disease It will be discussed in further detail later in this chapter

Chronic pulmonary changes such as pulmonary hypertension and pulmonary fi brosis are the respiratory sequelae of recurrent episodes of ACS and the widespread endothelial injury that occurs in sickle cell disease In one study, 90% of adults with sickle cell disease were found to have abnormal pulmonary func-tion tests, the majority of which demonstrated a restrictive physi-ology (76%) [20] It is estimated that approximately one - third of patients with sickle cell disease will develop pulmonary hyperten-sion The maternal mortality rate associated with pregnancy and pulmonary hypertension ranges from 30 to 50%, and in severe cases, termination of pregnancy is recommended for maternal benefi t In the event that pregnancy is continued, management should include frequent visits, serial cardiopulmonary evaluation (including transthoracic Doppler echocardiography), and a mul-tidisciplinary approach to care Successful medical management has been reported in some cases with the utilization of sildenafi l,

Sickling can be precipitated by a number of physiologic and

environmental factors Among the more common aggravating

factors are acidosis, dehydration, extremes of temperature (hot

or cold), hypoxia, elevation, and infection In the initial stages,

the sickling process is reversible with oxygenation However, with

repeated episodes of deoxygenation, the red blood cell membrane

becomes rigid and irreversibly sickled [10] The alterations in the

molecular structure of sickled cells signifi cantly reduce the

life-span of the erythrocyte While the lifelife-span of a normal red blood

cell is approximately 120 days, the life span of a sickled cell ranges

from 10 to 20 days These damaged cells are cleared by the

reticu-loendothelial system (largely the spleen and liver) where the

majority of the hemolysis occurs, with approximately one - third

of hemolysis occurring intravascularly A chronic compensated

anemia results via the bone marrow and extramedullary

hematopoiesis

Vaso - occlusive crises occur fi rst as a result of occlusion of the

microvasculature Unlike the more pliable normal red blood cells,

sickled cells lack the fl exibility to maneuver through the smaller

diameters of the microcapillary beds These rigid cells become

entrapped within the capillaries, producing a vicious cycle of local

hypoxia, deoxygenation, and more sickling

Secondary o rgan s ystem e ffects

Sickle cell disease effects may be seen in multiple organ systems

As a result of the wide variety of systemic effects, the pregnant

sickle cell patient is at increased risk for more frequent pain crises,

hypertensive disorders of pregnancy, intrauterine growth

restric-tion, preterm labor, and infections Maternal mortality is reported

to be 1% in this population, but is continuing to decline [14]

Though the effects of chronic sickling may be numerous, we have

decided to focus on those organ systems most commonly affected

in the gravid adult with sickle cell disease

Cardiovascular

Cardiac abnormalities are almost ubiquitous in this patient

popu-lation Cardiac output is increased to compensate for the reduced

oxygen - carrying capacity of the blood caused by anemia This

increase in output occurs without an elevation in heart rate and

thus must be accomplished by increasing stroke volume

Cardiomegaly is found in 80 – 100% of adults with sickle cell

disease The right and left ventricles and left atrium are usually

enlarged and the interventricular septum is thickened, though

contractility appears to remain normal [15,16] On an ECG, 10%

of sicklers have prolongation of PR interval and 50% have some

evidence of left ventricular hypertrophy [17] Fortunately, despite

the known effects of sickle cell disease on the cardiovascular

system, it is uncommon for women with sickle cell anemia to die

of cardiac disease However, the physiologic adaptations to

chronic anemia combined with the volume changes of pregnancy

put the pregnant sickle cell patient at an increased risk of heart

failure should volume overload occur

Chapter 30

sis (12 – 17 000 cells/ µ L) usually occurs even in the absence of infection and is most likely a reaction to tissue ischemia In the presence of infection the white blood cell count can exceed 20 000 with an associated bandemia Serum lactate dehydrogenase values (LDH), especially isoenzymes 1 and 2, are elevated in sickle pain crises most likely due to marrow infarction [17] Levels of LDH rise in proportion to the severity of systemic vaso - occlusion

