The CHIPS Trial

/

The CHIPS Trial: The Control of Hypertension In Pregnancy Study

Formal Publication Title: Less-Tight versus Tight Control of Hypertension in Pregnancy

https://www.nejm.org/doi/full/10.1056/nejmoa1404595

Some general background information

  • Who did the study and who published it?

    • An open, multicenter, international, randomized controlled trial. 

      • Coordinating center: University of British Columbia (go Canada again!)

    • Where was it published? The New England Journal of Medicine in 2015 

  • Why was the study done? 

    • Hypertension is common – at the time of this publication, it was estimated to affect 10% of pregnancies, with 1% being cHTN, 5-6% being gHTN, and 2-3% being preeclampsia.

    • Treatment of blood pressure at specific thresholds had not really been well defined.

      • On one hand – using antihypertensives liberally and early might help prevent maternal / fetal complications related to uncontrolled HTN.

      • On the other hand – antihypertensives might have their own consequences, as shown in other smaller studies (i.e., FGR).

  • What was the research question?

    • To compare tight versus less-tight control of non-proteinuric, non-severe hypertension in pregnancy

Methods

  • Who participated and when?

    • Subjects were recruited from March 2009 to August 2012 - 95 sites in 16 countries enrolled at least one patient.

    • Eligibility: 

      • Had non-severe, non-proteinuric preexisting hypertension or gestational hypertension

        • That’s right – they treated gHTN too! More on that later

        • Preexisting HTN defined as diagnosis pre-20 wks, gestational HTN defined as diagnosis after 20wks

      • A DBP of 90-105 if not receiving therapy, or 85-105 if already on treatment

        • BP were obtained at least 4 hours apart or at two consecutive outpatient visits, with the second measurement taken within 1 week prior to randomization.

        • Both BPs needed to be elevated to be included.

      • Live singleton fetus between 14w0d and 33w6d

    • Exclusion criteria

      • SBP of 160 or higher (but could be included later if they were treated and met all other eligibility criteria)

      • Proteinuria > 0.3mg/day on 24h, or a P:C >0.263, or a dipstic of 2+ or more

      • Used an ACE-I at or after 14 weeks

      • Had a contraindication to either trial group because of preexisting disease

        • Examples provided included pregestational diabetes or renal disease 

      • Multiple gestations, anomalies, or plans for TOP

      • Previous participation in the trial 

  • How was the study done?

    • Randomized in blocks of 2 or 4 patients using a telephone line and pager system

    • 1:1 ratio of less-tight control (defined as target DBP 100 or lower) versus tight control (target DBP 85 or lower)

      • Control of BP was expected to the target level until delivery, with a goal of between-group difference of DBP of 5mmHg (goal based on a pilot trial of the protocol).

    • Recommendation for labetalol as drug of first choice.

      • ACE-I, ARBs, renin inhibitors, and atenolol were not permitted prior to delivery.

      • No drugs were provided by the study – this was left to physician discretion. 

    • BP at subsequent prenatal visits were obtained 3x per visit. The average of the 2nd and 3rd DBPs obtained were considered to be the DBP for the visit and used for med targeting.

      • Participants also kept a diary to record this info as well as medications and co-interventions (i.e., ultrasound, clinic visit info)

    • Adherence to protocol based on a “clinically reasonable standard” was assessed within 4 weeks of randomization.

      • This isn’t totally elaborated on, but did follow to some degree blood pressure measurements in the patient’s diary and the interventions listed.

      • Thereafter, patients were seen on a schedule dictated by their doctor/midwife. 

    • A standardized questionnaire was then given to patients at 6 weeks postpartum to identify post discharge complications.

  • What outcomes were they looking for?

    • Primary outcome

      • Composite of pregnancy loss (miscarriage, ectopic, termination, stillbirth, or neonatal death) or high-level neonatal care (“greater than normal” newborn care) for more than48 hours until 28 days of life or discharge home, whichever was later.

    •  Secondary outcome

      • Maternal outcomes and complications up to six weeks postpartum, including:

        • Stroke, death, eclampsia, blindness, uncontrolled HTN, use of inotropic agents, pulmonary edema, respiratory failure, myocardial ischemia/infarction, hepatic dysfunction, hepatic hematoma or rupture, renal failure, and transfusion. 

    • Outcomes were adjudicated by a committee who were not aware of group assignments and not involved in patient’s care.

