Influenza

What is flu, and why do we care about it in pregnancy? 

1. We reviewed the flu vaccine in pregnancy previously, but we have never talked specifically about flu itself! 

1. Flu is a contagious respiratory illness caused by the influenza virus 

2. The virus is a negative sense RNA virus 

3. There are multiple strains, including A, B, C, D

1. We have probably heard about A and B, but C and D also can infect people 

1. A and B are known to cause more severe illness, while C can cause can cause a mild infection 

2. D can infect humans, but is not known to cause illness 

4. Transmission is through aerosols and contaminated surfaces 

2. Why do we care about flu so much? 

1. In typical years, as much as 5-15% of the population will contract flu

2. This leads to 3-5 million severe cases annually and up to 650,000 flu deaths a year in the world 

3. In the US, on average, 8% of the population gets sick from the flu, per the CDC 

3. Who is most likely to get sick? 

1. Children are most likely to get sick from flu and people 65 and older are least likely to get sick 

2. However, pregnant and postpartum individuals are at significantly higher risk of serious complications related to seasonal and pandemic influenza infections compared to non pregnant people 

How is flu prevented? 

1. Vaccination 

1. The CDC recommends that all adults receive an annual influenza vaccine and that individuals who are pregnant during the season receive an inactivated or recombinant influenza vaccine as soon as possible 

2. Timing: end of October is ideal, but any time during flu season vaccination should be encouraged 

3. Remember that it is safe to give the flu vaccine with other inactivated vaccines that may be needed in pregnancy (ie. Tdap, RSV, or COVID vaccines) 

4. It is also safe for lactating individuals to receive the flu vaccine 

5. Of note, the vaccine also benefits the newborn when it is given during pregnancy 

1. Randomized controlled trials and observational studies have shown neonatal protection from maternal influenza vaccination 

6. Importantly, studies show that when recommendations for the flue vaccine during pregnancy come from the patient’s Ob/Gyn or other obstetric health professional, and the vaccine was available in the office, the odds of vaccine acceptance and receipt are 5x-50x higher! 

7. For more information on the flu vaccine, check out our previous episode: https://creogsovercoffee.com/notes/2019/5/26/vaccines-i-tdap-and-influenza

2. Masks 

1. This is probably familiar to all of us now with the COVID-19 pandemic 

2. Mask wearing can help prevent transmission of many respiratory infections, particularly when community levels of circulating viruses are elevated 

3. When to wear a mask 

1. Local public health guidance and recommendations based on community-centered risks 

2. Individual’s specific vulnerability due to health conditions 

3. Clinical and health care professional recommendations 

3. Other methods 

1. Hand washing 

2. Cleaning surfaces regularly 

3. Make sure to to use usual techniques to minimize contamination/spread of disease 

How should we evaluate for influenza in pregnancy? 

1. Assess for symptoms 

1. Fever >100.4 F (38 C) and one of the following 

1. Cough, runny nose, sore throat, headache or body aches, fatigue, difficulty breathing or SOB 

2. If these symptoms are present, test for COVID and flu 

3. Also assess for illness severity 

1. Difficulty breathing or shortness of breath 

2. Chest pain/pressure 

3. Unable to keep down liquids 

4. Dehydration signs and symptoms 

5. Less responsive, confused

6. Symptoms are worsening 

4. If yes to any of the above, then encourage patient to go to emergency room or equivalent location to be treated 

5. If no, if there are other morbidities (ie. cardiovascular or pulmonary issues, immunosuppression, obstetric issues like preterm labor) → should be seen in a clinical setting as moderate risk 

6. Otherwise, patient is considered low risk and patient can be treated outpatient or even over the phone, with follow up in 24-48 hours 

How to Treat Respiratory Infection in Pregnancy 

1. Empiric treatment 

1. Oseltamivir is the preferred treatment for pregnant individuals 

1. Dosing: 75 mg orally twice a day for 5 days 

2. Zanamivir can also be used (two 5 mg inhalations twice daily for 5 days) 

3. Peramivir can also be given, but is 1 dose IV for 15-30 min 

4. Do not delay treatment while respiratory infection test is running

2. If suspected to have both COVID and flu, oseltamivir and Paxlovid can be prescribed and taken together 

3. Post Exposure chemoprophylaxis for flu 

1. Due to high potential for morbidity and mortality related to flu in pregnant and postpartum individuals, post exposure chemoprophylaxis can be considered for those who are pregnant and for those who are up to 2 weeks postpartum 

2. Recommendation: oseltamivir 75 mg 1x/day for 7 days 

3. Should be started within 48 hours of most recent exposure 

4. At risk family members of patients with flu should be referred to health care professionals for consideration of chemoprophylaxis 

COVID-19 Update #3: Treating the Pregnant Patient

Prevention of COVID-19: More Updates on Vaccination

• Vaccination is the #1 thing folks can do to protect themselves and their fetuses!

