Physiologic Changes and Laboratory Values
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Physiologic Changes and Laboratory Values
Copyright © 2013 Wild Iris Medical Education, Inc. All Rights Reserved.
COURSE OBJECTIVE: The purpose of this course is to review normal and abnormal physiologic changes that may occur during pregnancy and the laboratory values that indicate these changes.
Upon completion of this course, you will be able to:
- Describe normal and abnormal physiologic changes of pregnancy.
- Identify laboratory results for normal and abnormal physiologic changes during pregnancy.
TABLE OF CONTENTS
During pregnancy, the body undergoes normal physiologic changes in the cardiovascular, hematologic, renal, and gastrointestinal systems. These changes affect patient laboratory results. In the absence of illness, the body can generally compensate for these changes. However, in the presence of conditions such as anemia, clotting disorders, increased bleeding, preeclampsia, and trauma caused by motor vehicle accidents or intimate partner violence (IPV), the body may not be able to compensate for the changes. At this point, laboratory values can become significantly skewed from the values normally noted during pregnancy. Healthcare providers should be aware of both the normal and abnormal physiologic changes that occur during pregnancy and the resulting laboratory values.
CARDIOVASCULAR AND HEMATOLOGIC CHANGES
Normal and Expected Changes
Maternal circulation changes during pregnancy to accommodate an increase in blood volume of up to 50%. Due to the increase in workload, a split first sound, a systolic murmur, or even a third heart sound may be heard upon auscultation. The increased blood volume peaks in the third trimester and returns to pre-pregnant state somewhere around 6–12 weeks postpartum (Blackburn, 2013).
The increased blood supply includes a 45% to 50% increase in plasma volume and 20% to 30% increase in red blood cells. Since these percentages are not equal, the subsequent hemoglobin (HGB)/hematocrit (HCT) will reflect a normal physiologic anemia of pregnancy. The HCT will appear to 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, which relax smooth muscle, producing vasodilatation.
As a result of the increased volume and decreased resistance, cardiac output rises. Therefore, there is a normal lowering of the blood pressure, especially in the second trimester. This sometimes causes dizziness or feeling faint in women as they rise to standing during the second trimester. Their pressure should stabilize and approach pre-pregnancy numbers by the third trimester. An abnormal rise in blood pressure could be an indication of preeclampsia, which involves multiple systems of the patient. (Keep this expected decrease in SVR in mind when you read the preeclampsia section later in this course.)
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 (5,000–10,000 cells/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 clinical indicators—such as increased temperature, bacteriuria, WBC in urine, uterine tenderness, and fetal tachycardia—and document them.
|Hemoglobin (HGB)||12–16 gm/dl||11.5–15 gm/dl|
|Red blood cells (RBC)||4–5.3||no change|
|White blood cells (WBC)||4–10.6||6–20|
Pregnancy is typically considered a hypercoagulable state—meaning that most pregnant women clot more readily than normal and are predisposed to deep-vein thrombosis or other clot-related conditions. During pregnancy there is an increase in certain factors in the clotting cascade due to normal adaptation (see table). Platelets are usually unchanged in pregnancy, and increased levels of platelets are rare. Normal levels should be 140,000 to 300,000 per mm3.
|Antithrombin||80%–130%||Should remain stable (a decrease indicates increased thrombosis risk)|
The following changes represent abnormal findings:
- Diastolic murmur or very loud systolic murmur
- Rising blood pressure before the 20th week (see “Preeclampsia” below)
- WBC levels above 20–30,000 cells/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 anemia, the following laboratory values are taken into consideration:
If anemia is from low iron, you will see the following results:
- Microcytic/hypochromic red blood cells (smaller/paler than normal)
- 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); this is directly opposite of iron-deficiency anemia
Although all pregnant women experience some expected changes in clotting, there are defective clotting conditions that greatly affect the outcomes of some pregnancies.
Patients with histories of multiple, unexplained miscarriages or a history of deep-vein thrombosis are often worked up for clotting conditions, which include:
- Antiphospholipid antibodies
- Antithrombin deficiencies
- Factor V Leiden mutations
- Protein C and S deficiencies
Abnormal increased clotting arises either from abnormal functioning of factors that assist in clotting or abnormal functioning of factors that control or slow clotting.
Abnormal Clotting Conditions
Antiphospholipid syndrome (APS). According to Murray & McKinney (2010), “APS is an autoimmune condition characterized by the production of antiphospholipid antibodies.” Patients may experience thrombosis, fetal loss, preeclampsia, placental insufficiency and preterm labor. According to Witcher & Hamner (2013), antiphospholipid antibody syndrome (APS) “is characterized by the presence of antiphospholipid antibodies, lupus anticoagulant (LAC), and anticardiolipin antibody (ACLA) with arterial and/or venous thrombosis.”
