ACOG Preeclampsia Guidelines: Antenatal Management and Timing of Delivery

SUMMARY:

Recommendations for prenatal assessment and perinatal management, including delivery, are included in the ACOG preeclampsia and gestational hypertension guidelines.

Inpatient vs Outpatient Management

  • Ambulatory management (outpatient) appropriate for the following
    • Gestational hypertension without severe features or
    • Preeclampsia without severe features
  • Inpatient management appropriate for the following
    • Severe preeclampsia or
    • Poor adherence to monitoring recommendations

How to Measure BP

  • Recommended technique for BP monitoring
    • Appropriate cuff size: 1.5 times upper arm circumference
    • Avoid tobacco or caffeine: Use in the 30 minutes preceding the measurement may lead to temporary rise in blood pressure
    • Patient should be upright after a 10-minute rest period
    • Inpatient setting: Measurement may be taken either
      • Sitting up or
      • Left lateral recumbent with arm at the level of the heart

Fetal and Maternal Assessment (Outpatient – No Severe Features)

Fetal Assessment

  • Fetal growth assessment every 3-4 weeks
  • Amniotic fluid assessment weekly
  • Antenatal testing 1-2 times per week

Maternal Assessment

  • Labs weekly (more frequently if concern that patient status is deteriorating)
    • Serum creatinine | Liver enzymes | Platelet count
    • Gestational hypertension: Include proteinuria
    • Note: If proteinuria is present, additional proteinuria measurements are not necessary
  • Clinical evaluation: At least one visit per week in-clinic
    • Obtain BP and evaluate for severe features (see ‘Related ObG Topics’ below)
      • Combination ambulatory and in-clinic assessment
    • BP and symptom assessment are recommended “serially”, using a combination of in-clinic and ambulatory approaches, with at least one visit per week in-clinic

Note: No RCT data are available to determine optimal maternal or fetal monitoring protocols

KEY POINTS:

Delivery vs Expectant Management

  • Decision regarding management based on gestational age and results from the following evaluation
    • Maternal: CBC | Creatinine | LDH, AST, ALT | Proteinuria | Uric acid if superimposed preeclampsia suspected
    • Fetal: EFW | Amniotic fluid volume | Antenatal testing (BPP, NST)
  • Candidate for expectant management
    • Gestational hypertension or preeclampsia without severe features <37w0d
    • Reassuring antenatal testing
    • Intact membranes
    • No vaginal bleeding
    • No evidence of active preterm labor
    • Note: Delivery at 37w0d | HYPITAT trial showed no benefit to expectant management beyond 37 weeks
  • Candidate for delivery (expectant management not advised)
    • Severe range hypertension unresponsive to antihypertensive agent(s)
    • Persistent headache or persistent RUQ/epigastric pain unresponsive to treatment
    • Visual disturbance or altered sensorium or motor deficit
    • Stroke or MI
    • HELLP syndrome
    • Worsening renal function (Cr above 1.1 or double the baseline)
    • Pulmonary edema
    • Eclampsia
    • Placental abruption or bleeding in the absence of placenta previa
    • Abnormal antenatal testing
    • Fetal demise
    • Fetal lethal anomaly or extreme prematurity
    • UA Doppler REDF
    • Note: Fetal growth restriction, if other fetal assessment parameters are within normal range, is not an indication for delivery

Expectant Management for Severe Preeclampsia

  • Shared decision making: Consider risk/benefit
    • Expectant management for severe preeclampsia provides benefit to fetus/newborn but potential risk to mother
  • Risks of expectant management in the presence of severe features
    • Pulmonary edema | MI | Stroke | ARDS | Coagulopathy | Renal failure | Retinal injury
  • ≥34w0d: Delivery is recommended
    • Do not delay delivery to administer steroids in late preterm
  • <34w0d: Expectant management for women who are clinically stable 
    • Associated with higher GA (on average 1-2 weeks) at delivery | Improved neonatal outcomes
    • “Low maternal risk” in studies
    • Requires close maternal and fetal monitoring with serial laboratory testing
      • Deliver if maternal or fetal status deteriorates
    • Corticosteroid administration is recommended
      • “May not always be advisable” to delay delivery when indicated to provide full steroid course

Learn More – Primary Sources:

ACOG Practice Bulletin 222: Gestational Hypertension and Preeclampsia

Pre-eclampsia: pathophysiology and clinical implications

FIGO: A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre-eclampsia

Locate a Maternal Fetal Medicine Specialist

Maternal Fetal Medicine Specialist Locator-SMFM

ISUOG Recommendations: Fetal Ultrasound Follow-Up for Women with Established Preeclampsia

SUMMARY:

The ISUOG Clinical Standards Committee has released practice guidelines reviewing the latest evidence and provides recommendations regarding the role of ultrasound in follow-up for women diagnosed with preeclampsia.

