LEARNING OBJECTIVES

Upon completion of this course, you will be able to:

• Identify abnormal laboratory results for a variety of problems during pregnancy.
• Discuss differential diagnosis based on laboratory results and trends.
• Describe normal and abnormal physiologic changes of pregnancy.
• State anticipated orders for laboratory draws based upon the patient's chief complaint or status.

Before looking in depth at laboratory values and tests in pregnancy it is important to review some of the normal physiological changes that affect laboratory results. Each section of this course begins with a brief review of normal laboratory values, reviews the changes pregnancy brings, and then identifies deviations (abnormals) signifying pathologic changes. Note that reference ranges can vary from one laboratory to another, depending on how the testing is completed and reported.

Areas covered in this course include:

• Cardiovascular/hematologic: physiologic changes, hemoglobin/hematocrit, blood pressure, clotting factors, white count
• Renal: glomerular filtration and renal blood flow, bladder, fluid and electrolytes
• Gastrointestinal: hepatic function, glucose metabolism, and the gall bladder
• Trauma in pregnancy
• Ultrasound diagnostics: Doppler flow, amniotic fluid, and biophysical profile (BPP)
• Pregnancy-specific diagnoses

CARDIOVASCULAR AND HEMATOLOGIC CHANGES

Normal and Expected Changes

Maternal circulation in pregnancy must accommodate an increase in blood volume of up to 50%. To accomplish this, the heart must increase in size. Because of the increase in size and workload, upon auscultation you may hear a split first heart sound, a systolic murmur, or even a third heart sound. The increased blood volume peaks in the third trimester and returns to pre-pregnant state somewhere around 2 to 3 weeks postpartum (Luppi, 2001).

The increased blood supply is composed of an approximate 45% to 50% increase in plasma volume and 20% to 30% increase in red cells. Since these percentages are not equal, the subsequent hemoglobin (HGB) / hematocrit (HCT) will reflect a normal, physiologic anemia of pregnancy. The HCT will fall as the volume increases more than the packed cell count.

During pregnancy, the systemic vascular resistance (SVR) of the blood vessels lowers due to increased levels of hormones. This decreasing SVR is an expected result of the increasing progesterone and prostaglandin levels that relax smooth muscle and produce vasodilatation. Cardiac output rises as a result of the increased volume and decreased resistance. You will see a lowering of blood pressure, especially in the second trimester, which is sometimes the cause of dizziness or feeling faint in women as they rise to standing in this gestational period. Their pressure should stabilize and approach prepregnancy numbers by the third trimester.

White blood cell (WBC) counts, especially neutrophils, increase naturally during pregnancy. During active labor there may be another normal increase, even in the absence of infection. In nonpregnant patients a normal WBC count is somewhere between 5 and 10 (5000–10,000 mm³) but for pregnancy those normal values can be between 6 and 16 in the third trimester and may reach 20 to 30 in labor and early postpartum. When evaluating for infection, therefore, you need to look for other indicators—such as increased temperature, bacteriuria, WBC in urine, uterine tenderness, signs/symptoms, and fetal tachycardia—and assess and document them.

NORMAL HEMATOLOGIC VALUES

	Pre-pregnancy	Pregnancy
Hemoglobin (HGB)	12–16	11.5–15
Hematocrit (HCT)	36–48	32–36.5
Red blood cells (RBC)	4–5.36
White blood cells (WBC)	4–10.6	from 6 to 20 can be normal

Abnormal Changes

The following changes represent abnormal findings:

• Diastolic murmur or very loud systolic murmur
• Rising blood pressure before the 20th week
• WBC levels above 20 to 30 mm³ or shifts in the differential, especially a larger percentage of bands/stabs appearing, or a sharp increase in WBC level
• A true anemia: HGB <11.5 g/dl and HCT <30%

To evaluate the genesis of the anemia, the following laboratory values are taken into consideration:

• If anemia is from low iron, you will see the following on the smear results:
  • Microcytic/hypochromic cells
  • Serum ferritin <11 ng/ml (mg/L)
  • Transferrin saturation level <16%
  • Serum iron <30 mcg/dl
  • Mean corpuscular hemoglobin concentration (MCHC) <30 g/dl
  • Iron-binding capacity increased (>400 mcg/dl)
• If anemia is from folic acid deficiency, you will see:
  • Enlarged red blood cells—meaning the MCHC will be increased (higher), the opposite of iron anemia