• Since our last podcast, ACOG, SMFM, ASRM, ACNM, AABM (just to name a few) have all endorsed COVID-19 vaccination at any time for folks trying to conceive, who are pregnant, or postpartum and lactating!

• SMFM has released consensus guidance for healthcare providers regarding vaccine counseling:

  • Check out our previous episodes (#1 and #2) on vaccine effectiveness

  • We at CREOGs Over Coffee wholeheartedly recommend vaccination, especially with this stronger data regarding safety in reproduction, pregnancy, and lactation.

COVID and Pregnancy: What Options Are Available for Treatment?

We’re going to address the following major questions today:

• Does patient merit inpatient admission?

• If they can stay outpatient, does the patient qualify for any therapy?

• If they need to be inpatient, when to start therapeutics and what options are available? 

• When is delivery indicated for maternal benefit?

Decision to Admit:

COVID can be broken into asymptomatic disease, then mild, moderate, severe, and critical disease:

• Mild

  • Flu-like symptoms: fever, cough, myalgias

  • Anosmia

  • No dyspnea, shortness of breath, or abnormal chest imaging (if performed)

• Moderate:

  • Symptomatic dyspnea/shortness of breath, but able to maintain SpO2 > 94% on room air

  • Evidence of pneumonia on imaging

  • Refractory fever (>39C) to acetaminophen

• Severe:

  • Respiratory rate > 30

  • SpO2 < 94% on room air (so any O2 requirement!)

  • PaO2 / FiO2 < 300 

  • More than 50% lung area involvement of disease on imaging

• Critical:

  • Multiorgan failure or dysfunction, shock

  • Respiratory failure requiring high flow nasal cannula or mechanical ventilation

• Patients with mild disease or no symptoms can be safely monitored outpatient, with a 10-day self quarantine from positive test or onset of symptoms in accordance with CDC guidelines. 

• Patients with moderate disease will often require hospitalization in pregnancy, owing to risk of progression. However, this is an individualized decision, and non-pregnant folks might more typically stay outpatient in this scenario.

  • If patients remain outpatient, SMFM recommends ongoing check-ins from patients to their prenatal care providers to assess symptoms and ensure there is no concern for disease progression.

  • Also recommend a follow up visit (either in-person or via telemedicine) at least once within 2 weeks of diagnosis.

  • Necessary and indicated medical care should not be avoided due to a positive COVID status!

• Patients with severe or critical disease, obviously, will merit inpatient admission. 

• Patients with mild-moderate disease with other comorbidities may also be considered for hospitalization (i.e., patients with hypertension, diabetes, other maternal medical conditions), as these patients appear to be more prone to acute decompensation. 

Inpatient Care: Protocols and Hospital Disposition

• Vital signs and fetal monitoring as indicated when fetal intervention would be considered.

• ICU level of care should be considered with:

  • Rapidly increasing oxygen needs to maintain SpO2 >95%

  • Hypotension (MAP < 65) despite some measure of fluid resuscitation.

    • Owing to risk of pulmonary edema, SMFM recommends an initial 500-1000cc bolus of crystalloid to assess response, and conservative fluid management unless clearly hypovolemic.

  • Need for mechanical ventilation or intubation - 

    • Intubation is recommended if O2 requirements are >15L by NC or mask, >40-50L by high-flow NC, >60% FiO2 by Venturi mask, or altered mental status with inability to protect airway. 

  • Need for other end-organ support (i.e., hemodialysis)
    

• Prone positioning is possible in pregnancy! 

  • Proning in COVID (and other causes of acute respiratory distress syndrome) is well-studied

    • It is hypothesized to decrease ventilation-perfusion mismatch by bringing more blood to the more open anterior lung fields (rather than the often atelectasis-affected lower posterior lung).