KEY POINTS:

  • Close fetal surveillance is warranted as deteriorating fetal status may be an indication for earlier delivery
  • Sonographic follow up of PE should include
    • Fetal growth
    • Biophysical profile
    • Fetal Doppler assessments
  • Frequency and impact of sonographic follow up has yet to be determined by large-scale clinical trials

Role of B-mode Ultrasound

Ultrasound assessment should include

  • Fetal growth
    • Rule out impaired growth
  • Biophysical profile
    • BPP of >8: Normal – manifestation of fetal wellbeing
    • BPP of 6: Inconclusive – repeat test
    • BPP of ≤4: Non-reassuring – consider delivery
  • Amniotic fluid volume
    • Ensure presence of MVP >2 cm and/or AFI >5 cm
    • Evidence that MVP may result in fewer interventions (see ‘Related ObG Topics’ below)
  • Placentation
    • Thickness | Echogenicity | Uteroplacental interface
    • Severe PE may be associated with
      • Placental edema and diffuse echogenicity due to edema
      • Thick placenta and reduced vascularization
      • Cystic regions (infarctions/ hematomas)
    • Abruption (poor sensitivity with 50 to 75% missed on ultrasound
      • Hematoma (preplacental and retroperitoneal) | Subchorionic and marginal blood | Increased placental thickness and echogenicity

Role of Doppler Studies

  • 4 major Doppler exams
    • Umbilical artery (UA)
    • Fetal middle cerebral artery (MCA)
    • Fetal ductus venosus
    • Uterine arteries

Especially in the presence of maternal headache, abdominal pain, bleeding and/or reduced fetal movements consider

  • *UA
    • absent or reversed end-diastolic flow is strongly associated with poor perinatal outcomes
    • Increased resistance in the uterine arteries is not a useful indicator for timing of delivery
  • *Fetal MCA PI
    • Reduced MCA-PI <10th percentile (cephalization) may precede abnormal UA indices, and warrants close fetal surveillance
  • *Cerebroplacental ratio (CPR)
    • CPR: MCA PI / UA PI
    • CPR<10th percentile may represent hemodynamic redistribution
    • Warrants close fetal surveillance
  • Fetal ductus venosus
    • Unlike the above 3 indices (marked with *), ductus venosus is not included in ultrasound recommendation list (‘Good Practice Points’) for preeclampsia follow up
    • However, the guideline does point out that a reversed a-wave is strongly association with fetal cardiac deterioration

Note: ISUOG states that the above tests should also “be considered for women admitted for PE or with suspected PE, as well as for those with severe PE or HELLP syndrome” as a ‘Good Practice Point’.

Impact of Medications on Ultrasound Indices

  • Antihypertensives
    • Not associated with changes in maternal and fetal Doppler indices
  • Antenatal steroids
    • Associated with a transient decrease in vascular resistance in the UA and ductus venosus
  • Magnesium sulfate
    • Unclear

Learn More – Primary Sources:

ISUOG Practice Guidelines: role of ultrasound in screening for and follow up of pre-eclampsia

ISUOG Recommendations for Preeclampsia Prevention: Combined Screening and the Role of Ultrasound

SUMMARY:

The ISUOG Clinical Standards Committee, based on the latest evidence, has released practice guidelines that provide recommendations regarding the role of ultrasound in screening for and follow-up of preeclampsia. Preventative strategies (such as low-dose aspirin) for preeclampsia are effective if started in the first trimester and should begin as soon as high-risk status is identified.  

Given the superiority of combined screening, the use of Doppler cut-offs as a standalone screening modality should be avoided if combined screening is available (GRADE OF RECOMMENDATION: B)

Note: Screening refers to identification of at risk cases that may lead to prevention | Prediction refers to ability to identify at risk cases, but no evidence available regarding improved outcomes  

Combined Screening
Ultrasound Only
Multifetal Pregnancies

KEY POINTS:

Combined Screening (10-13 weeks) – Preferred where available   

  • ASPRE trial results with a 10% FPR (see ASPRE summary in ‘Related ObG Topics’ below) 
    • 100% detection rate for preeclampsia <32 weeks 
    • 75% detection rate for preeclampsia <37 weeks 
    • 43% detection rate for preeclampsia ≥37 weeks 

Combined screening approach is preferred over ultrasound alone and includes the following (see summary of ASPRE algorithm details in ‘Related ObG Topics’ below)   

  • Maternal factors 
    • History | Demographics | CVD and metabolic profile  
  • Maternal arterial BP
  • Placental growth factor (PlGF) 
  • Pulsatility index (PI) should be used to assess uterine artery resistance  
    • Transabdominal approach preferred as used for most studies   
    • Transabdominal: Use color flow mapping on a mid-sagittal view of the uterus at the level of the cervical internal os (transabdominal approach)  
    • Transvaginal: Also obtain mid-sagittal view of the uterus, with lateral movement until paracervical vascular plexus is seen and uterine artery is also at the level of the internal cervical os  
    • Identify an ascending or descending branch of the uterine arteries 
      • Narrow Doppler sampling gate (2 mm) 
      • Insonation angle <30 degrees 
      • Peak systolic velocity of a uterine artery should be greater than 60 cm/s 
      • PI measurement obtained when 3 identical waveforms are captured  
    • 95th percentile uterine artery mean PI (11-13 weeks) 
      • Transabdominal: 2.35  
      • Transvaginal 3.10 for CRL up to 65 mm 
    • Uterine artery PI may be affected by  
      • Ethnicity: African origin has higher PI 
      • Obesity: Decreasing PI with increasing BMI 
      • History of preeclampsia: Increased PI 

Note: Placental volume and vascularization indices are not recommended | Combined screening in the second trimester compares favorably to first trimester, but aspirin intervention is ineffective if initiated >20 weeks

Ultrasound Screening Only  

First Trimester Ultrasound Screening (10-13 weeks) 