    • Additional outcomes analyzed included fetal growth and newborn complications, and incidence of severe hypertension (> 160/110) in the mother

  • Some statistics interestingness:

    • This trial had some interesting analyses that we don’t frequently see in RCTs:

      • There were multiple levels of comparisons planned, and for this reason, the alpha level for significance (i.e., p value to look for) was 0.046.

      • Similarly, for secondary outcome, p<0.01 was needed, and for the additional subsequent outcomes, p<0.001 was needed.

        • We would love to have you super statistics-minded brains email us about why these adjustments are made – it has to do with the number of comparisons made and the two interim analyses that were performed to assure safety during the trial.

Results

  • Who did they recruit? 

    • 1030 eligible women were recruited - 519 for less-tight, and 511 for tight control

      • Ultimately, one site needed to be excluded due to concerns about data integrity – so 497 patients were assigned to less-tight, and 490 to tight control.

      • Six patients were lost to follow up or withdrew so no data was available

      • 24 patients discontinued BP treatment prior to delivery, but their data was included as part of an intention-to-treat analysis

      • 10 patients (five in each group) had incomplete data after they were lost to follow up for the postpartum survey. 

      • 21 patients were found to have been ineligible after data analysis.

    • “Clinically reasonable adherence” to assigned treatment protocol was slightly worse in the less-tight group (76.6%) versus the tight group (82%).

    • Baseline characteristics were overall very similar:

      • Similar BMI, nulliparity, gestational age at randomization, gestational DM rate, smoking rate.

      • 25% in each group had gestational hypertension, whereas 75% had chronic HTN

        • 16% in the less-tight and 12% in the tight group had a severe-range BP at some point prior to enrollment (only statistical difference at p=0.049)

        • About 57% in each group were on antihypertensive meds at enrollment

    • Blood pressure was higher in the less-tight control group by average of 5.8 mmHg systolic, and 4.6 mmHg diastolic.

      • SBP: 138.8 vs 133.1 mmHg, p<0.001

      • DBP: 89.9 vs 85.3 mmHg, p<0.001

    • Antihypertensive meds were taken by fewer patients in the less-tight control group after randomization (73.4% vs 92.6%) and this continued after delivery (65.5% vs 78.3%). 

    • Labetalol was most commonly used agent (68.9% vs 68.8% between groups)

      • Four protocol violations for use of atenolol prior to delivery.

  • Outcomes

    • Primary: neonatal composite – no difference. 

      • No significant differences with respect to other perinatal outcomes for newborns, including SGA <10% or <3%, or rates of respiratory complications.

  • Secondary outcomes

  • Maternal outcomes – no difference overall but rare serious events.

    • No maternal deaths.

    • In less severe events:

      • Frequency of severe hypertension was higher in the less-tight control group than tight control group (40.6% vs 27.5%, p<0.01)

      • Higher rates of abnormal labs consistent with severe preeclampsia in less-tight group (more frequent rates of thrombocytopenia, liver enzyme elevations) – however, these did not meet prespecified limit for statistical significance (0.001 for these other outcomes)

Conclusions and What We Do Now

  • The authors conclude from this study that: 

    • Infant: “tight versus less tight control of maternal hypertension resulted in no significant difference in risk of adverse perinatal outcomes”

    • Maternal: “Less-tight control did not significantly increase risk of overall serious maternal complications.” 

      • While there was a more significant rate of severe hypertension and markers of severe preeclampsia, they didn’t meet the study’s threshold for significance (admittedly very challenging at p<0.001).

  • CHIPS is interesting in that it has dictated how we treat hypertension and allowed for “less-tight control” as the dominant paradigm in US practice:

    • In most places, treatment of hypertension prior to more significant values consistent with severe BP is not performed.

    • Gestational hypertension is not typically treated unless severe-range pressures result

      • And nowadays, that’s classified as severe preeclampsia!

  • It is interesting to think about this and the challenges with preeclampsia management – maybe we would prevent some severe preeclampsia with more aggressive treatment?

    • Those numbers are so small though, it’s hard to know.

    • But severe BP control in preeclampsia we know is very important to prevent stroke, seizures, and other complications…

  • CHIPS did provide some reassuring data in that tighter and less-tight control paradigms didn’t seem to adversely affect birth weight.

  • Given some of the limitations of CHIPS and some of these open questions, the CHAP trial was performed to better evaluate the strategy for treatment of specifically mild chronic hypertension in pregnancy. 