The Clotting Cascade

Pregnancy is typically considered a hypercoagulable state—meaning that most pregnant women clot more readily than normal and are more disposed to deep-vein thrombosis or other clot-related conditions. However, we also encounter patients with opposite problems during their pregnancy—the tendency to bleeding or hemorrhage. First we will review the normal coagulation (clotting) cascade with expected changes during pregnancy; second, we will review the abnormals.

NORMAL AND EXPECTED CHANGES

If all clotting factors were consistently referred to in the same manner, the study of the coagulation cascade would be greatly simplified. However, every clotting factor has a number, and some have different names depending on what reference you are reading. You can quickly review them here. Note that in normal pregnancy there is an expected increase of certain clotting factors, leading to that phrase we have all heard: hypercoagulable state of pregnancy.

• Factor I*—Fibrinogen: Converts to fibrin when blood clots
• Factor II—Prothrombin: The inactive precursor of thrombin
• Factor III—Thrombokinase or thromboplastin: Converts prothrombin into thrombin
• Factor IV—Calcium ion: Calcium must be present for blood to clot
• Factor V*—Prothrombin accelerator: assists factors II and III in their change to thrombin. (This factor can have a specific defect called a Leiden mutation, making the blood more prone to clotting.)
• Factor VII*—Proconvertin or stable factor: A coagulation factor formed in the kidney under the influence of vitamin K
• Factor VIII*—Antihemophilic factor that includes the von Willebrand factor; the absence of this factor is associated with hemophilia A
• Factor IX*—Christmas factor: a clotting factor whose absence is associated with hemophilia B
• Factor X*—Prothrombinase: an enzyme that converts prothrombin to thrombin; can only work in the presence of calcium (Factor IV)
• Factor XI—Plasma thromboplastin antecedent: having a deficiency of this clotting factor results in a hemorrhagic tendency
• Factor XII—Hageman factor: having a deficiency of this results in prolongation of clotting time of venous blood
• Factor XIII*—Fibrinase: This catalyst causes fibrin to form a stable clot

*These factors all increase in normal pregnancy.

Referring to the following clotting cascade, you can see that both pathways are affected by pregnancy changes. Clotting can result from intrinsic damage (eg, high blood pressure in preeclampsia) or from extrinsic damage (eg, trauma). Remember that every factor in the cascade "activates" the next. For example, factor XI does nothing until it is activated, when it becomes XIa and, in turn, activates the next factor.

The clotting cascade. (Factors in blue are those that increase during pregnancy.)

Abnormal states include being more prone to clotting and being more prone to hemorrhage.

ABNORMAL CHANGES: INCREASED CLOTTING

Factor V Leiden mutation is the name of a specific mutation that results in thrombophilia, or an increased tendency to form abnormal blood clots in blood vessels. People who have the factor V Leiden mutation are at somewhat higher than average risk for a clot to form in veins, such as the deep veins of the legs (deep-vein thrombosis), or a clot that travels through the bloodstream and lodges in the lungs (pulmonary embolism). In a woman with multiple early miscarriages this mutation is suspected, because it will cause clots within the placenta that cut off nutrition and oxygen to the developing fetus.

Antithrombins are important regulators of the coagulation cascade because they inhibit thrombin (clot) formation. Antithrombin (AT) deficiencies can be inherited or pregnancy-induced. Antithrombins work mainly to inhibit factor Xa and factor IXa, so a deficiency means increased risk of clotting. (Heparin enhances the effect of antithrombin III—leading to more effective anti-clotting action. Since heparin enhances AT III, if this factor is not present, heparin may not be an effective anticoagulant for therapy.)

Protein S and Protein C are important inhibitors of the coagulation cascade. Protein S and/or protein C deficiencies increase the risk of clots, since the clotting cascade can continue unchecked. Think of these proteins as a checks-and-balance system (like the antithrombins). The protein deficiencies are usually genetic. Protein C helps to degrade the prothrombotic factor VIII (von Willebrand factor). Protein S is a co-factor to protein C.

