What are some changes seen in BV/cell counts/EPO level in pregnancy?
- Blood volume increases by 40-50%
- Plasma volume increase mostly in 2nd trimester
- Red cell mass increases mostly in late 2nd & 3rd TM
- Erythropoietin increases throughout pregnancy & maxes at 150% at delivery
- Platelet count change controversial
- WBC count rises, leukocytosis during labor degree correlated with length of labor
What are some physiologic changes seen in pregnancy designed to prevent women from bleeding out at birth?
- ESR rises due to anemia and gestational age (result of increased levels of globulins, fibrinogen, so use as a marker of inflammation difficult)
- vWF, fibrinogen, factors VII, VIII, X increase
- Factors II, V, XII stable
- Factors XI, XIII decrease
- Protein C & Antithrombin stable
- Protein S total & free decrease
- Fibrinolysis impaired by PAI I and PAI II
Iron deficiency anemia in pregnancy:
- Hb levels
- Requirements in pregnancy
Iron def is the commonest cause of anemia in pregnancy worldwide
- Up to 75% African pregnant women
- Hb under 11 in 1st and 3rd TMs
- Hb under 10.5 in 2nd TM Require 1 gm of iron during pregnancy
- Exceeds normal Fe storage (300 mg)
- Fetal requirements are always met...
Risks: in first 2 TMs, iron deficiency associated with:
- 2x increased risk of preterm delivery
- 3x increased risk of low birth weight
Assess Fe storage with ferritin and transferrin saturation; Fe supplements as needed
Pica is more common in Fe def pregnant women than other Fe def populations
What is the 2nd most common nutritional deficiency in pregnant women?
Folate deficiency (first is iron)
- Rare in the US
What are folate requirements in pregnancy?
When does anemia typically occur?
What complications may be seen?
- Doubled requirements of folate in pregnancy: 400-800 ug/d
- Anemia usually occurs in 3rd TM and responds in 1-3 days
- Severe pancyotpenia and HELLP-like states have been reported
What happens to B12 levels in pregnancy?
- B12 deficiency is rare in pregnancy, because it's hard to get pregnant if B12 is deficient
- B12 levels fall during pregnancy due to shift from serum to tissue stores (should not drop below 180 pmol/L)
- MMA levels should be normal if not B12 deficient
What is a common bleeding disorder in pregnancy?
- Most often from: placental abruption, retained dead fetus, amniotic fluid embolism (AFE)
----DIC in abruption depends on degree of abruption (delivery and correction of maternal coag are key)
----DIC due to fetal death may not be detectable for 3-4 wks after fetal demise
----DIC in AFE results from procoagulant properties of vernix, fetal squamous cells in circulation followed by a fibrinolytic response
- Clinically you will see oozing at IV sites, hematuria, hemoptysis, excessive uterine bleeding...
What does AFE (amniotic fluid embolism) look like?
- Heralded by vascular collapse
- Then DIC
- AFE mortality decreased the last few decades (now 30%)
What does Von Willebrand Disease look like in pregnancy?
- Clotting factor levels/changes
- Menorrhagia and post partum hemorrhage are common manifestations
- In types I and II, factor VIIIc and vWF rise in pregnancy, especially 3rd TM (Factor concentrates often unnecessary at delivery)
- Levels fall rapidly after delivery (high risk of hemorrhage)
- Type I pts: monitor VIIIc levels late pregnancy and 1-2 wks post partum
- Bleeding risk minimal if levels > 40 u/dL
What is seen in type 2B vWD in pregnancy? Treatment?
- Platelets may fall significantly in late pregnancy
- May need platelets or plasma derived vWF containing concentrates if they bleed Use of dDAVP is controversial due to risk of placental vasoconstriction and maternal hyponatremia
What treatment for type 3 vWD in pregnancy?
- Need infusion of vWF concentrate at delivery (40-80 IU/KG)
- Then 20-40 IU/kg daily for a week, then taper over a few weeks Use of dDAVP is controversial due to risk of placental vasoconstriction and maternal hyponatremia
What are the nuances for Hemophilia carriers in pregnancy?
- Ideally carriers identified before delivery
- Baseline factor levels measured at 1st visit & 3rd TM
- Remember: FIX (9) levels do not rise in pregnancy
- At a minimum the sex of the fetus should be known before delivery
- C/S not routinely necessary
- Factor VIII or IX level of 40 IU/dl safe for vaginal delivery
To protect potentially affected fetus (50% male offspring of female carrier)
- No vacuum extraction, no forceps
- No IM injections of newborn until status known
- Testing should be done on cord blood (no blood draws)
Mother’s factor level should be followed for several days
What may cause thrombocytopenia in pregnancy?
Gestational and Immune
- Gestational: late and asymptomatic (late b/c of increased plasma volume; dilutional)
- Immunologic: early and more severe
What is the diagnosis for thrombocytopenia in pregnancy?
Same as non pregnant
- Platelet count cutoff between the two = 70,000
When to treat thrombocytopenia in pregnancy?