Antithrombins (AT) are important regulators of the coagulation cascade because they inhibit thrombin (clot) formation. Antithrombin 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. Of note: 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.
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 for a clot that travels through the bloodstream and lodges in the lungs (pulmonary embolism). In a woman where this mutation is present, clots may form within the placenta, cutting off nutrition and oxygen to the developing fetus.
Protein S and protein C are important inhibitors of the coagulation cascade, and a deficiency increases the risk of clots. These 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.
A physician may order the following diagnostic and assessment laboratory tests in evaluating a patient with frequent miscarriages or history of clotting:
- Antiphospholipid syndrome. Medium-to-high positive IgG or IgM anticardiolipin antibodies or detection of lupus anticoagulant; APTT (activated partial thromboplastin time), KCT (Kaolin clotting time), dRVVT (dilute Russell’s viper venom time), and ELISAs (enzyme linked immunosorbent assay) for detection of cardiolipin antibodies.
- Thrombosis. Laboratories and panels checking for mutations and various clotting factors such as ANT (antithrombin), protein C, protein S, dRVVT, LAPTT (LA sensitive PTT), CLABORATORY (cardiolipin AB panel), HOMO (homocysteine), F5LDNA (factor 5 Leiden PCR), F2MUT (factor II mutation), HINTRP (thrombosis panel intrp), and LINTRP (LLI intrp).
Before starting therapy for clots or deep-vein thrombosis, several panels may be drawn at the same time to assess the patient’s status or to support a diagnosis of thrombosis. Ongoing laboratory tests will monitor for therapeutic goals. Therapy-monitoring laboratory tests include:
- PTT (partial thromboplastin time; looks at the intrinsic or contact activation pathway) and PT / INR (prothrombin time/international normalized ratio; the extrinsic or tissue factor pathway). Both monitor the effects of anti-coagulation therapy.
- Normal PTT is 23–37 seconds. 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.
- Normal PT is 11–13 seconds, and normal INR is 0.8–1.2 IU (international units). The goal is to increase INR to 2–3.5 IU. Warfarin (Coumadin) is used on the extrinsic pathway. (Note: Those using warfarin should avoid foods with vitamin K due to their effect on the extrinsic pathway. Pregnant women are not given warfarin until after delivery, due to its affects on fetal development and clotting.)
- Anti-Xa activity level is used for monitoring unfractionated heparin therapy and low-molecular-weight heparin (Lovenox).
|Note: All values are given in anti-Xa units/mL plasma.|
Patients at increased risk for bleeding are those lacking clotting factors or platelets, or whose clotting factors do not function properly.
Low platelets may result from:
- HELLP (hemolysis, elevated liver enzymes, and low platelets)
- ITP (idiopathic thrombocytopenia purpura)
- TTP (thrombotic thrombocytopenia)
- HUS (hemolytic uremic syndrome)
Platelets may also be lowered due to multiple microclots or for unknown reasons.
Platelet levels <100,000 per 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.
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 signs that the process has gotten out of hand, such as bleeding from intravenous (IV) or injection sites, hemorrhage, and cardiovascular collapse.
|Fibrinogen (factor I)||170–470 mg/dl||↓|
|Platelets||150,000–400,000 per mm3||↓|
|Fibrin split products*||<10 mcg/ml||↑|
|* Also called fibrin degradation products (FSP or FDP) when clots are broken down.
** D-dimer is made when clots are broken down.
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 the renal markers blood-urea-nitrogen (BUN) and creatinine. Increased filtration does not mean enhanced reabsorption, however. The increase in glucose load during pregnancy is often spilled into the urine and not reabsorbed. Therefore, spillage of some glucose in pregnancy is not always indicative of pathology.
The anatomy of the pregnant uterus causes changes in 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.
|Serum creatinine||0.6–1.4 mg/dl||0.53–0.9 mg/dl decrease|
|Serum BUN||7–31 mg/dl||8–10 mg/dl decrease|
|Serum uric acid||2.4–8.2 mg/dl||2–5.8 mg/dl|
|Urine Cr clearance||90–130 mL/min||150–200 mL/min|
|Urine uric acid||150–990 mg/24 hrs||Increases|
|Urine glucose||60–115 mg/dl||Increases|
Abnormal values include:
- 24-hour urinary protein >300 mg
- Serum creatinine rising (indicates renal damage, possibly from preeclampsia)
- WBC >5 from urine sample (high-powered microscopic field)
- Bacteria >20 in urine sample (centrifuged urinalysis) (indicates UTI)
Normal and Expected Changes
Increased progesterone levels also affect the gastrointestinal (GI) system of the pregnant woman. General tone, lower esophageal sphincter 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, this incidence increases.