  • Due to maternal effects and lesser performance, uterine artery PI is not preferred as a stand-alone test based on cut-offs, but should preferably be incorporated into a combined, multifactorial screening model (see above) 
  • Uterine artery PI >90th percentile in the first trimester detects  
    • 47.8% of women who will develop early PE (7.9% FPR) 
    • 26.4% of women who will develop any PE (6.6% FPR) 
  • PI is superior to resistance index (RI) or uterine artery notching as a preeclampsia predictive tool 
    • PI is more stable than RI, and may still be used in cases of absent or reversed diastolic values 
    • Uterine artery notching is a subjective measure with low specificity
      • Associated with 22-fold increased risk for preeclampsia and 9-fold increased risk for an SGA neonate 
      • However, may be observed in up to 50% of patients at 11-13th weeks 

Second Trimester Ultrasound Screening  

  • Uterine artery PI may be performed at time of the second trimester scan (10% FPR) 
    • 85% detection of early-onset preeclampsia  
    • 48% detection of late-onset preeclampsia  
  • 95th percentile uterine artery mean PI (23 weeks) 
    • Transabdominal: 1.44  
    • Transvaginal: 1.58  

Third Trimester Ultrasound Screening  

  • Use of PI during this period is not recommended due to insufficient outcomes data

Multifetal Pregnancies 

  • Use twin-specific reference ranges  
    • Increased placental mass and lower mean uterine artery resistance seen in multiple gestation 
    • Combined screening approach 
      • >95% detection 
      • 75% screen positive rate

Learn More – Primary Sources:

ISUOG Practice Guidelines: role of ultrasound in screening for and follow up of pre-eclampsia

Results from the SPREE Trial: How Does First Trimester Preeclampsia Screening Compare to Current Guidelines?

BACKGROUND AND PURPOSE:

  • Current NICE guidelines use maternal characteristics and medical history to identify women at high risk for preeclampsia (PE) who could benefit from aspirin
  • NICE guideline considers a pregnant woman at high risk if
    • Any one major factor
      • History of hypertensive disease in previous pregnancy
      • Chronic kidney disease
      • Autoimmune disease
      • Diabetes mellitus
      • Chronic hypertension
    • OR any two moderate factors
      • First pregnancy at age ≥ 40 years
      • Interpregnancy interval > 10 years
      • BMI at first visit ≥ 35 kg/m2
      • Family history of PE
    • Using more traditional approach of professional committees, each factor is considered separately
    • Tan et al. (Ultrasound in Obstetrics & Gynecology, 2018) compared the above NICE approach to screening PE to a method that uses Bayes’ theorem that combines maternal factors with biomarkers

METHODS:

  • Prospective multicenter cohort study
  • Screening program for pre-eclampsia (SPREE) study
  • Participants: Singleton pregnancies at 11–13 weeks’ gestation had recording of maternal characteristics and medical history and measurements of
    • Mean arterial pressure (MAP)
    • Uterine artery pulsatility index (UtA‐PI)
    • Serum placental growth factor (PlGF)
    • Serum pregnancy‐associated plasma protein‐A (PAPP‐A)
  • The performance of screening for PE by the Bayes’ theorem‐based method was compared with that of the NICE method
  • Primary outcome
    • Detection rate (DR) using NICE method vs mini‐combined test (maternal factors, MAP and PAPP‐A) in the prediction of PE at any gestational age (all‐PE) for the same screen‐positive rate determined by the NICE method
  • Secondary comparisons
    • DR of screening recommended by the NICE guidelines vs 3 Bayes’ theorem‐based methods for prediction of preterm PE (requiring delivery <37weeks)
      • Maternal factors, MAP and PAPP‐A
      • Maternal factors, MAP and PlGF
      • Maternal factors, MAP, UtA‐PI and PlGF

RESULTS:

  • 17,051 women were eligible and outcome data were obtained from 16,747
  • All-PE developed in 2.8% of the 16,747 pregnancies and preterm PE developed in 0.8%
  • NICE method for PE
    • Screen positive rate: 10.3%
    • DR for all‐PE: 30.4%
    • DR for preterm PE: 40.8%
    • There was only 23% compliance with aspirin recommendation
  • Mini-combined method for PE
    • DR of the mini‐combined test for all‐PE was 42.5%
    • Superior to that of the NICE method by 12.1% (95% CI, 7.9–16.2%)
  • Screening for preterm PE compared to NICE
    • Maternal factors, MAP and PlGF: DR was 69.0%, which was superior to NICE method by 28.2% (95% CI, 19.4–37.0%)
    • Maternal factors, MAP, UtA‐PI and PlGF: DR was 82.4%, which was to NICE method by 41.6% (95% CI, 33.2–49.9%)

CONCLUSION:

  • NICE detection rates and compliance were lower than using a Bayesian approach that incorporates serum markers
  • The authors state that a PE methodology that combines biomarkers with maternal factors is a substantial improvement over current recommendations

Learn More – Primary Sources:

Comparison of diagnostic accuracy of early screening for pre‐eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: results of SPREE

Fetal Medicine Foundation Preeclampsia Risk Calculator

Eclampsia and Role of Magnesium Sulfate

SUMMARY:  

Eclampsia is a severe, life-threatening manifestation of preeclampsia.  While long-term neurologic damage is rare, there is risk of maternal hypoxia and death. Most women will experience signs such as headaches or visual changes prior to a seizure.