C - reactive protein is elevated within 1 – 2 days of onset of a crisis and the erythrocyte sedimentation rate is decreased Approximately, one - third of pain crises are associated with infection The most common infections during pregnancy are pneumonia, urinary tract infections, endomyometritis and osteomyelitis

Standard management of sickle pain crises is supportive: rest, hydration, oxygenation, and pain control The majority of patients will be dehydrated due to an inability to concentrate urine Fluid resuscitation should be initiated with normal saline Fluid therapy probably has no effect on irreversibly sickled cells but euvolemia will decrease blood viscosity and thereby decrease the predisposition to ongoing vaso - occlusion Input and output should be followed closely to limit the occurrence of pulmonary edema, though Foley catheterization should be avoided, if pos-sible, to decrease the risk of infection If infection is suspected, blood and urine cultures and a chest radiograph should be taken and broad - spectrum antibiotic coverage should be started empirically

Fetal a ssessment

During and immediately after a vaso - occlusive crisis, there is signifi cant risk for fetal distress, premature labor, and fetal loss Continuous electronic fetal monitoring should be initiated for fetuses at the age of viability, and continued until the patient is stable A non reactive fetal heart tracing is common during vaso -occlusive crises One - third of fetuses will have a biophysical profi le score of 6 or less [29] Fetal assessments typically improve

as the sickle crisis resolves The maternal condition should be stabilized and intrauterine resuscitation initiated before emergent operative delivery is considered Once the patient is well hydrated, oxygenation optimized, her vital signs stabilized, there is no evi-dence of major organ involvement or severe infection, and her pain is well controlled, continuous fetal monitoring can be replaced by intermittent fetal assessments such as daily or twice weekly non - stress testing or biophysical profi les for fetuses 26 weeks and older As with most pregnancy complications, antena-tal assessments should be individualized to the patient and her clinical situation

Chest s yndrome

Acute chest syndrome (ACS) or pulmonary crisis is a potentially fatal complication of sickle cell disease characterized by fever, pleuritic chest pain, tachypnea and pulmonary infi ltrates If a cough is present it is usually non - productive

The syndrome results from infarction of the pulmonary vas-culature or pulmonary infection or a combination of these The

inhaled nitric oxide, and L - arginine therapy [21 – 24] Though

data are limited regarding pulmonary fi brosis in pregnancy,

scat-tered case reports demonstrate that successful outcomes are

pos-sible with close follow - up [25,26]

Renal

Sickle cell anemia is also associated with alterations in renal

morphology and function Light microscopy has demonstrated

sickled blood cells in glomerular capillaries and afferent

arteri-oles The glomerulus is prone to glomerulosclerosis, which may

lead to proteinuria, nephritic syndrome, or renal failure [27] In

sickle cell disease, destruction of the vasa recta through exposure

to the hypertonic interstitium of the medulla leads to

hyposthe-nuria, the inability to maximally concentrate the urine, further

potentiating sickling and dehydration Hemorrhage from

sur-rounding medullary veins is thought to be responsible for

occa-sional self - limited bouts of hematuria which are commonly seen

in patients with sickle cell disease [28]

As pregnant patients with sickle cell disease are at an increased

risk for urinary tract infections, it is recommended that they

undergo routine urinary screening The authors use urine

dip-sticks at each visit, with serial urine cultures at least every

trimester

Sickle cell disease affects almost every organ system From

cerebrovascular accidents, Moya - Moya disease (chronic

cerebro-vascular disease characterized by severe bilateral stenosis or

occlusion of the arteries around the circle of Willis with

promi-nent collateral circulation), and sensorineural hearing loss, to

proliferative retinopathy and acute retinal artery occlusion with

resultant vision loss, the complications are many A high index

of suspicion and a low threshold for further investigation is

imperative

Sickle c risis m anagement (Figure 30.1 )