Platelets are usually unchanged in pregnancy, and increased levels of platelets are rare. Normal levels should be 140,000 to 300,000 mm³.

Fibronectin is a contact-promoting protein responsible for adhesion and aggregation during primary hemostasis and released during activation of the coagulation process. Its level should stay within pre-pregnancy limits. Increased fibronectin may promote clots.

Black (2006) writes about antiphospholipid syndrome (APS):

In APS, antiphospholipid antibodies consist of lupus anticoagulant, anticardiolipin antibodies, and antibodies that recognize specific target molecules such as beta2 glycoprotein I, prothrombin, protein C, protein S, and annexin V (Leiden). The exact mechanism in which these antibodies cause or promote thrombosis is not known.

In pregnancy, some of the levels change slightly due to normal adaptation (see table).

NORMAL LEVELS FOR CLOTTING FACTORS

	Nonpregnant	Pregnant
von Willebrand factor	46–178	120–260
Factor V	50–150	Increased
Protein S	61–161	30–70
Antithrombin	80–130	Should remain stable (decrease indicates increased thrombosis risk)

Before starting therapy for clots or deep-vein thrombosis, you may be drawing several panels to assess the patients' status or to support a diagnosis of thrombosis. Ongoing laboratory tests will monitor for therapeutic goals.

Diagnostic and assessment laboratory tests:

• Antiphospholipid syndrome: history of clots and early pregnancy loss; medium-to-high positive IgG or IgM anticardiolipin antibodies or detection of lupus anticoagulant; APTT, KCT, dRVVT, and ELISAs for detection of cardiolipin antibodies.
• Thrombosis laboratories or panels: checking for mutations and various clotting factors such as ANT, Protein C, Protein S, dRVVT, LAPTT, CLABORATORY, HOMO, F5LDNA, F2MUT, HINTRP, and LINTRP.

Therapy-monitoring laboratory tests:

• PTT (partial thromboblastin time; the intrinsic pathway) and PT/INR (prothrombin time/international normalized ratio; the extrinsic pathway): both monitor the effects of anti-coagulation therapy.
  • Normal PTT is 11–15 seconds, normal PT is 11–12 seconds, and normal INR is 0.8–1.2 IU (international units). Goal is to increase INR to 2–3.5 IU. Coumadin is used on this extrinsic pathway. (This is why Coumadin teaching includes avoiding foods with vitamin K—take a closer look at the extrinsic pathway in the cascade above.) Pregnant women are not given Coumadin until after delivery!
  • Normal PTT is 23–37 sec. The PTT used to be the standard monitoring laboratory test for heparin therapy. Heparin therapy is now monitored by measuring the unfractionated heparin assay laboratory result (anti-Xa activity), not the PTT.

The anti-Xa test is the most accurate assay for monitoring unfractionated heparin therapy and is the only assay available for monitoring low-molecular-weight heparin (Lovenox):

• Therapeutic unfractionated heparin: 0.3–0.7 anti-Xa units/mL plasma
• Prophylactic unfractionated heparin: 0.1–0.4 anti-Xa units/mL plasma
• Therapeutic low-molecular-weight heparin: 0.5–1.0 anti-Xa units/mL plasma
• Prophylactic low-molecular-weight heparin: 0.2–0.4 anti-Xa units/mL plasma

ABNORMAL CHANGES: INCREASED BLEEDING

Patients at increased risk for bleeding are those lacking clotting factors or platelets, or whose clotting factors do not function properly.

Von Willebrand disease is genetically transmitted. Blood plasma or certain factor VIII preparations may be used to decrease incidence of bleeding/hemorrhage. Factor VIII is an anticoagulation factor that is bound to the von Willebrand factor and thus requires both aspects to function properly. There are three major types of von Willebrand disease:

• Type 1: A low level of the von Willebrand factor. This is the mildest and most common form of the disease.
• Type 2: Due to a defect, the von Willebrand factor does not work as it should. Type 2 is divided into 2A and 2B. Each is treated differently, so it is important to know the exact type. (If you get a patient with this disease your hematologist will be closely involved.)
• Type 3: People with this type usually have no von Willebrand factor and low levels of factor VIII. Type 3 is severe and very rare.