    • We’ll review this in a future podcast – but as a preview, it seems to favor more tight control! So perhaps a new strategy is already being employed at your institution or is incoming!

Retirement and Investing, feat. Michael Foley

/

Today we welcome back Michael Foley for another episode in our financial series alongside SMFM. We talk through retirement accounts and the most important ways to set up your savings.

How to get in touch if other questions come up?

·         Michael.foley@northstarfinancial.com

·         Can offer you a complimentary, no obligation, initial review and more in-depth financial consultations available for those who might have more in depth questions.

Michael is a comprehensive financial advisor who runs his practice out of Scottsdale, Arizona, under North Star Resource Group. Michael was trained at Duke University and holds his Certified Financial Planner designation alongside his Certified Student Loan Professional designation. Although Michael serves a diverse group of clients with their financial and student loan needs, with two physician parents, Michael has found a specialty in working with those in the healthcare space. 

North Star Resource Group is independently owned and operated. 6720 N Scottsdale Rd Ste 290, Scottsdale, AZ 85253.

Separate from the financial plan and his role as financial planner, Michael may recommend the purchase of specific investment or insurance products or accounts. These product recommendations are not part of the financial plan and you are under no obligation to follow them. Financial Professionals do not provide specific tax/legal advice and this information should not be considered as such. You should always consult your tax/legal advisor regarding your own specific tax/legal situation.

Exercise in Pregnancy

/

Additional reading for today in ACOG Committee Opinion 804!

What are the definitions of physical activity and exercise? 

  • Per ACOG: 

    • Physical activity: bodily movement produced by contractions of skeletal muscles in all stages of life

    • Exercise: physical activity consisting of planned, structured, and repetitive bodily movements done to improve one or more components of physical fitness 

    • Physical activity can maintain and improve cardiorespiratory fitness, reduce the risk of obesity and associated comorbidities, and results in greater longevity 

Is exercise safe in pregnancy?

  • Yes!

    •  Not just in pregnancy, but for all individuals, the US Department of Health and Human Services Physical Activity Guidelines for Americans says: 

      • At least 150 min of mod intensity aerobic activity per week

      • Recommended also in pregnancy and postpartum period 

      • Those that engaged in vigorous-intensity aerobic activity or who were physically active before pregnancy can continue those activities 

      • Few maternal conditions that would not allow aerobic exercise 

  • What are the downsides of not exercising?

    • Physical inactivity is the 4th leading risk factor for early mortality worldwide 

    • Physical inactivity and weight gain in pregnancy have been recognized as independent risk factors for maternal obesity and pregnancy related complications like GDM  

  • What are the benefits of exercising? 

    • Increased likelihood of vaginal delivery! 

    • Low incidence of: excessive weight gain, GDM, gestational hypertensive disorders, preterm birth, c-section, lower birth weight 

  • What exercises are safe? 

    • Aerobic: walking, stationary bike, aerobic exercises, dancing, stretching, water aerobics 

    • Anaerobic: resistance training (weights, elastic bands) 

    • Borg rating of perceived exertion: 6 - 20 (6 to 7 is very, very light, and 19-20 is very, very hard) 

      • Recommend moderate intensity, which is about a 13-14 (somewhat hard) 

        • About 20-30 min per day for most days of the week 

      • Also talk test: if you can talk while exerting yourself, likely not over exerting 

Note: ACOG issued a correction to this table; it should read “First Trimester, Less Than 12 Weeks Gestation.”

What are some modifications we should consider in pregnancy? 

  • Changes in pregnancy 

    • Weight gain, difference in weight distribution 

      • About 60% of pregnant patients will experience low back pain 

    • Increase in blood volume, heart rate, stroke volume, cardiac output = normal (recall our very first few episodes on physiologic changes in preg!)