Uncomplicated a cute p ain c risis

Pain crises without major organ involvement are the most

common types of crises during pregnancy Clinical features of

acute pain crises vary with age and sex and frequently recur in a

pattern, which is stereotypical for each individual Pregnancy and

the puerperium are associated with an increased frequency of

painful episodes

Musculoskeletal pain, limited motion and swollen tender

joints with effusions may be present Dark urine is a common

complaint refl ecting excretion of urinary porphyrin

The diagnosis of pain crisis is a diagnosis of exclusion because

objective laboratory and physical fi ndings are lacking

Approximately 50% of patients with pain crises have alterations

in vital signs including mild to moderate fever (37.8 ° C or higher),

elevations of blood pressure, tachycardia and tachypnea Fever

can occur in the absence of infection due to release of endogenous

pyrogens by ischemic tissue Nonetheless, when fever is

encoun-tered, an infectious cause should be sought Moderate

leukocyto-keep arterial oxygen tension above 70 mmHg Hypoventilation due to pleuritic chest pain can worsen hypoxia Likewise, narcot-ics should be used cautiously to prevent respiratory depression Use of an incentive spirometer may minimize atelectasis and infi ltrates [31] Empiric antibiotic coverage for community acquired pneumonia should be started In a multicenter trial with

538 patients, the most frequent organisms identifi ed in sputum were Chlamydia pneumoniae , Mycoplasma pneumoniae , and

respiratory syncytial virus [30] Transfusion to increase the level

of hemoglobin A to 30 – 50% without exceeding a hematocrit of

differential diagnosis of chest syndrome includes pulmonary

embolus, fat embolus from bone marrow infarction, and

amni-otic fl uid embolus [30] The ventilation – perfusion scan may be

abnormal due to recurrent episodes of pulmonary infarction It

is important to realize that chest syndrome is often a secondary

diagnosis, developing in hospitalized sicklers or in the immediate

postoperative period

Treatment is supportive The goals of therapy are adequate

oxygenation, hydration, treatment of infection, and pain relief

An arterial blood gas should be obtained and oxygen provided to

Admit to hospital

Continuous fetal monitoring

if fetus viable

CBC with differential and platelets, reticulocyte count, LDH, type and screen, urinalysis Hgb electrophoresis Blood and sputum cultures

if indicated

Pleuritic chest pain, tachypnea, cough

Bone and joint pain, swelling, limitation of motion

Right upper quadrant pain, N/V, elevated transaminases

hepatic crisis

ABG, EKG Chest X-ray with abdominal shielding

IV hydration Pain management Radiograph of affected area Consider simple transfusion or partial exchange transfusion

IV hydration Antibiotics Pain management

12 or 24 hour urine collection for protein and creatinine clearance Serial liver function tests, uric acid, CBC with platelets Oxygen

Cautious IV hydration*

Incentive spirometer Empiric antibiotics Pain management**

Partial exchange transfusion ***

*

**

***

Avoid fluid overload and pulmonary edema Assess for respiratory depression that can worsen hypoxia

Partial exchange transfusion may be life saving in severe cases

Consider ICU admission

Figure 30.1 Proposed clinical management approach for the patient in sickle cell crisis

Chapter 30

morphine is the preferred opioid, the type of opioid used should

be based on the type and expected duration of the pain Demerol should be avoided if possible, because of the increased potential for dependency and abuse

Morphine should be given in a loading dose to provide pain relief The loading dose should be based on the patient ’ s previous use of narcotics A possible starting dose is 4 mg of morphine sulfate IV or 8 – 10 mg IM After the loading dose, subsequent doses are titrated with the goal of providing quick and sustained relief of the pain The patient should be reassessed frequently for amount of pain and sedation One - fourth of the initial loading dose should be given at each reassessment until the pain is relieved

or there is concern about sedation Once relief of pain is achieved, maintenance dosing should be started either at scheduled inter-vals or by patient - controlled pump Sickle cell patients with pain crises who are given patient - controlled analgesia use less medica-tion, develop less respiratory depression, and report better pain control than those receiving bolus injections on demand [36] The maintenance dose can be calculated as the medication required during the titration phase divided by the number of hours over which it was given