Low platelets may result from: HELLP (hemolysis, elevated liver enzymes, and low platelets); ITP (idiopathic thrombocytopenia purpura); TTP (thrombotic thrombocytopenia); or HUS (hemolytic uremic syndrome). Platelets may also be lowered due to multiple microclots, or for unknown reasons. Platelet levels below 100,000 mm³ need to be monitored carefully. Continued declining levels are suspicious for micro-clotting conditions and disseminated intravascular coagulation (DIC).

As clots form and break down, clotting factors and fibrinolytic factors are used up. The presence of fibrin split products and an elevated D-dimer indicate that clots are being broken down in the body. Disseminated intravascular coagulation (DIC) occurs if the process is taking place too rapidly for the body to replace the factors used. Laboratory values will show that clotting has taken place, but in DIC there are often signs that the process has gotten out of hand, such as bleeding from intravenous (IV) or injection sites, hemorrhage, and cardiovascular collapse.

VALUES FOR DISSEMINATED INTRAVASCULAR COAGULATION

	Normal	DIC
*Also called fibrin degradation products (FSP or FDP) when clots are broken down. **D-Dimer is made when clots are broken down.
Fibrinogen (Factor I)	170-470 mg/dl	Decreased or falling
Platelets	140,000–300,000 mm3	<100,000 mm3
Fibrin split products *	<10 mcg/ml	Increased
D-dimer**	0–0.5 mcg/ml	>0.5 mcg/ml

RENAL CHANGES

Normal and Expected Changes

The renal system undergoes many changes in pregnancy to accommodate increased metabolic and circulatory requirements. The system now clears the body of both maternal and fetal waste and is affected by the increased blood volume and lowered systemic vascular resistance. As previously mentioned, progesterone has a relaxing effect on vascular tissue, thus enhancing the renal blood flow and function. The increased plasma flow into the renal system causes the glomerular filtration rate (GFR) to rise dramatically.

Renal clearance of many substances is generally elevated in pregnancy, causing lower-than-usual serum levels of many renal markers, including blood-urea-nitrogen (BUN) and creatinine. Increased filtration does not mean enhanced reabsorption, however. The increase in glucose load in pregnancy is often spilled into the urine and not reabsorbed, predisposing the pregnant woman to urinary tract infections (UTIs). Spillage of some glucose in pregnancy is not always indicative of pathology.

The anatomy of the pregnant uterus changes the location and pressure of other internal organs. The bladder becomes slightly concave and is displaced forward and upward. The uterus causes the ureters to become dilated and more tortuous, especially the right ureter. Detectable hydronephrosis or hydroureter during pregnancy is considered normal and may take 3 to 4 months post delivery to fully resolve.

NORMAL VALUES FOR RENAL FUNCTION

	Nonpregnant	Pregnant
Serum creatinine	0.6–1.2 mg/dl	0.53–0.9 mg/dl
Serum BUN	8–10.4 mg/dl	9–11 mg/dl
Serum uric acid	4.5–5.8 mg/dl	2–5.8 mg/dl
Urine Cr clearance	90–130 mL/min	150–200 mL/min
Urine uric acid	250–750 mg/24 hr	Increases
Urine glucose	60–115 mg/dl	Increases

Abnormal values include:

• 24-hr urinary protein >300 mg
• Serum creatinine rising; indicates renal damage, possibly from preeclampsia
• WBC >5 (high-powered microscopic field)
• Bacteria >20 (centrifuged urinalysis); indicates UTI

GASTROINTESTINAL CHANGES

Normal and Expected Changes

Increased progesterone levels also affect the gastrointestinal (GI) system of the pregnant woman. General tone, lower esophageal spincter tone, and motility are decreased. This predisposes the woman to increased incidence of reflux (heartburn) and constipation. As the gravid uterus displaces the internal organs, incidence increases.

The liver increases its production of lipids and cholesterol. This, combined with delayed gallbladder contraction (due to progesterone-influenced relaxation), may lead to increased gallstone formation or gallbladder disease (abnormal). The liver also plays a role in the production of the clotting factors previously discussed.

