Influenza

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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 


Pre-Exposure Prophylaxis (PrEP) for HIV

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Reading: 

What is PrEP?

  • Pre-exposure prophylaxis specifically for prevention of HIV 

  • Use of antiretroviral medication to individuals who do not have HIV, but are at risk for it.

    • Has been recommended by the CDC since 2012.

Why is PrEP needed?

  • HIV remains a significant public health problem in the USA and around the world.

    • 1.2 million persons have HIV as of 2021, with 87% aware of their diagnosis.

    • About 36,000 people receive HIV diagnosis per year.

      • Heterosexual contact accounts for ~22% of all HIV diagnoses.

      • Injection drug use accounts for ~7% of diagnoses.

    • The majority of new infections occur during reproductive years – about 20k of the 36k diagnoses per year are under the age of 35.

    • Persons of color and trans persons are disproportionately affected – and PrEP can be part of solution to fight inequity.

  • PrEP is effective, but underutilized:

    • 23% of persons who can benefit from PrEP are prescribed it – lots of room for improvement!

    • Discuss more on efficacy later.

    • As part of CDC’s End the HIV Epidemic initiative, they hope to increase PrEP coverage to 50% by 2025.

How effective is PrEP?

  • Very! Let’s quickly review some major trial data in heterosexual couples:

  • 2012: TDF2 Study Group, NEJM

    • RCT in Botswana randomizing to daily tenofovir-emtricitabine or placebo.

      • Two reverse transcriptase inhibitors

      • Brand names: Truvada, Descovy

    • 1219 men and women underwent randomization (45.7% women) and followed for a median of 1.1 years, but max 3.7 years.

    • 9 persons in treatment group and 24 persons in the placebo group became infected.

      • Estimated efficacy: 62.2%.

      • Higher rates of nausea/vomiting and dizziness in treatment group, but not long enough following to determine long-term safety data.

  • 2012: Partners PrEP Study Team, NEJM.

    • RCT in Kenya and Uganda for HIV-1 serodiscordant heterosexual couples, with three arms: daily tenofovir; daily combination tenofovir-emtricitabine; or placebo.

    • 4747 couples were followed.

      • In 38% of couples, the seronegative partner was female.

    • 17 infections in the tenofovir group; 13 infections in the combo drug group; and 52 infections in the placebo group.

      • Risk reduction of 67% with tenofovir alone, and 75% with the combo drug.

      • Rates of serious adverse events similar across groups.

  • 2012: FEM-PrEP Study Group, NEJM

    • RCT in multiple countries in Africa 

    • 2120 HIV-negative women to tenofovir-emtricitabine or placebo daily over two years.

    • 33 infections in combo drug group, 35 infections in placebo group.

      • No difference. Why?

        • Hypothesized that adherence was poor – while pill-count data suggested 88% of meds were taken, drug level testing suggested target plasma level was only identified in about 25% of participants tested.

        • Remember that a daily pill regimen can be challenging!

  • The CDC currently says that PrEP is:

    • 99% effective in reducing risk of HIV acquisition from sexual activity

    • 74% effective in reducing risk of HIV acquisition from IV drug use, when taken as prescribed.

CDC - PREP GUIDANCE

CDC - PREP GUIDANCE

Who should receive PrEP?

  • Patients at the highest risk are those who do not have HIV, but are known to have a male sexual partner that is infected with HIV (a “sero-discordant couple”). 

  • Other high-risk candidates where PrEP should be prescribed:

    • Engage in sexual activity within high HIV-prevalence area or social network, with:

      • Limited or no condom use

      • Diagnosis of other STIs

      • Use of IV drugs or alcohol dependence, or both

      • Incarceration

      • Exchange of sex for commodities, such as drugs, shelter, food, or money

  • Otherwise – if your patient is sexually active, with a partner with unknown HIV status or if they’ve had a bacterial STI in the last six months – it’s a good idea to at least discuss PrEP!

    • Currently, the CDC has a very simple flowsheet for determining if PrEP prescriptions are immediately appropriate. But discuss with your sexually active patients!

      • Including adolescents – ACOG Practice Advisory was a limited update to encourage PrEP discussion in this population.

      • PrEP is OK for anyone > 35 kg / 77 lbs.

How should I prescribe PrEP?

  • Preparation:

    • Determine baseline HIV status with testing – if positive, need treatment, not PrEP

      • Remember – if they’ve had a potential HIV exposure or acute HIV infection symptoms in prior 4 weeks, may need re-testing before determining if they are positive.

    • Determine STI status for other infections such as gonorrhea, chlamydia, and syphilis.

    • Assess hepatitis B status

      • Because emtricitabine and tenofovir can be used to treat hepatitis B, it’s important to test for this – stopping the medicine suddenly in an infected person can lead to rebound hepatitis.

        • If HBV is found or a patient is known to be HBV positive → counsel about this risk and monitor LFTs / HBV viral loads if they discontinue PrEP.

    • Assess kidney function:

      • Oral tenofovir can cause some minor renal damage, and rarely acute renal failure.

        • If CrCl > 60 mL/min, OK to proceed with oral PrEP.

        • If CrCl > 30 mL/min, OK to proceed with injectable PrEP (more on that later!)

    • Assess lipid profile:

      • Oral PrEP may cause changes in lipid profile – baseline assessment should be performed with triglycerides.

    • Same day prescribing of PrEP is OK for most patients as these labs are drawn – but do not prescribe in patients where testing can’t be obtained, patients with concerning history for acute HIV infection or renal disease/associated conditions, or without confirmed means of contact for discussing lab results.