An alternative to morphine, for those patients who report morphine allergies, is butorphanol An intramuscular injection

of 2 mg of butorphanol has equivalent analgesic effect to 10 mg

of IM morphine or 80 mg of IM meperidine It is a mixed ago-nist – antagonist and can precipitate withdrawal in addicted patients In a study comparing butorphanol to morphine for the control of pain due to sickle cell crisis, no difference was found

in pain relief or level of alertness [37] Butorphanol can be given

as 2 mg IM or 1 mg IV with assessment of the patient in 30 minutes and repeated doses until pain is relieved Maintenance dosing should be the initial dose given at schedule times every

2 – 4 hours

Adjuvant analgesics are often added to improve the effect of the opioids and minimize side effects The most commonly used adjuvants are antihistamines [12] They counteract the opioid induced release of histamines that cause pruritus, reduce nausea, and have a mild sedative effect In the event that sedatives and anxiolytics are needed, they should always be used in combina-tion with analgesics and not alone in the management of pain, as they may mask the behavioral response to pain without providing analgesia [35]

Once consistent pain control has been achieved, the parenteral opioids should be tapered over several days while maintaining pain control with oral opioids Once pain control is achieved, the patient may be followed in the outpatient setting, with oral anal-gesia for home use Of note, long - term opioid use produces opioid tolerance and physical dependence This should be expected to develop over time, and should not be confused with psychologic dependence [35] The authors have also experienced great success in the outpatient population with fentanyl patches, which provide a more steady level of analgesia over time, and may also be utilized in patients who suffer from chronic pain as a result of their disease process

30% has been shown to reverse acute respiratory distress during

pulmonary crisis [30,32]

Davies [33] recommended exchange transfusion for worsening

hypoxia, continuing fever and tachycardia, or worsening chest

radiograph Atz [34] reported the successful use of inhaled nitric

oxide in two patients with chest syndrome Inhaled nitric oxide

selectively dilates the pulmonary vasculature, increases

oxygen-ation, and potentially alleviates the vaso - occlusive process

Hepatic c risis

Hepatic crisis due to disseminated vaso - occlusion of the hepatic

microvasculature with sickled red cells simulates acute

cholecys-titis with fever, right upper quadrant pain, leukocytosis, and

elevations in transaminases and bilirubin Differentiating this

syndrome from cholecystitis or the syndrome of hemolysis,

ele-vated liver enzymes and low platelets (HELLP) can be a

diagnos-tic challenge It is reasonable to manage such patients with

parenteral hydration, broad - spectrum antibiotics, pain control,

and serial laboratory assessments of liver function, uric acid, and

complete blood count with platelets

Pain m anagement

The management of pain (Figure 30.2 ) in the sickle cell

popula-tion presents diffi culties to the clinician for multiple reasons

Sickle cell patients are often economically disadvantaged and

sometimes non - compliant There are no objective criteria for

identifying a pain crisis or for quantifying the pain The patient ’ s

self - report of her level of pain is the only assessment tool

avail-able Factitious disorder and Munchausen ’ s syndrome are well

documented among sickle patients On the other hand, patients

who require large doses of narcotics to control their pain may be

incorrectly labeled as drug seeking In an effort to optimize the

management of pain associated with sickle cell, the American

Pain Society released the fi rst evidence - based guideline for acute

and chronic pain management in sickle cell disease This

guide-line includes a comprehensive initial pain assessment which

includes the patient ’ s treatment history, physical factors,

demo-graphic and psychosocial factors, dimensions of pain, and the

impact of pain on functioning [35]

The initial dose of pain medicine should be individualized

based on the patient ’ s prior use of analgesia, including the type,

route and frequency of dosage Traditional therapy includes non

opioid and opioid analgesics with analgesic adjuvants

For mild pain, peripherally acting oral analgesia, such as

acet-aminophen, may be suffi cient, combined with aggressive oral

hydration Acetaminophen provides analgesia and antipyresis

The recommended adult dosage should not exceed 6 g in a 24

hour period Mild to moderate pain can be managed by the

addition of codeine

Hospitalization is recommended for greater than mild to

mod-erate pain, as severe pain should be considered a medical

emer-gency, with timely and aggressive management provided until the

pain becomes tolerable [35] Opioids combined with non - opioids

and adjuvant analgesics are the mainstay of treatment Though

been shown to improve both maternal and fetal outcomes in one study [39] In contrast, no improvement in pregnancy outcome was found in a retrospective review of matched patients who received prophylactic exchange during pregnancy compared to those who did not [40] The major disadvantage is the potential for isosensitization Patients can become so severely sensitized that cross - matching becomes nearly impossible During an emer-gency requiring transfusion, inability to fi nd compatible blood can be fatal During pain crises, exchange transfusion has been shown to provide symptomatic relief within 1 hour of initiation