In addition to increased production of lipids and certain clotting factors, some enzymes found within the liver are also increased without indicating pathology. It is important to distinguish a normal rise in these levels from a pathologic change caused by organ damage or destruction arising, for example, from preeclampsia or hepatitis. In preeclampsia, microclots in the liver and capsule edema are danger signs and, if clotting factors become affected, the patient is at a high risk for DIC. Diagnoses are not based upon a single abnormal value.

NORMAL HEPATIC VALUES

Liver Enzymes	Nonpregnant	Pregnant
Alanine transaminase (ALT)	3–78 U/L	Unchanged
Aspartate aminotransferase (AST)	3–70 U/L	Unchanged
Alkaline phosphatase (ALP) prepregnant level	20–145 ImU/ml	> up to 2–4 times
Lactate dihydrogenase (LDH) 300–650 U/L	300–650 U/L	Upper end of normal

TRAUMA IN PREGNANCY

Trauma in pregnancy may result from a loss of balance related to a changing center of gravity. Pregnancy is also is a time of increased domestic violence. Depending on gestational age, a woman admitted after a trauma-related event (eg, car wreck, fall) generally requires fetal monitoring, possible ultrasound evaluation, and blood work. The priority of assessment is maternal and fetal well-being. Blood work will assess for maternal or fetal bleeding.

After establishing immediate safety, continued assessment is aimed at evaluating safety and observing for placental abruption, which is a risk after traumatic abdominal events.

Every woman should be screened prenatally for risk of domestic violence and counseled on safety issues. Names and numbers of local agencies should be made available to the woman should she need help escaping from violence. Screening should be done in private, if at all possible, as the woman may not feel free to admit to danger in front of her family or the abuser. To establish privacy, it is sometimes possible to resort to bathroom facilities.

Abnormal signs upon assessment include:

• Maternal bleeding: Falling hemoglobin and hematocrit or abnormal CBC (complete blood count); signs and symptoms of placental abruption, which can be partial and/or hidden; signs and symptoms of DIC from abruption or alterations in the normal clotting cascade
• Domestic violence: Bruises and injuries inconsistent with their explanation; blows or "falls" visible on the abdomen; poor weight gain; frequently missed prenatal appointments; among others
• Fetal bleeding: Signs include electronic fetal monitoring changes such as tachycardia followed by bradycardia, absent variability, decelerations and/or sinusoidal tracing. A Kleihauer-Betke (KB) screen may be ordered to look for fetal blood cells that have entered maternal circulation; normally there are none.

Keep in mind that an establishing pattern of fetal movement is indicative of fetal well-being.

ULTRASOUND DIAGNOSTICS

Ultrasound has become ubiquitous as a diagnostic tool during pregnancy. The provider uses a bedside scan or orders more detailed exams by an expert ultrasound technician. Ultrasound is commonly used to assess fetal growth, development, and well-being. Some of the more common tests and results include:

• BPP (biophysical profile). The BPP evaluates several parameters. The fetus is given a score of either 0 (not meeting criteria) or 2 (meeting criteria) in each area. A perfect score of 10 indicates that all criteria are met. If the fetal heart rate tracing (nonstress test, or NST) is not obtained as part of the test, then the perfect score is 8. Areas assessed are:
  • Fetal tone: assesses for one or more episodes of extension of fetal extremities with return to flexion
  • Breathing movements: one of more episodes of rhythmic fetal breathing movements of at least 30 seconds in duration
  • Amniotic fluid: largest area of fluid is greater than 2 cm without containing loops of the umbilical cord, or a calculated amniotic fluid index (AFI) between 8 and 18
  • Fetal movement: movements of the arms, legs, or body observed
  • Reactive heart rate tracing: NST that is reactive
• NST (nonstress test). The nonstress test is completed by placing the patient on an electronic fetal monitor. A reactive tracing looks for:
  • Normal heart rate baseline: depending on gestational age, somewhere between 120 and 160
  • Accelerations: increases in the fetal heart rate above the baseline. In a fetus of >32 weeks' gestation, in a 20-minute period you should see at least 2 accelarations of at least 15 beats above the baseline for at least 15 seconds each time. In a fetus of <32 weeks' gestation, the accelerations may only be 10 beats for 10 seconds
  • Variability: of the fetal heart rate between 2 and 25 beats per minute. A flat fetal heart rate baseline or one that undulates (sinusoidal tracing) are signs of potential fetal compromise
  • Decelerations: no decelerations below the fetal heart rate baseline
• Umbilical artery flow velocity. Fetal and placental blood flow is measured by Doppler ultrasound studies. Abnormal fetal circulation is shown by absent or reversed end diastolic flow velocity in the fetal umbilical artery or aorta, which suggests intrauterine fetal compromise. Absent end diastolic flow velocity is thought to result from increased downstream vascular resistance. This has been associated with an increased risk of necrotizing enterocolitis, cerebral hemorrhage, and neonatal morbidity.