What is the cutoff platelet level for vaginal delivery/C-section?
- Platelets < 10K require treatment
- Platelets >30-50K without bleeding: no treatment
- Platelets 10-30K late in pregnancy or bleeding: treat
- Maternal platelet counts >50,000 safe for vaginal delivery and C/S (but may not be approved for epidural)
- IVIg & steroids are safe, but may have no effect on the fetus
- Splenectomy, if necessary, best in 2nd TM
- Less that 5% of babies born to mothers with ITP will have platelet counts less than 20K
- No clear recommendations on mode of delivery
- Newborns should be monitored for 5-7 days
What is HELLP?
Hemolysis Elevated, Liver Enzymes, Low Platelets
- Clotting a bigger issue than bleeding
- Can cause seizures in pregnant women
- Hematologic manifestations usually resolve with delivery
- Steroids do not help
- If symptoms persist beyond postpartum day 3 – consider TTP and start plasma exchange
What can acute fatty liver of pregnancy cause?
What is the risk of thromboembolic events in pregnancy?
Factors influencing it?
Where do they typically occur?
Risk of venous thromboembolism is 2-6x that of nonpregnant women
- Obstruction of venous return
- Venous atonia from hormonal change
- Changes in clotting factor levels
- Inherited predispositions (50%)
90% in the left iliofemoral system due to compression by right iliac/ovarian arteries (from big gravid uterus)
- Post partum rates are probably higher (6-12 wks)
Antiphospholipid Antibody (APLA) syndrome is implicated in what?
- 20% of women with recurrent fetal loss have APLA
How are thromboembolic events diagnosed in pregnancy? Is D-dimer msmt helpful?
- Symptoms often common to pregnancy
- Compression U/S best test
- V/Q scan can be done
- MRI or MRV if available
- D-dimer levels rise during normal pregnancy and in complications, so may not be useful
What prophylactic treatment can be done for thromboembolic events in pregnancy?
- NO warfarin due to teratogenesis
- LMW heparin anticoagulant of choice
- Postpartum anticoagulation should be continued for 6-8 weeks
What is the treatment for thromboembolic events in pregnancy?
- Full dose LMW heparin
- Ideally elective induction of labor
- Stop heparin 24 hrs before induction
- If risk is very high, give IV heparin up to 4-6 hrs pre-delivery
- No epidural!!
- Heparin and warfarin are safe postpartum even if breast feeding (organs already formed)
Describe the symptom and treatment nuances of lymphoma in pregnancy
- Outcome is not worse
- Staging can be difficult due to imaging limitations; can do CXR with shielding Chemotherapy
- Risk to fetus is greatest in 1st TM (organogenesis); can give chemo after
- No evidence that dosing should be changed
- Time treatment to prevent cytopenias at delivery XRT (Radiation)
- May be a higher risk of breast cancer after XRT to chest in pregnant or lactating women (2-6x increase)
- Vigilance for 2nd malignancies and hypothyroidism (especially important in women of childbearing years- baby will become hypothyroid)
Describe the symptom and treatment nuances of acute leukemia in pregnancy
- 1 in 75,000 pregnancies
- Cannot delay treatment to continue pregnancy
- Risk of fetal loss or maternal death around 2% each based on meta analysis
- Risk of congenital defects ~8%
- ATRA probably safe after 1st TM
- NO BREAST FEEDING!
Describe Essential Thrombocytosis in pregnancy
- Thrombotic risk increases pregnancy risk: common 1st TM fetal loss
ASA may help
Interferon indicated if:
- Platelet count > 1,000,000
- Hx of major thrombosis or bleeding
- Familial thrombophilia
- Cardivoascular risk factors Avoid hydroxyurea
Sickle syndromes in pregnancy
- Nutritional requirements
- High risks
- Need folate (1 mg/d)
- No Fe unless iron deficiency is documented (typically iron overload)
- Stop hydrea 3 months before pregnancy
Increased risk for:
- IUGR (Intrauterine Growth Retardation)
- Low birth weight
- Prematurity, preterm labor
No evidence that prophylactic transfusions improve outcome
Most experts recommend avoiding induction of labor, but epidurals are safe
B thalassemia in pregnancy
- Nutritional requirements
Pts with B thal minor typically have no problems
- Higher doses of folic acid recommended before conception and in 1st trimester (4 mg)
- Transfusion recommended to keep Hb~ 10 g/dL
- Iron chelator hiatus during pregnancy
a thalassemia in pregnancy
- What happens to the anemia
- HbH sensitivities
- Anemia often worsens during pregnancy
- Pts with HbH disease are sensitive to oxidizing compounds and medicines
What does hematopoiesis look like in the neonate?
- Begins in yolk sac (probably "seeds" the liver, but longer term SCs migrate to liver from AGM [aorto-gonad-mesonephros] region)
- Marrow hematopoiesis begins ~ 10 wks, but liver is predominant until about 6 mo
- Lymphopoiesis begins in thymus and lymph plexus at about 9 wks
When do HbF levels really drop off?