      • Maintaining supine positioning after 20 weeks may lead to decrease venous return → can lead to SOB, dizziness, hypotension, etc 

    • Minute ventilation increases by 50% 

  • Other modifications: 

    • Remember to stay well hydrated, wear loose-fitting clothing, and avoid high heat and humidity (ie. hot yoga) 

    • Exercise by itself isn’t expected to increase body temp to point of concern 

  • Fetal response 

    • Studies show some minimal to mod increase in fetal heart rate by 10-30 bpm during maternal exercise 

    • Three meta-analyses show that there is minimal to no difference in birth weight 

    • However, women who continue to exercise vigorously in third trimester are more likely to deliver babies weighing 200-400g less than controls, though no increased risk of FGR 

When to stop exercising 

  • Don’t exercise if:

    • Have vaginal bleeding, abdominal pain, regular painful contractions, leaking fluid 

    • Dyspnea before exertion, dizziness, headache, chest pain

    • Muscle weakness affecting balance, calf pain or swelling  

Special considerations 

  • Obesity

    • Encourage patients to have healthy lifestyle modification in pregnancy that include physical activities and judicious diets 

    • Can start with low-intensity, short periods of exercise if not exercising already 

    • Then can build up gradually 

  • Athletes

    • Vigorous-intensity exercise even in 3rd trimester appears to be safe and healthy for most pregnancies 

    • Further research is needed for exercise intensity exceeding 90% of max heart rate  

Perinatal Mental Health, feat. Dr. Tiffany Moore-Simas and Dr. Nancy Byatt

/

Today on the podcast, we’re addressing perinatal mental health. While we’ve talked about depression on the show before, there’s so much more in this sphere as we’ll discuss today.

 

Joining us are two experts in this field who share their passion for this work with us. Dr. Tiffany Moore Simas is Chair and Professor of OB/GYN at UMass Memorial Health and UMass Chan Medical School as well as co-Chair of the ACOG Maternal Mental Health Expert Work Group. And Dr. Nancy Byatt is a tenured Professor of Psychiatry and OB/GYN at UMass Memorial Health and UMass Chan Medical School. Both serve as senior leaders with the Massachusetts Perinatal Psychiatry Access Program, MCPAP for Moms, and Lifeline For Moms.

 

Importance of Perinatal Mental Health

  • Mental health conditions are the most common complications of pregnancy – 1 in 5!

    • More common in adolescents, veterans, marginalized populations (BIPOC, poverty).

  • Untreated mental health conditions carry both short- and long-term consequences that can affect whole family:

    • o   Less engagement in medical care

    • o   Smoking, substance use

    • o   Preterm delivery, low birth weight, NICU admission

    • o   Lactation challenges, bonding issues

      • Parent with untreated mental health disorder is considered an Adverse Childhood Experience (ACE) for the infant.

    • o   Adverse partner relationships

  • Mortality: leading cause of preventable maternal mortality.

    • 100% of maternal deaths due to mental health, including suicide, overdose, are preventable!

  • Underdetected and undertreated

  • OB/GYNs can screen and help manage mental health conditions. The majority (80%) of depression, for example, is managed by primary care providers, not psychiatrists. As obstetric care clinicians, we are the primary care providers to pregnant and postpartum individuals and thus, we should be providing mental health care!

Screening for Perinatal Mood and Anxiety Disorders

  • In this context, perinatal refers to during pregnancy and the first year after pregnancy ends

  • Perinatal Mood and Anxiety Disorders primarily include depression, bipolar disorder, and anxiety or anxiety-related conditions (generalized anxiety disorder, PTSD, OCD).

  • Screens should be performed with validated tools that query the last 7-14 days of symptoms for anxiety and depression.

    • o   Validated tools:

      • PHQ-9, EPDS (depression)

      • GAD-7 (generalized anxiety)

    • o   ACOG recommends screening patients at least once during the perinatal period for depression and anxiety symptoms. If a patient is screened during pregnancy, additional screening should occur during the comprehensive postpartum visit.

      • We recommend screening: new OB visit, later in pregnancy (i.e., 3rd trimester) and postpartum given the almost even distribution of onset predating pregnancy, onset in pregnancy, and onset postpartum.

    • o   Data suggests that early detection and treatment improves outcomes.

  • Bipolar disorder screening:

    • o   In one study, 1 in 5 patients screening positive for postpartum depression actually had bipolar disorder.

      • Recall: bipolar disorder can worsen with antidepressant treatment (unopposed SSRIs) – thus, need to screen for bipolar before initiating pharmacotherapy and ideally universally to prevent harm!

    • o   Patients with bipolar disorder have higher risk of postpartum psychosis

      • Rare: 1-2/1000 perinatal individuals; but 70% have bipolar disorder!

      • 4% risk of infanticide with postpartum psychosis

      • This is a psychiatric emergency.

        • Often occurs within the first days of delivery and most cases occur within the first 3 weeks.