PREGNANCY-SPECIFIC DIAGNOSES

Other common tests for the obstetric population include the following.

Preterm Labor/Delivery

FETAL FIBRONECTIN (fFn) TEST

Fetal fibronectin (fFn) is found in cervicovaginal fluid until about 22 weeks' gestation. It then is absent until it reappears within 2 weeks of term or preterm delivery. Serial tests done on a woman experiencing preterm contractions or labor are used as a predictor of preterm delivery. A positive fFn >50 in a singleton pregnancy is a moderate predictor that delivery will occur within 1 to 2 weeks.

FETAL LUNG MATURITY TEST

The lecithin/sphingomyelin (L/S) ratio is a test of amniotic fluid obtained through amniocentesis to determine fetal lung maturity. A ratio of 2 or greater in the presence of phosphatidyl glycerol (PG) is indicative of sufficient lung surfactant for prevention of neonatal respiratory distress syndrome (RDS). The test is often used to determine when a patient can be safely induced for labor before 39 weeks.

Preeclampsia

The following tests are used to assess for conditions associated with preeclampsia:

• DIC panel: see test results above
• Magnesium level: Preeclamptic patients on IV magnesium sulfate may have laboratory values drawn to establish therapeutic goals.
  • A normal magnesium level in an unsupplemented patient is 1.5–2.5 mg/dl (mEq/L).
  • The goal is 4–7mg/dl (mEq/L) for patients receiving IV magnesium therapy
  • Magnesium levels > 9 mg/dL (mEq/L) are potentially life threatening.
• Liver function panel: used to assess whether preeclampsia is causing organ damage and/or HELLP syndrome. See reference laboratory values above.
• 24-hour urine protein: assesses whether kidney function is being affected by vascular spasming and microclotting found with preeclampsia. A level of >300 mg is indicative of mild preeclampsia, a level of >5 gm is indicative of severe preeclampsia.

Fetal Anomalies or Fetal Compromise

A patient who has a suspicious fetal heart rate (FHR) tracing on early monitoring (eg, sinusoidal tracing, bradycardia, tachycardia), or a patient who presents with signs of a viral illness, abnormal ultrasounds, or an unexpected delivery of an infant with anomalies, may prompt the provider to order a TORCH panel. The panel, named for the mnemonic TORCH (see below), will measure the immune system status regarding exposure to the following illnesses that are know to cause fetal deformaties or compromise:

• Toxoplasmosis: can cause eye deformity, eye infections and mental retardation by invading brain tissue
• Other: physician may order other tests to screen for infectious diseases
• Rubella: Infants born with rubella may show signs of heart disease, retarded growth, ocular defects, or pneumonia at birth. They may also develop problems later in childhood, including autism, hearing loss, brain involvement, immune system disorders, or thyroid disease. (We immunize postpartum patients if their prenatal results were rubella nonimmune or equivocal to protect future pregnancies.)
• Cytomegalovirus (CMV): Mothers exposed to CMV may have infants who suffer from hearing loss (15%) or mental retardation (30%). Newborns who acquire CMV during the birth process or shortly after birth may develop pneumonia, hepatitis, or various blood disorders.
• Herpes: Disseminated herpes infections attack the liver, adrenal glands, and other body organs of the infant. Without treatment, the mortality rate is as high as 80%.

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