  • Padding and support devices may need to be used for appropriate support in pregnancy.

  • In non-intubated patients, lateral-decubitus or full-prone positioning is also permissible and can help improve oxygenation.
    

• Thromboprophylaxis is generally recommended in at least hospitalized patients, given critical illness increases hypercoagulability risk further in pregnancy.

  • Prophylaxis is generally not recommended after discharge, unless other specific comorbidities exist.

    • SMFM offers use of a risk scale, the IMPROVE Risk Score, as well as deferring to clinical expertise to guide use of pharmacologic prophylaxis once discharged from the hospital.
      

• Extracorporeal membrane oxygenation (ECMO)

  • Allows for oxygenation of the lungs (VV ecmo) and possibly combining with pumping action (VA ecmo) in patients with severe ARDS refractory to other methods of therapy. 

    • It gets even more complicated than this, but that’s the basics!

  • ECMO is a significant intervention with its own set of morbidities and risks, and should be reserved for significant, severe cases of pregnancy where it may be helpful and delivery may not/cannot be considered at that present moment (i.e., previable or periviable gestation). 

  • These conversations are often very individualized by institution, so we’ll hold off on further discussion from here! 

Therapeutics and Indications

• Outpatient:

  • Monoclonal antibody therapy (i.e., Regeneron)

    • FDA Emergency Use Authorization indicated for patients over age 12 who have mild-to-moderate COVID-19, weigh at least 40kg, and are at high risk of progression to severe disease or hospitalization. The criteria are:

      • BMI > 35

      • Chronic kidney disease

      • Diabetes

      • Immunosuppresive therapy 

    • Data is limited on their use in pregnancy, but other monoclonal antibodies are generally well-tolerated with no fetal effects. Thus, they can be used in appropriate pregnant patients. 

• Inpatient:

  • Dexamethasone

    • Associated with decreased risk of mortality in those requiring mechanical ventilation

    • Also has small decrease in mortality for those requiring oxygen generally

      • (RECOVERY Trial)

    • Recommended dosing: 6mg IV or PO daily x 10 days.

      • NOT recommended in those who do not require oxygen

    • Dexamethasone does cross the placenta measurably: it is the alternative steroid to betamethasone for fetal lung maturity!

      • FLM dosing: 6mg IM q12h x 4 doses

      • Thus, it is appropriate to use in appropriate pregnant patients; FLM dosing should be given for the first 48h of therapy. 

  • Remdesivir

    • Associated with decreased duration of disease in patients requiring oxygen therapy (ACTT-1 Trial)

    • Recommended if SpO2 < 94% on mechanical ventilation or ECMO

    • No fetal toxicity is known, and can be used on an emergency / compassionate use basis.
      

When to deliver the hospitalized patient:

• SMFM recommends that in patients with refractory hypoxemia, delivery at/after 32 weeks is reasonable if it will allow for further care optimization given:

  • Low risk of neonatal mortality at 32 weeks (0.2%) and

  • Overall low risk of major morbidity (8.7% at 32 weeks). 

    • This also logistically is often more appropriate - controlled delivery is certainly more preferable to chaos! 

• In those who are critically ill, decision for delivery is certainly individualized.

  • Mechanical ventilation alone is not an indication for delivery.

  • Proning, ECMO, and other ventilator methods should be considered especially under 30-32 weeks. 

COVID-19 Updates for Pregnancy

Since our update in March, we now have much more data – so much in fact that it may be really hard for everyone to synthesize it all. Our hope is to help a little with the synthesis and present the information out there in a digestible way – obviously we won’t be totally comprehensive, but we’ll do our best!

Pregnancy and COVID-19 Risk

The CDC released a new morbidity and mortality weekly report (MMWR) in November 2020:

• Looked at data from 1/22-10/3/2020 with delay for data updates up to 10/28/2020 in both pregnant and nonpregnant symptomatic women between the ages of 15-44 (reproductive age).