The liver increases its production of lipids and cholesterol. This change, combined with delayed gallbladder contraction (due to progesterone-influenced relaxation), may lead to increased gallstone formation (expected) or inflammation of the gallbladder (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 capsular edema are danger signs, and if clotting factors become affected, the patient is at a high risk for disseminated intravascular coagulation (DIC). Diagnoses are not based upon a single abnormal value.
|Alanine transaminase (ALT)||14–67 U/L||Unchanged|
|Aspartate aminotransferase (AST)||6–58 U/L||Unchanged|
|Alkaline phosphatase (ALP)||38–150 ImU/ml||> up to 2–4 times|
|Lactate dihydrogenase (LDH)||117–224 U/L||Upper end of normal to 700 U/L|
Abnormal Changes: Preeclampsia
Preeclampsia is a condition in which high blood pressure and protein in the urine develop in the late second or third trimester of pregnancy. Preeclampsia potentially affects every organ of the pregnant patient. Microclots develop within the vascular tissue, and their effects are typically seen according to which organ develops the clots.
Preeclampsia is diagnosed when there is a:
- Blood pressure of ≥140 mm Hg systolic or ≥90 mm Hg diastolic that occurs after 20 weeks of gestation in a woman with previously normal blood pressure
- Proteinuria, defined as urinary excretion of ≥0.3 g protein in a 24-hour urine specimen
Severe preeclampsia is diagnosed if one or more of the following are present:
- Blood pressure of ≥160 mm Hg systolic or ≥110 mm Hg diastolic on two occasions at least 6 hours apart while the patient is on bed rest
- Proteinuria of ≥5 g in a 24-hour urine specimen or ≥3 g on two random urine samples collected at least 4 hours apart
- Oliguria of <500 mL in 24 hours
- Cerebral or visual disturbances
- Pulmonary edema or cyanosis
- Epigastric or right upper-quadrant pain
- Impaired liver function
- Fetal growth restriction
ASSESSING FOR COMPLICATIONS AND TREATMENTS
The following tests, signs, and symptoms are used to assess for complications or treatments of preeclampsia:
- DIC panel. A patient in severe preeclampsia may develop HELLP and/or DIC. (See DIC in the “Increased Bleeding” section above and HELLP in the “Pregnancy-Specific Diagnoses” section below.)
- 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 liver organ damage and/or HELLP syndrome. Assessment of the patient will reveal abdominal pain and tenderness in the upper-right quadrant, which may be caused by microclots and lead to liver capsular edema.
- 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. A patient with falling urinary output is especially at risk for magnesium overdose if clots from preeclamptic processes are affecting the renal blood flow.
- Neurological signs. Edema from leaking vascular tissue puts pressure on the optic nerve, and patients may report a distortion in their vision. Edema in the brain can cause severe headache and potentially life-threatening seizures.
Emergency medical personnel are called to the home of a patient at 35-weeks’ gestation whose husband reports that the patient is having severe headaches, blurred vision, and her face “seems to twitch.” Upon EMS’s arrival to the home, the patient states that “every once in a while I get this really bad pain right here” and points to the right, upper quadrant of her abdomen. Suddenly, the patient has a seizure. Emergency personnel note tonic-clonic seizures lasting 60 seconds. Evidence of the rupture of the amniotic membranes is not present. Vital signs are temperature 98.8 °F, heart rate 104 bpm, RR 24, blood pressure 174/114, pulse ox levels are 90% on 10 L/min of oxygen via face mask. Generalized edema and 3+ pedal edema are noted. Fetal heart tones are 110–120 beats per minute.
In the presence of severe headache, blurred vision, elevated blood pressure, and seizure activity, the patient is most likely experiencing eclampsia. Eclampsia may develop in the presence of preeclampsia. Eclampsia is characterized by elevated blood pressure in the presence of seizure activity. Initially, patients will present with seizure activity such as facial twitches. Later, the patient may experience tonic-clonic activity. In addition to eclampsia, the patient may be experiencing HELLP syndrome (hemolysis, elevated liver enzymes and low platelets), which often presents with right upper quadrant abdominal or epigastric pain and/or severe edema.
As a result of uterine irritability, the patient’s amniotic membranes may rupture and delivery may be imminent following seizure activity. Therefore, emergency personnel must be prepared for possible delivery. They should also follow local protocols to ensure the patient’s safety during and following seizure activity. Once at the hospital, orders will be given for a DIC panel, liver function panel, and 24-hour urine. Orders can also be anticipated for chest radiography and arterial blood gas to identify aspiration following seizure activity (Murray & McKinney, 2010).
TRAUMA IN PREGNANCY
A pregnant woman being evaluated after a trauma-related event (e.g., car wreck, fall, domestic violence) requires immediate, simultaneous assessment of both maternal and fetal well-being. The woman should undergo the standard post-trauma focused history and physical exam to determine whether she has sustained any injuries.