Eclampsia

  • Defined as convulsions during pregnancy and/or postpartum
    • Tonic-clonic, focal, or multifocal
    • New onset
    • Unexplained by other neurologic pathology
  • Consider other underlying cerebral conditions when
    • Seizures occur 2 to 3 days postpartum
    • Patient on magnesium sulfate

Note: Not all women will demonstrate classic features of preeclampsia (hypertension, proteinuria)

Magnesium Sulfate – Seizure Prophylaxis  

  • Magnesium sulfate is the treatment of choice for seizure prophylaxis (ACOG recommended dosing) 
    • Loading dose of 4–6 g of magnesium sulfate administered per infusion pump over 20–30 minutes (i.e., slowly) followed by a maintenance dose of 1-2 g per hour as a continuous intravenous infusion  
    • Continue 24 hours postpartum
  • Recurrent seizures
    • Additional dose of 2-4 g can be infused over 5 minutes
  • Refractory seizures
    • Sodium amobarbital: 250 mg IV in 3 minutes
    • Thiopental or phenytoin: 1,250 mg IV at a rate of 50 mg/minute
    • Patient should be managed in ICU
    • Consider neuroimaging
  • IM option
    • 10 g initially as a loading dose (5 g IM in each buttock) followed by 5 g every 4 hours
    • Use if IV access limited
    • Mix with 1 mL xylocaine 2% to alleviate pain

Note: Magnesium sulfate should not be considered an antihypertensive agent

Magnesium Sulfate – When to Use

  • Severe features of preeclampsia 
    • Administer to all women 
  • No severe features of preeclampsia and systolic BP > 140 and < 160 mm Hg or diastolic BP > 90 and < 110 mm Hg 
    • There is no consensus on this matter as prophylaxis will reduce eclampsia but 1 in 100 to 129 women need to be treated and side effects (although not life threatening) will increase
    • ACOG states that the decision to use magnesium sulfate when severe features are not present should be the decision of the “physician or institution, considering patient values or preferences, and the unique risk-benefit trade-off of each strategy” 

Delivery and Postpartum 

  • Vaginal delivery
    • Continue infusion 24 hours postpartum
  • Cesarean
    • Begin infusion (if not yet running) before surgery and continue 24 hours postpartum
    • Discontinuing prior to operative vaginal birth or cesarean section to avoid uterine atony or anesthetic drug interactions is not recommended

 Prevention of Magnesium Sulfate toxicity 

  • Place Foley to monitor renal function (hourly output)  
  • Confirm normal serum creatinine  
  • Serial evaluation of patellar deep tendon reflexes 
  • Monitor respiratory rate  
  • Serum magnesium levels not routinely required
    • Monitor serum magnesium levels in setting of renal dysfunction and/or absence of patellar reflexes 
    • Maintain serum concentrations 5 to 9 mg/dL (4–7 mEq/L) range  
  • Predictive symptoms of magnesium sulfate toxicity  
    • Loss of deep tendon reflexes >9 mg/dL (greater than 7 mEq/L)  
    • Respiratory depression >12 mg/dL (greater than 10 mEq/L) 
    • Cardiac arrest >30 mg/dL (greater than 25 mEq/L) 

Pending toxicity 

  • Notify appropriate health care provider  
  • Discontinue magnesium infusion  
  • Administer supplemental oxygen  
  • Obtain a serum magnesium level  
  • Reverse magnesium 
    • 10 mL of 10% calcium gluconate IV (1 g total) and over 3 min (i.e., slowly) to avoid hypotension and/or bradycardia 
    • Calcium effect (competitively inhibits magnesium at neuromuscular junction) can wear off if magnesium level stays high 
    • Furosemide may help increase urinary excretion
  • Respiratory arrest: Intubation and assisted ventilation as indicated

Other Prophylactic Agents

  • Magnesium sulfate is superior to diazepam, phenytoin and lytic cocktail (chlorpromazine, promethazine, pethidine) in reducing significantly the risk of seizure recurrence  
    • Cochrane Review 2010: Magnesium sulfate reduced eclampsia compared to phenytoin (relative risk 0.08, 95% CI 0.01 to 0.60)   
  • Morbidity related to pneumonia, mechanical ventilation and admission to an intensive care unit are significantly reduced with the use of magnesium sulfate compared with phenytoin  
  • Magnesium sulfate does not cause maternal or newborn CNS depression 
    • Diazepam or lorazepam does stop or shorten seizures, but risk of maternal apnea and/or cardiac arrest
  • Diazepam and phenytoin may be considered if
    • Patient on these medications to treat epilepsy
    • Magnesium sulfate is contraindicated
      • Myasthenia gravis | Hypocalcemia | Moderate-to-severe renal failure | Cardiac ischemia | Heart block | Myocarditis

Learn More – Primary Sources:

National Partnership for Maternal Safety: Consensus Bundle on Severe Hypertension During Pregnancy and the Postpartum Period 

ACOG Practice Bulletin 222: Gestational Hypertension and Preeclampsia

Management of pre-eclampsia: issues for anaesthetists 

Acute pulmonary oedema in pregnant women 

Cochrane Review: Magnesium sulphate and other anticonvulsants for women with pre-eclampsia 

ASPRE Trial: A Combined Risk Algorithm and Use of Aspirin to Prevent Preterm Preeclampsia

BACKGROUND AND PURPOSE:

  • Multiple studies have demonstrated beneficial effects of low dose aspirin for prevention of preeclampsia
  • ACOG supports the key USPSTF findings and recommends considering the use of low dose aspirin (81 mg/day) between 12 and 28 weeks’ gestation in women with known clinical risk factors including
    • History of preeclampsia, especially if accompanied by an adverse outcome
    • Multifetal gestation
    • Chronic hypertension
    • Diabetes (Type 1 or Type 2)
    • Renal disease
    • Autoimmune disease (for example, systematic lupus erythematosus, antiphospholipid syndrome)
  • An alternative Bayesian risk algorithm that combines multiple clinical, biochemical and fetal sonographic (functional) findings at 11 to 13 weeks has been well studied an appears to have superior performance characteristics when compared to clinical factors alone
    • Applicable to general pregnant population, not just high risk
  • Previous studies have found that (1) starting aspirin ≤ 16 weeks provides greater preventative benefit; (2) prevention is limited to preterm preeclampsia; (3) there is a positive dose-dependent benefit effect beyond 81 mg/day; (4) taking aspirin in the evening may be beneficial
  • Purpose: The goal of the Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial (Rolnik, NEJM 2017) was to determine if 150 mg of aspirin at night could reduce the incidence of preterm preeclampsia in women identified at high risk using the combined Bayesian model approach

METHODS:

Randomized, double-blind, placebo-controlled trial (RCT)

  • Population: Women undergoing their routine prenatal visit at 11 weeks 0 days through 13 weeks 6 days
  • Screening tool: Bayesian risk algorithm which assesses the following factors
    • Age
    • Weight and height (BMI)
    • Racial/ethnic origin (white, Afro-Caribbean, South Asian, East Asian, and mixed)
    • Medical History
      • Chronic hypertension
      • Systemic lupus erythematosus or antiphospholipid syndrome
      • Diabetes mellitus type 1 or 2
    • Mode of conception – spontaneous vs. assisted
    • Obstetrical history
      • Parity ( ≥ 24 weeks)
      • Previous preeclampsia
      • Gestational age and weight at delivery in the last pregnancy
      • Interval since last pregnancy
    • Family history of preeclampsia in the patient’s mother
    • Biomarkers
      • Mean arterial pressure (MAP)
      • Uterine artery pulsatility index (UtA-PI)
      • Pregnancy associated plasma protein-A (PAPP-A)
      • Placental growth factor (PlGF)
  • Intervention:  150 mg dose/day of aspirin or placebo from 11 to 14 weeks until 36 weeks
    • 2971 women out of 26,941 women (11.0%) were ‘screen positive’ for risk of preterm preeclampsia
    • Following exclusion, withdrawal and loss to follow up, 798 participants remained in the aspirin group and 822 in the placebo group

RESULTS:

Delivery with preeclampsia < 37 weeks:  Definition of preeclampsia based on International Society for the Study of Hypertension in Pregnancy criteria

  • 1.6% in the aspirin group had preterm preeclampsia vs. 4.3% in the placebo group (odds ratio 0.38; 95% CI 0.20 to 0.74; P=0.004)

Secondary Outcomes:  Such as abruption, stillbirth, miscarriage, neonatal morbidity and mortality

  • No statistical differences found but study not powered to draw definitive conclusions

Adverse Events: Including maternal, fetal and neonatal

  • No statistical differences between groups overall, including anemia, vaginal, nasal and other bleeding

CONCLUSION:

  • Aspirin did not reduce the incidence of term preeclampsia
  • In singleton pregnancies, using a combined Bayesian risk assessment tool, 150 mg of aspirin nightly from 11-14 weeks until 36 weeks led to a 62% reduction in the rate of preterm preeclampsia compared to placebo

Learn More – Primary Sources:

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

Competing risks model in screening for preeclampsia by maternal characteristics and medical history

Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks’ gestation

 

Gestational Thrombocytopenia – a Diagnosis of Exclusion

Thrombocytopenia is a common finding which occurs in 7-12% of pregnant women. The cause of isolated thrombocytopenia may be differentiated by history, physical examination, laboratory investigation, and medical imaging.

CLINICAL ACTIONS:

When evaluating a patient for gestational thrombocytopenia (GT), consider the following

  • ≥Use platelet count <150 x 109/L to define thrombocytopenia in pregnancy
    • Normal platelet range in nonpregnant women is 165-415 x 109/L
    • Expect lower platelet counts in pregnant women, especially 3rd trimester
  • Order the following tests to assist with diagnosis/underlying cause
    • complete blood count and peripheral smear
    • liver enzymes
    • thyroid function tests
    • vitamin B12 and folate
    • HCV,HIV,HBV
    • PT/PTT
    • antinuclear antibody, anticardiolipin antibodies, lupus inhibitor
    • Based on clinical context, may require medical imaging to evaluate splenic size
  • Diagnose GT in the absence of historical, clinical, hematological and biochemical findings that would suggest another underlying condition
  • Transfuse platelets to achieve minimum platelet counts if
    • <10 x 109/L even without surgery and/or procedures
    • <50 x 109/L if active bleeding present unless undergoing cesarean in which case prophylactic platelet transfusion is recommended  (or other major surgery as per AABB guidance)
  • Epidural and spinal “are considered acceptable” if ≥70 x 109/L prior to epidural and
    • Platelet level stable | No coagulopathy | Platelet function normal | No antiplatelet or anticoagulant therapy
    • Limited evidence regarding low-dose aspirin combined with thrombocytopenia and neuraxial blockade

SYNOPSIS:

GT is the most common cause of thrombocytopenia in pregnancy and accounts for 80% of such cases.  GT may be a result of hemodilution and enhanced platelet clearance. The low platelet counts associated with GT are seen during the second and third trimesters with the nadir rarely lower than 70 x 109/L. The diagnosis of GT is made by the presence of a decreased platelet count during pregnancy and should be considered a diagnosis of exclusion. GT usually resolves within days to two months postpartum.