  • 409,462 symptomatic women 

  • 23,434 (5.76%) symptomatic pregnant women 

• Suggestion: pregnant women are MORE likely to have severe COVID-19 associated illness. After adjusting for age, race, other med conditions, pregnancy women were: 

  • More likely to be admitted to the ICU (10.5 vs 3.9/1000 cases, ARR 3.0) 

  • More likely to receive ventilation (2.9 vs 1.1/1000, ARR 2.9) 

  • Receive ECMO (0.7 vs 0.3/1000, ARR 2.4) 

  • And die… (1.5 vs 1.2/1000, ARR 1.7) 

• Some other interesting findings: 

  • Older pregnant women were more likely to have ICU admission/severe disease, comparing women 35-44 with women 15-24 (19.4 vs 7.6/1000 cases) 

  • Black women had higher risk of death (made up of 14.1% of all women involved, but represented 36.6% of deaths overall, including 26.5% of pregnancy deaths) 

  • Increased risk of ICU admission for Asian women (ARR 6.6) and native Hawaiian/Pacific Island women (ARR 3.7) 

  • In pregnant Hispanic women, pregnancy was associated with 2.4x risk of death 

•     Some limitations: 

  • COVID-19 cases rely on voluntary report by health care providers and public health officials/agencies 

  • Reporting bias – we might report more if there is more severe disease (less likely to report asymptomatic or mild disease) 

  • Severe outcomes might require more time to ascertain (why they had time lag of 10/28 when looking at cases reported through 10/3/2020).

Smaller studies have been performed to assess other pregnancy outcomes. Studies may be too small to be powered for these differences, but are still being actively studied:

• Preterm labor/stillbirth 

  • Overall during the pandemic:

    • Danish report showed decreased preterm birth rates overall;

    • Another UK study showed increased rates of both;,

    • JAMA Dec 7, 2020 in Philadelphia did not show increased rate during the pandemic. But conflictingly, a study in the same city in October showed that there was a decreased PTB rate at one hospital 

    • Could hypothesize these varying outcomes may be due to different time periods, different lock-down methods, etc. 

• PEC/cesarean deliveries/PTB in people with COVID 

  • One study from Texas looked at 3374 women who were tested for COVID, of whom 252 were positive.

  • In positive women, there was no difference in composite outcome of PEC w/ SF, cesarean delivery, or PTB.

• Looking at PTB from the Birth and Neonatal Outcome MMRC from CDC: there was a preterm birth rate of 12.9% in women with COVID-19 infection, which was higher than general population in 2019 (10.2%), so maybe there is an increased risk for preterm delivery.

Birth and Neonatal Outcomes after COVID-19 

There has been concern about perinatal infection in women who are COVID-19 positive and laboring. Fortunately we’ve got some reassuring data on this front from the CDC:

• 5252 women with lab-confirmed COVID-19’s babies  610 (21.3%) of infants had reported COVID results

  • Perinatal infection – uncommon (16, 2.6%) and occurred primarily among infants whose mother had COVID ID’ed within 1 week of delivery.

  • 8 of the infants were born preterm (26-35 weeks) and admitted to NICU 

  • 8 term infants who were positive, one was admitted to NICU for fever and O2, the others were not admitted, and one did not have info.

COVID-19 Vaccination in Pregnant and Breastfeeding People  

When we recorded the episode, we spoke primarily about the Pfizer vaccine. This information should apply in broad strokes the the Moderna vaccine as well, now that it has received approval as the 2nd mRNA vaccine.

• mRNA vaccine – What is it, how does it work? 

  • mRNA: messenger RNA. It is single-stranded RNA molecule that is complementary to one of the DNA strands of a gene. Reaching back to med school: mRNA leaves the cell nucleus and moves to the cytoplasm where they code for different protein synthesis. Ribosome will move along the mRNA, read the base sequence, and use the genetic code to translate three-base triplet (codon) into its corresponding amino acid 

  • tRNA: which is attached to an amino acid, will match with mRNA to generate a sequence of amino acids to make up a protein 

• The COVID-19 mRNA vaccine gives instructions to our cells to create a “spike protein,” which is a harmless piece of protein that is found on the surface of the virus that causes COVID-19 

• Once the mRNA is used, the cell gets rid of the material… so you can’t get infected with COVID-19. It also doesn’t get encoded into our DNA!

  • Once your cell makes the protein, it presents it on the surface of the cell. The immune system will recognize that this protein doesn’t belong there and begin to build up an immune response and make antibodies, kind of like what would happen in the natural infection against COVID-19. 

  • At the end of the process, your immune system will recognize these surface proteins from COVID-19 and have the ability to fight them off, so if you come into contact with COVID-19, your immune system will be ready 

• How was it developed so fast? 