of the procedure [41] This procedure rapidly decreases the amount of hemoglobin S and increases hemoglobin A, thereby improving oxygenation and decreasing the risk of sickling and associated complications The goal is to achieve a hemoglobin A concentration of at least 60 – 70% with a hematocrit of 30 – 35% Tables are available to calculate the required volume of trans-fusion given a target percentage of hemoglobin A, the hematocrit

of the transfused blood, and the patient ’ s weight in kilograms

Therapeutic o ptions

Oxygen t herapy

The benefi t of oxygen therapy in non - hypoxic patients is

uncer-tain Although oxygen has been shown to reduce the number of

reversibly sickled cells in vitro , clinical trials of such therapy have

not produced a reduction in the duration of pain, analgesic

administration, or length of hospitalization [38] The therapeutic

goal is to maintain a normal P a O 2

If oxygen therapy is needed, 3 L supplied by nasal cannula is

usually suffi cient In severe oxygenation failure refractory to

supplemental oxygen, continuous positive airway pressure or

positive end - expiratory pressure may be necessary

Exchange t ransfusion

Prophylactic partial exchange transfusion during pregnancy,

before the onset of a vaso - occlusive crisis, is controversial It has

Admit to hospital

Loading dose of morphine

plus antihistamine

Assess patient for pain and level of sedation, every

30 min

Pain not

IM

Scheduled doses of morphine or PCA **

Taper parenteral drugs over 3–5 days; add oral opioids

* Butorphanol may also

be used (see text) Maintenance dose is medication required to control pain divided by the time over which it was given

**

Acetaminophen

Figure 30.2 Pain management approach for patients with sickle cell crisis

Chapter 30

and the United States [50] have reported on a total of 116 patients with sickle cell disease Though cure rates are reported at 80 – 85%

in both studies, the mortality ranges from 5 to 10% Complications are high, with 25% neurologic morbidity (including intracranial hemorrhage) and 10% incidence of graft - versus - host disease The transplants have been predominantly performed in children and young adults [49,50] There are no reports of bone marrow transplantation during pregnancy, and the procedure remains unproven in adults Due to concerns over safety, bone marrow transplantation has been reserved for only the most severe cases

of sickle cell disease It is hoped that further advances may someday make bone marrow transplantation a more plausible treatment option for a greater majority of patients

References

1 Seoud MAF , Cantwell C , Nobles G , Lerry DL Outcome of pregnan-cies complicated by sickle cell and sickle - C hemoglobinopathies

Am J Perinatol 1994 ; 11 : 187

2 Sun PM , Wilburn W , Raynor BD , Jamieson D Sickle cell disease

in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia Am J Obstet Gynecol 2001 ; 184 ( 6 ):

1127 – 1130

3 Mehta SR , Afenyi - Annan A , Byrns P , Lottenberg R Opportunities to

improve outcomes in sickle cell disease J Am Fam Pract 2006 ; 74 ( 2 ):

303 – 310

4 Bain BJ Haemoglobinopathy Diagnosis London : Blackwell Science ,

2001 : 113 – 117

5 Whitten CF , Whitten - Shurney W Sickle cell Clin Perinatol 2001 ;

28 ( 2 ): 435 – 448

6 Sergeant GR , Sergeant BE Sickle Cell Disease , 3rd edn Oxford :

Oxford University Press , 2001

7 Pauling L , Itano HA , Singer SJ , Wells IC Sickle cell anemia: a

molecu-lar disease Science 1949 ; 110 : 543 – 549

8 Herrick JB Peculiar elongated and sickle - shaped red blood corpuscles

in a case of severe anemia Arch Intern Med 1910 ; 6 : 517 – 521

9 Dauphin - McKenzie N , Gilles JM , Jacques E , Harrington T Sickle cell anemia and the female patient Obstet Gynecol Surv 2006 ; 61 ( 5 ):