    • o   Screening options:

      • Mood Disorder Question (MDQ) – self administered

      • CIDI – clinician administered with branching logic

    • o   Appropriate to refer to psychiatry if bipolar disorder is suspected – more on resources to help later!

Positive Screening   General Principles of Treatment

  • Just like a glucola, our questionnaires for mental health concerns are screening tests. Subsequent assessment is critical to confirm diagnosis.

    • o   See resources collection at the end of these notes for help!

  • For depression and anxiety, there are three pillars of treatment:

    • o   Psychotherapy

    • o   Pharmacotherapy or medication

      • o   Adjunctive interventions

  • Treat based on level of severity. For information on assessing and treating perinatal mental health conditions, visit the ACOG website.

  • If pharmacotherapy is indicated/started, patients may have some concerns:

    • o   Provide reassurance

    • o   Frame risk/benefit discussion in treated disease vs. untreated disease as not treating is associated with risks - just like any other disease!

    • o   Use lowest effective dose and monotherapy when able

  • Find more information on educating patients about treatment on ACOG’s website.

Concerns for Suicidality or Harm To Baby

  • These can represent urgent clinical scenarios and further assessment and response is critical:

    • o   Thoughts of harming self or baby are common yet not all are necessarily a psychiatric emergency.

    • o   When assessing for risk of harm to self or others it is important to assess:

      • Ideation – Do they have thoughts of harming themselves or someone else?  Are the thoughts fleeting or do they persist?

      • Intent – Are they intending to act on it? Have they thought of how they could do harm themselves or someone else or die by suicide?

      • Plan - Are they planning to act on it?  Have they developed a plan for how to die by suicide or to harm someone else?

    • o   If you are concerned that the patient is at risk of harm to self or others, then it is important to obtain further assessment which includes an evaluation for whether the patient may need psychiatric hospitalization

    • o   Regardless of whether these are a psychiatric emergency, the presence of thoughts of harming self or baby are indicative of higher illness severity.

  • More information on ACOG’s website.

 Resources for Integrating Perinatal Mental Health Care into Your Practice

 

Sickle Cell Disease, feat Dr. David Abel

/

Here’s the RoshReview Question of the Week:

Which of the following is a precipitating factor for a painful crisis in a pregnant woman with sickle cell disease?

Check out the answer at the links above and get a sweet deal on RoshReview!

Today we’re joined once again by Dr. David Abel, an assistant professor in the Department of Obstetrics and Gynecology at Oregon Health Sciences University. Dr. Abel has previously joined us to talk about thalassemias and von Willebrand’s disease — he shares his passion for blood disorders again with us today to talk more on sickle cell!

Listen to our last sickle podcast here. 

Epidemiology of Sickle Cell Disease (HbSS)

  • Most common inherited hemoglobinopathy in the United States, and in fact is the most common inherited disease worldwide.

    • Autosomal recessive fashion — both parents need to be carriers.

  • Affects approximately 10 million people worldwide and approximately 100,000 people in the United States.

    • This translates into a prevalence of about 1 in 375 who have the disease.

  • Predominantly affects people of African ancestry

    • Two thirds of those that are affected reside in West Africa.

    • 50% of children born with sickle cell disease are born in Nigeria.

  • Sickle Cell Trait: 1 in 12 are carriers.

    • In the United States, approximately 7% to 9% of the African American population.

    • As the gene is widely distributed, other populations may be affected including those residing in the areas of the Mediterranean, Caribbean, South and Central America, as well as East India.

  • More than 90% of children with sickle cell disease in the United States survive into adulthood.

    • Compared to the general population, however, their lifespans are two or threedecades shorter and limited by both acute and chronic morbidity.

  • Sickle cell trait confers a survival advantage in malaria-endemic regions such as in sub-Saharan Africa where almost 80% of individuals with sickle cell anemia live — resulting in “positive screening” with respect to human evolution.

Hemoglobin Structure in Sickle Cell and Pathophysiology

  • Remember: thalassemias represent quantitative defects globin synthesis. By contrast, hemoglobin S is characterized by a qualitative defect of the beta globin gene.

    • HbS results from a single nucleotide substitution, an adenine- to-thymine substitution in the sixth codon of the beta globin polypeptide which replaces glutamic acid with valine.

      • From this one amnio acid change, rather than forming tetramers, under conditions of low oxygen tension, this hemoglobin S forms long inflexible chains or fibers.