  • Most of the time, vaccine trials take a long time because there are hang-ups in things that have nothing to do with science: funding, IRBs approval, etc.

  • But because this was coronavirus, there was a lot of funding and momentum from Operation Warp Speed.

    • OWS is a partnership with the Department of Health and Human Services, CDC, NIH, Biomedical Advanced Research and Developmental Authority (BARDA), and Department of Defense 

    • Since March, the HHS has given a TON of money to vaccine research:  https://www.hhs.gov/coronavirus/explaining-operation-warp-speed/index.html#:~:text=August%2011%3A%20HHS%20announced%20up,the%20option%20to%20acquire%20more.

  • Pfizer received $1.95 billion in July for production of 100 million doses of vaccine, and Congress directed almost $10 billion to the overall effort of vaccine development/distribution. Most of the time, vaccine research does not get this much money all at once! 

• Is it safe?

  • For the Pfizer vaccine, the Phase 3 clinical trial began on July 27 and enrolled 43,661 participants, and 41,135 received a second dose

  • The trial concluded 11/13/2020, so there is at least 3.5 months’ worth of data. We don’t really expect long term outcomes to be different… since mRNA gets destroyed by the body so quickly.

  • Findings: 

    • Looking at 28 days after first dose of vaccine (remember, we need time for the vaccine to work), there were 170 confirmed cases of COVID-19: 162 in the placebo group vs. 8 in the vaccine group.

    • Efficacy was consistent across age, gender, race, and ethnicity demographics.

    • Efficacy was 95% overall, and 94% in adults >65 years of age.

    • Safety in general: well tolerated across all populations, no serious safety concerns observed. The only Grade 3 adverse event >2% in frequency was fatigue (3.8%) and headache (2.0%). Older adults tended to report fewer and milder solicited adverse effects following vaccination 

  •  What about reports of the 6 people that died in the Pfizer Phase III trial? 

    • 6 people did die in the trial. 4 were in the placebo arm, and 2 were in the actual vaccine arm.

      • Of the two that died: 1 was reported to have serious adverse event related to arteriosclerosis and died 3 days after dose 1; the other had a cardiac arrest 60 days after dose 2 and died 3 days later. Both were > 55 years of age. 

      • Of the 4 that died in placebo arm: 1 died 8 days after dose 1 with unknown event, one died of hemorrhagic stroke 15 days after dose 2, one died 34 days after dose 2 (unknown event), one died of MI 16 days after dose 1. 

  • Other serious adverse events 

    • The non-fatal SAE was 0.6% in the vaccine group and 0.% in the placebo group 

    • Vaccine group had higher rates of appendicitis (0.04%), acute MI (0.02%), and CVA (0.02%)

    • Placebo arm had higher rates of pneumonia (0.03%), afib (0.02%), and syncope (0.02%) 

  • Editorializing here: but the overall small numbers, the variety of things that occurred, and the lack of biologic plausibility in these SAEs suggest these likely happened by chance.

• Should pregnant and breastfeeding people get vaccinated? 

  • Unfortunately, pregnant and breastfeeding people were excluded from the study 

  • Currently, the FDA has not excluded pregnant and breastfeeding people from getting the vaccine 

  • SMFM is in agreement – recommend that pregnant and lactating people have access to the vaccine 

  • Can engage in discussion about potential benefits and unknown risks with their providers 

Vaccines II: MMR, Varicella, and HPV

Let’s tackle the second part of our vaccinations series with some of the more common live-virus vaccines: MMR, Varicella, and HPV. Check out the CDC vaccine guides linked here.

MMR

• Measles, mumps, and rubella - all are live attenuated strains of the virus

• Should NOT be given during pregnancy

• Immunity is about 97% against measles and rubella after 2 doses, and 88% against mumps after 2 dose

• Given ideally before pregnancy to protect against congenital rubella

  • Otherwise, after pregnancy and not during

  • This is because during pregnancy, the adaptive immune system is not as robust as when one is not pregnant and higher risk of the live attenuated virus actually causing disease.

    • If an adult is not immune to MMR (and we screen for rubella during pregnancy), at least one dose should be given postpartum.