343 – 352

10 Bunn HF Pathogenesis and treatment of sickle cell disease N Engl J Med 1997 ; 337 ( 11 ): 762 – 769

11 Rust OA , Perry KG Jr Pregnancy complicated by sickle

hemoglobin-opathy Clin Obstet Gynecol 1995 ; 38 ( 3 ): 472 – 484

12 Steinberg MH , Rodgers GP Pathophysiology of sickle cell disease:

role of cellular and genetic modifi ers Semin Hematol 2001 ; 38 ( 4 ):

299 – 306

13 Lonergan GJ , Cline DB , Abbondanzo SL Sickle cell anemia

Radiographics 2001 ; 21 ( 4 ): 971 – 994

14 Howard RJ , Tuck SM Sickle cell disease and pregnancy Curr Obstet Gynaecol 1995 ; 5 ( 1 ): 36 – 40

15 Covitz W , Espeland M , Gallagher D , Hellenbrand W , Leff S , Talner

N The heart in sickle cell anemia: the Cooperative Study of Sickle

Cell Disease (CSSCD) Chest 1995 ; 108 : 1214 – 1219

16 James TN , Riddick L , Massing GK Sickle cells and sudden death:

morphologic abnormalities of the cardiac conduction system J Lab Clin Med 1994 ; 124 : 507 – 520

Patients usually require placement of a double - lumen central

catheter before the procedure and should be premedicated as for

any blood transfusion We have found that a standard exchange

of 6 units of washed packed red blood cells results in

approxi-mately 70% of hemoglobin A

Simple t ransfusion

Simple transfusion of packed red cells is indicated for hematocrit

less than 15% or hemoglobin less than 6 g/dL A hematocrit of

30 – 35% is considered optimal This should not be exceeded due

to the increased viscosity of sickled cells which can precipitate a

crisis when the hematocrit is elevated

Hydroxyurea

Hydroxyurea is an antineoplastic agent that has been shown to

induce production of hemoglobin F It is commonly used in non

pregnant sicklers and has been shown to decrease the frequency

of pain crises, acute chest syndrome, and the necessity of

transfu-sions [42 – 44] Hydroxyurea works by selectively killing cells in

the bone marrow thus increasing the number of erythroblasts

producing hemoglobin F [43,44] Because it is cytotoxic, the risk

of teratogenesis when used during the fi rst trimester, its long

term effect, and the risk of carcinogenesis are a concern No

randomized studies exist on its use in pregnancy There are case

reports reporting favorable outcomes even in the fi rst trimester

of pregnancy Diav - Citrin [45] reported a case of hydroxyurea

use during the fi rst 9 weeks of pregnancy and additionally

reviewed case reports of 15 other exposures to the drug during

pregnancy Nine cases had fi rst - trimester exposure All of those

pregnancies had phenotypically normal children However, there

is no long - term follow - up on those children Though the

avail-able data suggest that use of hydroxyurea during pregnancy is not

commonly associated with adverse short - term outcomes, at this

time, use of hydroxyurea in pregnancy cannot be advocated [46]

However, for patients with unplanned exposure to the drug

during pregnancy, the prognosis may not be as grim as expected

There are no human data available regarding reproductive

toxic-ity of hydroxyurea in the female patient

Erythropoietin

Erythropoietin is a hormone that stimulates red blood cell

pro-duction It has been shown to increase the number of

reticulo-cytes containing fetal hemoglobin in humans [47] It has been

used alone and in alternating doses with hydroxyurea to increase

the amount of hemoglobin F [43,47] Studies have produced

confl icting results about its effi cacy in either augmenting the

effect of hydroxyurea or of enhancing production of fetal

hemo-globin [47,48] Erythropoietin is currently not used for induction

of fetal hemoglobin in sickle cell patients, but may be useful in

sickle patients with renal insuffi ciency

Bone m arrow t ransplant

Bone marrow transplantation has emerged as the only cure for

the patient with sickle cell disease Two large trials in Europe [49]