KEY POINTS:

Primary immune thrombocytopenia (ITP) may be difficult to distinguish from GT

  • ITP induces development of platelet autoantibodies that may cross the placenta
  • Features that may help distinguish GT from ITP
    • GT usually mid-late 2nd & 3rd trimester / ITP all trimesters
    • GT only in pregnancy / ITP may occur outside pregnancy
    • GT will resolve postpartum / ITP may not resolve
    • GT does not affect fetus or neonate / ITP may cause neonatal thrombocytopenia
  • If the diagnosis thrombocytopenia is unclear at the time of delivery, assume ITP and manage accordingly due to fetal/newborn risk for thrombocytopenia
    • Mode of delivery in ITP should be based on obstetric indications alone
  • ITP treatment options comparable to non-pregnant management – corticosteroids and intravenous immune globulin (IVIG)
    • In pregnancy, may start at lower end of prednisone dose (10-20 mg daily) and titrate up
  • Both GT and ITP may recur

Other disorders resulting in non-isolated thrombocytopenia that will present with other related findings include

  • Primary thrombotic microangiopathies (TMA)
    • ADAMTS13-deficient TMA – Thrombotic thrombocytopenic purpura (TTP)
    • Complement-mediated TMA – Atypical hemolytic uremic syndrome
  • Preeclampsia
    • 50% of women with preeclampsia will have <150 x 109/L
    • HELLP syndrome
  • Disseminated intravascular coagulation (DIC)
    • Severe preeclampsia
    • Intrauterine fetal demise (IUFD)
    • HELLP syndrome
    • Acute fatty liver of pregnancy
  • Infection (e.g., HIV, hepatitis C, CMV, Helicobacter pylori)
  • Drug induced (e.g. heparin, antimicrobials, anticonvulsants)

Learn More – Primary Sources:

Thrombocytopenic syndromes in pregnancy

ACOG Practice Bulletin 207: Thrombocytopenia in Pregnancy

Platelet Transfusion: A Clinical Practice Guideline From the AABB

Locate a Maternal Fetal Medicine Specialist:

Maternal Fetal Medicine Specialist Locator-SMFM

ACOG Guidance: Emergency Treatment for Severe Hypertension in Pregnancy

Summary:

Severe hypertension can be a life-threatening event during pregnancy and requires special vigilance in the postpartum period, particularly following hospital discharge. The goal of treatment is to control hypertension and prevent seizures.  Uncontrolled hypertension can lead to heart failure, myocardial ischemia, renal injury and stroke.

When to Treat:

Urgently treat acute onset severe hypertension in pregnancy or postpartum period

  • SBP ≥160 and and/or DBP ≥110 mm Hg persisting for 15 minutes
    • systolic BP a predictor of maternal morbidity/mortality

First Line Therapy:

Nifedipine

Hydralazine

Labetalol


Immediate Release Oral Nifedipine

Onset

  • 5 to 10 minutes

Administration

  • 10 to 20 mg orally
  • Repeat in 20 minutes if needed
  • Then 10 to 20 mg every 2 to 6 hours
  • Maximum dose: 180 mg

Medication Risks

  • Maternal tachycardia and headaches

IV Hydralazine

Onset

  • 10 to 20 minutes

Administration

  • IV
    • 5  to 10 mg IV (or IM)
    • Then 5 to 10 mg IV every 20 to 40 minutes
  • Infusion
    • 0.5 to 10 mg/hr
  • Maximum dose: 20 mg

Medication Risks 

  • Maternal hypotension and headaches
  • Abnormal FH tracings

IV Labetalol

Onset

  • 1 to 2 minutes

Administration 

  • IV
    • 10 to 20 mg IV
    • Then 20 to 80 mg every 10 to 30 minutes
  • Infusion
    • 1 to 2 mg/min
  • Maximum dose: 300 mg

Medication Risks 

  • Avoid in the following clinical settings
    • Asthma
    • Preexisting myocardial disease | Decompensated cardiac function | Heart block | Bradycardia

Note: ACOG states that “any of these agents can be used to treat acute severe hypertension in pregnancy” | An approach detailed in ACOG guidance uses “an initial regimen of labetalol at 200 mg orally every 12 hours and increase the dose up to 800 mg orally every 8–12 hours as needed (maximum total 2,400 mg/d). If the maximum dose is inadequate to achieve the desired blood pressure goal, or the dosage is limited by adverse effect, then short-acting oral nifedipine can be added gradually”


Seizure Prophylaxis: Magnesium Sulfate

  • Remains drug of choice for seizure prophylaxis
  • Magnesium sulfate should not be used to reduce blood pressure
  • See more on magnesium sulfate in ‘Related ObG Topics’

When to Use

  • Severe features of preeclampsia
    • Administer to all women
  • No severe features of preeclampsia and systolic BP > 140 and < 160 mm Hg or diastolic BP > 90 and < 110 mm Hg
    • There is no consensus on this matter as prophylaxis will reduce eclampsia but 1 in 100 to 129 women need to be treated and side effects (although not life threatening) will increase
    • ACOG states that the decision to use magnesium sulfate when severe features are not present should be the decision of the “physician or institution, considering patient values or preferences, and the unique risk-benefit trade-off of each strategy”