• Ingredients

  • Chicken embryo cell culture - medium

  • Human diploid lung fibroblasts - medium

  • Vitamins, amino acids, sucrose, glutamate, human albumin, sorbitol, gelatin, sodium phosphate, sodium chloride

  • Fetal bovine serum - medium

  • Neomycin - antibiotic

• Side effects

  • Can get rash, temperature, loss of appetite 2-3 days

  • Can get a VERY mild form of measles or mumps

  • Extremely rare: severe allergic reaction

Varicella

• Protects against chickenpox and shingles

  • 88-98% effective at preventing varicella after two doses, and 85% effective after 1 dose.

  • Ideally given before pregnancy to protect against chickenpox complications during pregnancy (ie. pneumonia) and congenital varicella syndrome or neonatal varicella.

  • Don’t give it during pregnancy.

• Ingredients

  • Human diploid cells with DNA and protein

  • Sucrose, gelatin

  • Sodium chloride, monosodium-glutamate, sodium phosphate, potassium phosphate, potassium chloride, EDTA

  • Neoomycin

  • Fetal bovine serum

• Side effects

  • Common: sore arm, fever, mild rash, temporary pain and stiffness

  • Severe: (very uncommon) - severe infection, pneumonia

HPV

• Gardasil 9 protects against human papilloma virus 16, 18 (causes 80% of cervical cancer cases), 6, 11 (90% of genital wart cases), and another 5 types (31,33,45, 52, 58) that can lead to cervical cancer.

  • 3 separate shots for people aged 15-45 - high efficacy, with close to 100% prevention of HPV virus

  • If 9-14, 2 shots are sufficient

  • Not currently recommended during pregnancy

    • Good time to give it: immediately pp in hospital (dose 1), then 6 weeks pp  

• Ingredients

  • Vitamins, amino acids, mineral salts, carbohydrates

  • Amorphous aluminum hydroxyphosphate sulfate

  • Sodium chloride

  • Polysorbate 20

  • Neomycin, yeast protein

• Side effects

  • Common: pain, redness, swelling of arm where shot was given

  • Less likely: fever, headache, feeling tired, nausea, muscle or joint pain.

Vaccines I: Tdap and Influenza

Today we get a little political to arm you with the most up-to-date information on vaccines. We’ll start with the two vaccines recommended in pregnancy: Tdap and Flu. We summarize some of the salient details below:

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(C) CREOGs Over Coffee

Now onto some of these controversial ingredients:

• Formaldehyde - this is used to inactivate viruses and detoxify bacterial toxins

  • Why are people concerned? Because they hear that formaldehyde is used in glues and adhesives, used in preserving dead bodies,  used in insulation materials. In high levels and long-term exposure, formaldehyde IS linked to cancer development.

  • But it is safe! There is always a small amount  of formaldehyde in humans at all times as a normal part of our metabolism (it’s in the air and all around us). In a normal two-month old, there is around 1.1mg of formaldehyde circulating in the body, which is 50-70x more formaldehyde than is present in one dose of vaccine.

• Octylphenol ethoxylate (Triton X-100) - basically a detergent. Present in trace amounts

• Sodium phosphate-buffered isotonic sodium chloride solution - this is salt water, it’s used as a buffer

• Thimerosol - mercury containing ingredient that acts as a preservative.

  • Why are people concerned? The word mercury. Large amounts can be harmful

  • In vaccines this is ethylmercury, which is different from methylmercury, which is the mercury compound that is harmful. Ethylmercury is much more quickly metabolized and removed from your body.

    1. It’s like being afraid of sodium.  Sodium on it’s own will explode if you put it on water. Sodium chloride is salt that you eat.

    2. Even now… only multi-dose flu vaccines have thimerosol, and thimerosal-free vaccines are widely available.

• 1,2-phenoxyethanol - preservative; it is metabolized and excreted.

• Aluminium phosphate - used as an adjuvant in vaccines. Makes it more effective by strengthening immune system response, so people need fewer doses of the vaccine to build immunity.

  • Why are people concerned? There has been concern that long-term exposure to high amounts of aluminum can contribute to brain and bone disease

  • Why are we not concerned? There are trace amounts of aluminum in water, food, breast milk

    • A breast-fed patient will ingest about 7 mg of aluminum in 6 months of life . The standard vaccine administered over the first six months of life averages to just 4.4 mg. The amount in a single vaccine is so small that there is no noticeable raise in the base amount found in the blood even immediately after injection.