      • They distort the red blood cell membrane, resulting in this sickled shape.

      • These distorted red blood cells are destroyed by the reticuloendothelial system, resulting in a moderate to severe anemia.

        • Compared to the normal life span of a red blood cell of 120 days, the life span of these sickled red blood cells is reduced to an average of 15 days.

  • These distorted red blood cells clog up the microvasculature —> obstruction and local ischemia which clinically manifests as a vasoocclusive crisis.

    • Repeated vasoocclusive crises can lead to interruption of normal perfusion of multiple organs, including the spleen, lungs, kidneys, heartand brain.

    • Adults with sickle cell disease are essentially functionally asplenic — increased incidence and severity of infection in patients with sickle cell disease.

  • Sickled red cells are also prone to lysis which releases free hemoglobin.

    • Damages the endothelium and may also lead to thrombosis.

    • Also consumes nitric oxide, an important vasodilator and thus can lead to an exacerbation of the ischemia.  

Testing for Sickle Cell Disease and Trait

  • Foundation of screening: CBC, Hb electrophoresis. High suspicion in patients with family history / ancestry and MCV < 80.

    • HbSS (disease) electrophoresis:

      • 85-95% hemoglobin S

      • Remaining mostly hemoglobin F, small component of hemoglobin A2

    • HbSB (trait) electrophoresis (assuming normal second beta gene):

      • 50-60% hemoglobin A (normal adult Hb)

      • 35-45% hemoglobin S

      • Small amounts hemoglobin F, hemoglobin A2

  • There are many other sickle genotypes:

    • Homozygous hemoglobin SS constitutes about 70% of these genotypes.

    • Hemoglobin C, which differs from hemoglobin S only in that the amnio acid lysine instead of a valine replaces glutamic acid in the beta globin gene, can exist in combination with hemoglobin S, thus is called hemoglobin SC disease.

    • Hemoglobin S may coexist with beta-thalassemia.

      • Hemoglobin S beta thalassemia zero is also identified as sickle cell anemia and is just as severe as hemoglobin SS.

      • Hemoglobin S beta thalassemia plus is not as severe as there is some hemoglobin A that is preserved.

Maternal and Fetal Considerations with Sickle Cell

  • During pregnancy, the increase in red blood cell mass that normally occurs does not in those with sickle cell anemia.

    • 50%–70% of pregnancies with sickle cell disease require at least one hospitalization

    • 30%–40% will require a transfusion.

    • In the United States, the maternal mortality rate is approximately 10 times higher than it is for patients without sickle cell disease.

  • Vasoocclusive Crisis / Pain Crisis is most common cause of recurrent morbidity.

    • Can be precipitated by such factors as cold, physical exertion, dehydration and stress.

    • Opioids are a mainstay of treatment for a pain crisis — it is important not to withhold treatment for these patients.

  • Acute chest syndrome severe life-threatening form of a vasoocclusive crisis

    • Presents similarly to pneumonia.

      • Fever, tachypnea, chest pain, hypoxia and infiltrates noted on chest x-ray.

      • In addition to infectious agents, acute chest syndrome may also result from fat emboli, intrapulmonary aggregates of sickled red blood cells, atelectasis or pulmonary edema.

    • Patients with a history of frequent hospitalizations and/or episodes of acute chest syndrome correlate with increased risks during pregnancy.

    • The treatment of acute chest syndrome typically consists of antibiotics, usually ceftriaxone and azithromycin, pain control, and if needed oxygen and transfusion.

  • Other complications

    • Stroke: occurs in almost 25% by the age of 25

    • Splenic sequestration / asplenia

    • Acute renal failure

    • Acute cholecystitis

    • Pulmonary hypertension: 6 to 11% of patients with sickle cell disease

    • Venous thromboembolism: ocurs in 10-25% of those with sickle cell disease by age 40

      • In pregnancy risk elevates: 2x increased risk of stroke, 5x increased risk of cerebral vein thrombosis, 2x increased risk of pulmonary embolism, 2.5x increased risk of deep vein thrombosis.

    • Maternal infection complications: asymptomatic bacteriuria, pyelonephritis, sepsis and an almost ten-fold increased risk of pneumonia.

  • Placental Consequences:

    • Placental hypoperfusion with endothelial damage is the main contributor to adverse pregnancy outcomes.