By about 6 mo after delivery
What are hemoglobin levels/allotypes in fetus/neonate?
- HbF (a2y2) is major Hb of fetal life
- At birth, HbF is about 60% of total Hb
- At 6 mo, it's under 3%
- B thalassemia and sickle cell dz (involving faulty B chains) do not manifest until about 3-6 mo old (a thalassemia is the major globin at birth; manifests early)
What is the fetal Hb at delivery? What is the sequence of events after delivery?
- Hb level at birth ~ 17 g/dL
- Hb level subject to asphyxia and time the cord is clamped
- Hb level falls for about 2 mo to a level of 11 then EPO levels increase
- This is "physiologic anemia" of the newborn
How do fetal RBCs in neonates differ from adult?
- Red cell antigens of neonates differ slightly
----Express i antigen (adults express the more complicated I antigen)
----A and B antigens are weakly expressed
- Red cell lifespan is shorter (60-80 days)
- Serum ferritin levels are high at birth, rise for a month or so and then fall to about 30 mg/dl at 1 year
- Neonatal RBCs may be more sensitive to oxidative stress
What do the WBCs in neonates look like?
- Neutrophil count rises from about 8,000/ml at birth to 12,000/ml at 24 hrs, then back to 4,000/ml at 3 days
- Neutrophils predominate in the first 4 days, then lymphocytes rise and predominate for first 4 years of life
- Newborns are particularly susceptible to bacterial infection largely due to diminished opsonization of particular organisms, especially in preemies
- Phagocytosis usually normal
- CD4/CD8 ratio higher in infants and children
- Most cellular immunity is present in newborn (Ag recognition/binding, ADCC, graft vs host reactivity), but decreased
- Fetal lymphocytes synthesize little IgG
- Neonate IgG levels similar to maternal due to transplacental passage of IgG
- Breastfeeding provides IgA, lysozyme, lactoferrin
- Newborn splenic function is limited
Characterize coagulation in the neonate?
- Platelet counts are normal at birth
- Bleeding times of neonates are generally shorter than adults or children
- One platelet antigen to be aware of is the human platelet antigen (HPA)-1a
- If the mother is (HPA)-1a negative (2% of Europeans) and father is (HPA)-1a positive, mother can develop antibodies in 1st pregnancy that destroy platelets in 2nd and subsequent pregnancies.
Neonates will be severely thrombocytopenic – neonatal alloimmune thrombocytopenia (NAIT)
- Factor VIII and vWF levels similar to adults
- Factors II, IX, X, XI, XII levels are reduced
- Factors II, VII, IX, X require vitamin K for synthesis and levels fall for first 3-4 days
- Vitamin deficiency common in the newborn due to an immature liver, low vitamin K content of breast milk, a sterile gut, and poor placental transfer of vitamin K.
- IM Vitamin K given at birth to prevent hemorrhagic disease of the newborn (HDN)
- Although not well understood – hypoxia during birth seems to lead to clotting disorders – usually prolonged PT/PTT
- Clotting disorders – arterial and venous are common and usually related to catheters
Hempohilia in the neonate
- Incidence of Hemophilia A/B?
- De novo mutations
- Hemophilia A: 1/5,000
- Hemophilia B: 1/25,000
Both A and B are X-linked
30% of mutations are de novo
- Hemophiliac babies have different manifestations than older children
- Recognized by rabbis in 2nd century when circumsizing babies
- Most bleeds in infants are iatrogenic (not in the muscles or joints)
- Factor VIII levels are within the normal adult range at birth, whereas Factor IX is low (making diagnosis a bit more difficult).
- Neonates with unexplained bleeding symptoms should be investigated for inherited hemostatic disorders.
What causes a dramatic increase in hematologic malignancies after the age of 50?
Age related effects on cellular DNA
What hematologic complications arise in the elderly population?
- Increased hematologic malignancies
- Decrease in immune function (impact on vaccines and resistance to infection)
Aging and hematopoeisis
- What happens?
- Marrow depletion
- Marrow cellularity
- Normal diploid cells reach a state of replication senescence (?telomere shortening) – may not be true in hematopoietic stem cells
- NO evidence for exhaustion of marrow stem cells with aging
- Marrow cellularity decreases with aging from (30% by age 75)
How do cell counts change with age?
- In men, Hb level falls by under 1 g/dl by age 80, may not fall in women
- Never ignore anemia in the older patient (evaluate for Iron, B12, folate and Heme malignancy)
- The leukocyte count and the proportion of neutrophils rise much less in response to bacterial infection in individuals > 70
- Platelet count does not change with age
How does immune response change with age?
Thymic atrophy occurs by middle age. T lymphocyte development disappears. Older individuals dependent on existing T lymphocyte pool to mediate T cell–dependent immune responses.
- Naive T cells numbers decrease with age and memory T cells are the predominant type
- B lymphocyte function depends on T cell accessory roles, thus the decreased ability to generate antibody responses, especially to primary antigens.