To assess the fetus’s heath, the pregnant woman should be asked immediately about:
- Leakage of blood and/or fluid from her vagina
- Any traumatic force directed at her abdomen
- New-onset abdominal pain
- Changes in or absence of previous fetal movements (if indicated by gestational age)
Further assessment of fetal well-being can be done by fetal monitoring, ultrasound evaluation, and maternal blood work.
After establishing immediate safety, continued assessment is aimed at evaluating safety and observing for placental abruption, which is a risk after traumatic abdominal events.
INTIMATE PARTNER VIOLENCE (IPV)
Pregnancy is a time of increased intimate partner violence. Signs may include bruises and injuries inconsistent with their explanation, blows or “falls” visible on the abdomen, poor weight gain, and frequently missed prenatal appointments. 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.
Maternal bleeding may be indicated by falling hemoglobin and hematocrit or abnormal CBC (complete blood count); signs and symptoms of placental abruption (apparent or concealed vaginal bleeding, uterine tenderness, uterine irritability, abdominal pain, and/or pain in the lower back), which can be partial and/or hidden; and signs and symptoms of DIC from abruption or alterations in the normal clotting cascade.
Fetal bleeding may be indicated by 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.
The nurse is caring for a patient at 32-weeks gestation admitted for abdominal trauma. Upon assessment, the nurse notes a fetal baseline of 165 bpm without accelerations or decelerations. Uterine irritability is present. The nurse notes a small amount of dark red vaginal bleeding and a “board-like” abdomen. Amniotic membranes are intact. Bruises at various stages of healing are also noted on the wrists and ankles. The patient states, “I’m so clumsy. I bumped into the doorknob.” Vital signs are temperature 98.9 °F, heart rate 104 bpm, RR 22, and blood pressure 102/66.
In the presence of dark red vaginal bleeding, a board-like abdomen, and uterine irritability, the patient is most likely experiencing abruptio placentae as a result of abdominal trauma. Bruising at multiple stages of healing and an explanation that is inconsistent with the level of injury (e.g., walking into a doorknob) are strong indicators of IPV. Hemoglobin lab testing should be conducted to determine blood oxygenation levels. A KB screen should also be ordered to assess for the presence of fetal blood cells in the maternal circulation. After the patient is stabilized, an IPV screen can be completed in the absence of the patient’s family or friends. A social services consult should be obtained if suspected or confirmed IPV is noted.
Other common tests for the obstetric population include the following:
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 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) (Van Leeuwen et al., 2013). A fetal lung maturity test should be performed before 38 weeks of gestation, or if gestational age is unknown, to determine the fetus’s ability to breathe outside the womb (Murray & McKinney, 2010).
Fetal Anomalies or Fetal Compromise
A patient who has a suspicious fetal heart rate (FHR) tracing on early monitoring (e.g., 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), measures the immune system status of the mother’s exposure to pathogens known to cause fetal anomalies or compromise.
|Toxoplasmosis||Toxoplasmosis can cause eye deformity, eye infections, and mental retardation by invading brain tissue. Obtained from raw meat, cat feces and soil.|
|Other||This includes any additional physician-ordered tests to screen for other infectious diseases, such as group B-strep (GBS), HIV, Varicella virus (Chickenpox), Parvovirus B19 (Fifth disease).|
|Rubella||Infants born with rubella may show signs of heart defects, 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. Postpartum mothers may be immunized if their prenatal results were rubella non-immune or equivocal in order to protect future pregnancies. Live virus vaccines, such as the rubella vaccine, should not be given to pregnant women.|
|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%. Mothers with active lesions are delivered via cesarean section to avoid neonatal exposure to lesions.|
In caring for pregnant women and their unborn infants, it is important for the healthcare provider to understand the normal physiologic changes that occur during pregnancy. The provider can utilize various laboratory tests and diagnostic tools to assess the magnitude of these changes and to identify abnormal changes.
NOTE: Complete URLs for references retrieved from online sources are provided in the PDF of this course (view/download PDF from the menu at the top of this page).
Blackburn S. (2013). Maternal, fetal, and neonatal physiology: a clinical perspective (4th ed.). Maryland Heights, MO: Elsevier Saunders.
Murray S & McKinney E. (2010). Foundations of maternal-newborn and women’s health nursing (5th ed.). Maryland Heights, MO: Elsevier Saunders.
TriCore Reference Laboratories. (2011). Reference ranges. Retrieved from http://www.tricore.org
Van Leeuwen AM, Poelhuis-Leth DJ, & Bladh ML. (2013). Davis's Comprehensive Handbook of Laboratory and Diagnostic Tests With Nursing Implications (5th ed.). Lecithin/sphingomyelin ratio. Retrieved from http://www.unboundmedicine.com
Witcher PM & Hamner L. (2013). In N Troiano, C Harvey & B Flood-Chez (Eds.), AWHONN high-risk & critical care obstetrics (3rd ed.). New York: Lippincott.