    • Increased risk of preeclampsia and eclampsia, placental abruption, antepartum bleeding and alloimmunization.

  • Fetal consequences:

  • 2x increased risk of preterm birth

  • 3x risk of small-for-gestational age

  • 4x increased risk of stillbirth.

    • Serial fetal growth assessments and antepartum testing are needed.

  • Possible increased risk of neonatal abstinence syndrome due to the use of opioids to treat pain crises.

Should transfusion be used prophylactically?

  • 2015 meta-analysis of 12 observational studies with almost 1300 patients demonstrated a reduction in both maternal and perinatal mortality as well as a reduction in pain events and preterm birth.

  • 2016 Cochrane review that included only randomized controlled trials did not demonstrate a benefit with prophylactic when compared with selective transfusion.

  • Management strategy:

    • CBCs should be checked frequently, and a goal of maintaining a hemoglobin around 10 (same might say up to 12) and a percentage of hemoglobin S less than 35 to 40% is reasonable.

    • It is important to avoid iron overload when considering transfusion therapy which may lower target Hb for some individuals.

Treating Sickle Pain Beyond Opioids

  • Amitriptyline

  • Gabapentin

  • Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs)

  • Complementary (CAM) therapies

  • Hydroxyurea

    • Mainstay of treatment in the non-pregnant patient, as it reduces the risk of a vasoocclusive crisis and acute chest syndrome, thereby leading to improved survival and quality of life.

      • Patients with sickle cell disease who have higher amount of fetal hemoglobin tend to do better, and hydroxyurea increases fetal hemoglobin as well as reduces red blood cell adhesion and increases nitric oxide, the vasodilator we discussed earlier.

    • Has been found to cause birth defects in animals, although it has not been found to increase the risk of birth defects in humans. Still, it is generally avoided during pregnancy.

 Preconception Counseling for Sickle Cell

  • Discuss the increased risk of both maternal and fetal complications, though many can have a successful pregnancy.

    • Know history — past need for transfusions, the frequency of hospitalizations due to vasoocclusive crises and if there is a history of acute chest syndrome.

  • Due to the possibility of iron overload due to multiple transfusions, it is important to check a ferritin prior to prescribing iron.

  • ACOG recommends 4 mg of folic acid daily.

  • Screen for hypertension and treat if warranted to maintain a blood pressure less than 140/90.

  • A dilated eye examination performed by an ophthalmologist should be performed if not done within the past year.

  • If there are any concerns for nephropathy, refer to nephrology — screen for proteinuria.

  • If there are any concerns for pulmonary hypertension, an echocardiogram is recommended with cardiology referral if needed.

  • As most patients are functionally asplenic, pneumococcus, haemophilus influenza type b, and meningococcus immunizations are recommended.

  • Check antibody screen — possible risk of alloimmunization.

Cure for Sickle Cell Disease?

  • Have been accomplished with hematopoietic stem cell transplantation.

    • In this case, the donor may be related or unrelated.

  • Stem cell transplantation offers a cure, but can result in death, graft rejection, graft versus host disease, and sterility due to chemotherapy.

  • Gene therapy for sickle cell disease, where patients receive their own genetically modified hematopoietic stem cells, is still experimental and there are several clinical trials underway.  

Final Important Points on Managing Sickle Disease in Pregnancy

  • Hydroxyurea should be discontinued if it has not been already.

    • There are some who might consider restarting this after the fetal anatomical survey shows no evidence of abnormalities.

  • Chelation agents should also be discontinued.

  • Low-dose aspirin for preeclampsia risk reduction is recommended.

  • Monthly urinary cultures monitoring for asymptomatic bacteriuria and watching for any signs or symptoms of pyelonephritis.

    • Also reasonable to do in patients with sickle trait as risk is also increased in that population.

  • Frequent CBC monitoring, usually monthly is reasonable.

  • Interval fetal growth assessments every 3-4 weeks are recommended.

  • Antepartum testing starting at 32 weeks is indicated, with a delivery goal of 37 to 39 weeks.

  • Watch for preeclampsia is very important.

  • If a cesarean delivery is required, a preoperative transfusion may be prudent to increase hemoglobin levels to 8 to 10 g/dl.

  • Thromboprophyalxis: SCDs definitely; anticoagulation should be individualized.

    • Assuming the patient did not have a thromboembolic event during the pregnancy, could consider prophylactic low-molecular weight heparin for six weeks postpartum.