Delivery and Postpartum

  • Vaginal delivery
    • Continue infusion 24 hours postpartum
  • Cesarean
    • Begin infusion (if not yet running) before surgery and continue 24 hours postpartum
    • Discontinuing prior to operative vaginal birth or cesarean section to avoid uterine atony or anesthetic drug interactions is not recommended

Administration

  • Loading dose of 4 to 6 g administered per infusion pump over 20 to 30 minutes (i.e., slowly) followed by a maintenance dose of 1 to 2 g per hour as a continuous intravenous infusion
  • IM option if IV access limited
    • 10 g initially as a loading dose (5 g IM in each buttock) followed by 5 g every 4 hours
    • Mix with 1 mL xylocaine 2% to alleviate pain

Learn More – Primary Sources:

ACOG Practice Bulletin 222: Gestational Hypertension and Preeclampsia

ACOG II Severe Hypertension in Pregnancy Bundle

FIGO: A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre-eclampsia

Diagnosing Preeclampsia – Key Definitions and ACOG Guidelines

WHAT IS IT?

Preeclampsia is a pregnancy specific hypertensive disease with multi-system involvement. It usually occurs after 20 weeks of gestation and can be superimposed on another hypertensive disorder. While preeclampsia was historically defined by the new onset of hypertension in combination with proteinuria, some women will present with hypertension and multisystemic signs in the absence of proteinuria. The presence of multisystemic signs is an indication of disease severity.

SUMMARY:

Diagnostic Criteria

Blood Pressure Criteria

  • Hypertension – systolic BP > 140 mm hg or diastolic BP > 90 mm hg or both
    • On two occasions at least 4 hours apart after 20 weeks gestations with previously normal BP
    • Considered ‘mild’ until diastolic BP > 110mm hg or systolic BP ≥160 mm Hg
  • Severe Hypertension – systolic BP > 160 mm hg or diastolic BP > 110 mm hg or both
    • Can confirm using a short time interval (e.g., minutes) to facilitate timely antihypertensive therapy

Note: Gestational Hypertension

  • ACOG defines gestational hypertension as “hypertension without proteinuria or severe features develops after 20 weeks of gestation and blood pressure levels return to normal in the postpartum period”
  • Caution and close follow-up is warranted as up to a half of women with gestational hypertension will go on to manifest signs an symptoms consistent with preeclampsia
  • Women with severe gestational hypertension, even in the absence of proteinuria should be managed similar to women with severe preeclampsia
  • ACOG states

Women with gestational hypertension with severe range blood pressures (a systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher) should be diagnosed with preeclampsia with severe features.

Proteinuria Criteria

  • 24 hour urine collection >300 mg protein or
  • Single voided urine protein/creatinine ratio ≥0.3
  • Dipstick reading of 2+ (use only if other quantitative methods not available)

Preeclampsia Definitions

Preeclampsia

  • Hypertension and proteinuria or
  • In absence of proteinuria, new-onset hypertension with the new onset of any of the following
    • Thrombocytopenia: Platelets <100 x 109/L
    • Renal insufficiency: serum creatinine >1.1 mg/dl or doubling of serum creatinine in the absence of other renal disease
    • Impaired liver function: Elevated blood concentrations of liver transaminases to twice normal concentration
    • Pulmonary edema
    • Neuro: Unexplained new-onset headache unresponsive to medication (without an alternative diagnosis) or visual symptoms

Preeclampsia with severe features

  • Preeclampsia diagnosis, above, with any of the following
    • Severe hypertension
      • On two occasions at least 4 hours apart while on bed rest (unless already on antihypertensive therapy)
    • Thrombocytopenia: Platelets <100 x 109/L
    • Impaired liver function (without an alternative diagnosis): Elevated liver transaminases greater than twice upper limit of normal or severe persistent right upper quadrant or epigastric pain not responsive to medications
    • Progressive renal insufficiency: serum creatinine >1.1 mg/dl or doubling of serum creatinine in the absence of other renal disease
    • Pulmonary edema
    • Neuro: Unexplained new-onset headache unresponsive to medication (without an alternative diagnosis) or visual symptoms

Note: The following are not diagnostic criteria for the diagnosis of preeclampsia or preeclampsia with severe features

  • Clinically evident edema
  • Rapid weight gain
  • Massive proteinuria
    • Does not qualify as a ‘severe feature’
  • Fetal growth restriction
    • ACOG states that while it is important to monitor fetal status, FGR in the setting of all other fetal assessment being within normal limits (e.g., AFV, Doppler), expectant management ‘may be reasonable’ if mother and fetus appear stable and no other clinical indication is present that would indicate the need for early delivery
  • Uric acid
    • Hyperuricemia in hypertensive pregnancy is not a diagnostic marker, but is an important finding as a risk factor for adverse maternal and fetal outcomes
      • Small for gestational age (SGA) infant
      • Prematurity
      • Risk for adverse maternal outcomes if include patients with preeclampsia and risks increase with increasing concentration of uric acid
    • May be warranted in the setting of ‘diagnostic dilemmas’ such as diagnosing superimposed preeclampsia in the setting of chronic hypertension

Learn More – Primary Sources

ACOG Practice Bulletin 222: Gestational Hypertension and Preeclampsia

National Partnership for Maternal Safety Consensus Bundle on Severe Hypertension During Pregnancy and the Postpartum Period

Plasma uric acid remains a marker of poor outcome in hypertensive pregnancy: a retrospective cohort study

Pre-eclampsia: pathophysiology and clinical implications

Aspirin Treatment for Women at Risk for Preeclampsia – ACOG, SMFM and USPSTF Recommendations

FINDINGS:

ACOG/SMFM have released guidance aligned with USPSTF regarding the use of low-dose aspirin during pregnancy to prevent preeclampsia.  When indicated, low-dose aspirin should be started between 12 to 28 weeks and continued until delivery.  Optimally, aspirin usage should begin <16 weeks.

Recommended (high risk)

  • Offer low-dose aspirin (81 mg/day) to women with 1 high risk factors
    • History of preeclampsia, especially if accompanied by an adverse outcome
    • Multifetal gestation
    • Chronic hypertension
    • Diabetes (Type 1 or Type 2)
    • Renal disease
    • Autoimmune disease (for example, systematic lupus erythematosus, antiphospholipid syndrome)

Moderate Risk Factors

  • Offer low-dose aspirin (81 mg/day) to women with ≥2 moderate risk factors
    • Nulliparity
    • Obesity (BMI >30)
    • Personal history
      • Low birthweight or SGA
      • Previous adverse pregnancy outcome
      • >10-year pregnancy interval
    • Family history of preeclampsia
      • Sister or mother
    • Social and demographic characteristics
      • Black race (as a proxy for underlying racism)
      • Lower income
      • Maternal age ≥35 years
    • IVF

Note: USPSTF does allow for consideration of aspirin prophylaxis if ≥1 moderate risk factor is present and states “Clinicians should use clinical judgment in assessing the risk for preeclampsia and discuss the benefits and harms of low-dose aspirin use with their patients”

Universal Implementation

  • Evidence supports a risk-based approach
  • ACOG/SMFM acknowledges that in some settings, a majority of patients will fall in to either high or moderate risk categories, and therefore

In these instances, universal implementation (eg, offering low-dose aspirin to all patients within such practices or institutions) may be medically reasonable

Not Recommended Without Preeclampsia Risk Factors

  • Low risk: Previous uncomplicated full-term delivery
  • Insufficient Evidence
    • Prior unexplained stillbirth (insufficient evidence)
    • Prevention of fetal growth restriction
    • Prevention of spontaneous PTB
  • No Benefit
    • Prevention of early pregnancy loss

USPSTF Guidance

  • The USPSTF recommends the use of low-dose aspirin (81 mg/d) as preventive medication for preeclampsia after 12 weeks of gestation in persons who are at high risk for preeclampsia as per categories above (B recommendation – offer or provide this service)

Benefits

  • The most recent systematic evidence review (see ‘Learn More – Primary Sources) provided more precise estimate of the association between aspirin and the prevention of perinatal mortality (4% to 44% reduction in fetal and neonatal deaths)
  • Otherwise, benefits of low-dose aspirin for women at risk for preeclampsia were similar to previous reviews with lower risks for the following (moderate certainty)
    • Preeclampsia: Pooled relative risk (RR) 0.85 (95% CI, 0.75-0.95)
    • Perinatal mortality: Pooled RR 0.79 (95% CI, 0.66-0.96)
    • Preterm birth: Pooled RR 0.80 (95% CI, 0.67-0.95)
    • Intrauterine growth restriction: Pooled RR 0.82 (95% CI, 0.68-0.99)

Harms

  • No significant association was found for
    • PPH or other bleeding-related harms
    • Rare perinatal or longer-term harms
  • Long-term child developmental outcomes in offspring from in utero exposure to low-dose aspirin
    • Follow-up data from the Collaborative Low-dose Aspirin Study in Pregnancy (CLASP), found no differences in physical or developmental outcomes at 12 to 18 months

KEY POINTS:

  • Risk factors used for ACOG/SMFM recommendations only include factors obtained from the medical record
    • Uterine artery Doppler ultrasonography and biochemical markers are not included
    • ACOG/SMFM acknowledge that other studies, in particular the ASPRE trial (see ‘Related ObG Topics’ below), have incorporated ultrasound and maternal serum markers as well as doses >81 mg, but state

Further, the screening algorithm used includes first-trimester serum markers, including placental growth factor and pregnancy-associated plasma protein-A, as well as uterine artery dopplers, which limits the generalizability to a U.S. population. Therefore, a higher dose or doubling of the available 81-mg dose cannot be recommended at this time.

Screening for Preeclampsia

  • Various studies have incorporated not only clinical risk factors but also biochemical markers and ultrasound to determine which women are at risk for early onset preeclampsia and may benefit from aspirin prevention (see ‘Related ObG Topics’)
  • ACOG/SMFM considers the supporting data for the use of such combined risk assessment algorithms to be limited and without more prospective clinical utility trials, states that

…biomarkers and ultrasonography cannot accurately predict preeclampsia and should remain investigational.

Learn More – Primary Sources:

ACOG Practice Advisory: Low-Dose Aspirin Use for the Prevention of Preeclampsia and Related Morbidity and Mortality

ACOG Practice Bulletin 222: Gestational Hypertension and Preeclampsia 

USPSTF: Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality

USPSTF: Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

ACOG/SMFM Committee Opinion 743: Low-Dose Aspirin Use During Pregnancy