  • Medications and Monitoring:

    • Daily Oral PrEP:

      • Truvada or Descovy (both are combinations of emtricitabine and tenofovir)

        • Truvada has been approved for heterosexual women, as well as MSM and trans women.

        • Descovy has been approved only for MSM and trans women (not for heterosexual women).

      • Patients should be monitored with:

        • HIV testing q3 months

        • Syphilis, gonorrhea, chlamydia testing approximatley every 6 months

        • Creatinine clearance estimate every 6 months

        • Lipid panel yearly

    • Injectable PrEP:

      • Relatively new (Dec. 2021): injectable cabotegravir (brand name: Apretude)

        • FDA approved for heterosexual women, MSM, and trans women at risk of HIV infection.

        • Injection schedule is 2 injections x 1 month apart, followed by q2 month injection.

      • Patients should be monitored with recommended surveillance STI testing:

        • HIV testing with every injection visit

        • Gonorrhea, chlamydia, syphilis on an approximately every 6 month basis.

    • 2-1-1 Oral PrEP

      • This is event-driven / “coitally-timed” PrEP.

        • This can be used by adult MSM, but is not recommended by the CDC and not FDA approved at this time. 

        • It hasn’t been studied in heterosexual women or trans patients.

What if my patient becomes pregnant on PrEP?

  • Women seeking to conceive and pregnant/breastfeeding women can use oral PrEP.

  • Important to understand in HIV is the “undetectable, untransmissible” or U/U principle:

    • Women whose sexual partner has a viral load <200 copies/mL have effectively no risk of sexual acquisition.

      • If partner remains on maximally effective antiretroviral therapy and has undetectable VL, PrEP may not provide additional protective benefit.

    • PrEP may be continued if desired, and a antiretroviral pregnancy registry is available to prospectively and anonymously submit information to obtain further data (www.apregistry.com) 


Further info

  • The CDC maintains a very extensive prescriber’s guide that is worth looking through to implement your own PrEP practice!

    • There is also a National Clinician Consultation Center at 855-448-7737 (855-HIV-PREP) that is available 9A to 8P ET on M-F to have clinician consultation for testing, prevention, treatment, and pre-exposure prophylaxis, and post-exposure prophylaxis resources.

  • The ACOG Practice Advisory also notes PrEP is widely covered with state Medicaid as preventive healthcare, and medication assistance is widely available – check out the end of the advisory for a list of resources.

Viral Hepatitis in Pregnancy, with Dr. Brenna Hughes

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We were lucky enough to get a sneak peak at ACOG’s newest Clinical Practice Guideline #6 on Viral Hepatitis in Pregnancy. We sat down with co-author Dr. Brenna Hughes, professor of obstetrics and gynecology and Vice Chair of Obstetrics and Quality at Duke University, to get highlights of the newest updates and changes concerning hepatitis in pregnancy.

Background

  • There are five types of viral hepatitis: A, B, C, D, E

    • A and B are preventable through vaccination

    • B and C are recommended for screening in pregnancy.

  • Screening and vaccination is important, as these infections cause morbidity for pregnant folks.

  • Hepatitis A — small case-fatality and rare complications

    • Associated with food-borne outbreaks

    • Fecal-oral contamination or foodborne outbreaks related to contaminated food/water

  • Hepatitis B — highly pathogenic and infectious

    • Perinatal transmission is single largest cause of chronic infection worldwide.

    • Also associated with sexual contact, IV drug use, contaminated blood product.

    • Mortality 1%

      • 85-90% of adults will experience resolution of physical findings and develop antibody.

      • 10-15% will develop chronic infection, with a minority of those continuing with viral replication and active viral DNA synthesis.

  • Hepatitis C

    • Most commonly reported bloodborne infection in the US

      • Principal risk factor: IV drug use

    • 75% of individuals are asymptomatic with infection

    • Can be concomitantly spread with HIV

  • Hepatitis D

    • Incomplete viral particle that exists only in presence of hepatitis B

    • Transmission primarily blood borne

    • Produces more severe disease than other forms of chronic hepatitis

      • 70-80% develop cirrhosis and portal hypertension, 15% within 2 years of initial onset of acute illness

        • This is compared to just 15-30% of patients with Hep B alone who develop cirrhosis and portal hypertension over time.

  • Hepatitis E

    • Similarly to hepatitis A, associated with fecal-oral transmission

    • Generally self-limited viral illness

      • In pregnant persons, higher risk of fulminant hepatitis E with 20-35% fetal mortality and significant maternal morbidity (including need for transplant).

      • Rare in US

New Updates in Screening for Hepatitis B

  • ACOG recommends triple panel screening for all pregnant patients without documented negative triple screen after age 18, or haven't completed HepB vaccine series, or who have ongoing risk for HepB infection regardless of prior vaccination / testing.

    • This encompasses obtaining a:

      • HepB surface antigen (Hep B sAg)

      • HepB anti-surface antibody (anti-HBs)

      • HepB total core antibody (total anti-HBc)

    • A triple panel provides opportunity to inform decisions regarding treatment (if needed) or vaccination.

    • If positive surface antigen — additional testing will help determine type of infection and chronicity.

  • ACOG still recommends early universal prenatal screening for HepB sAg in all pregnancies regardless of testing and vaccination status.

    • 12-18% of patients still don’t receive even this baseline level of screening.

ACOG CPG 6

Managing Hepatitis B in Pregnancy

  • Pregnancy is well tolerated in those with hepatitis B infection without advanced liver disease.

    • There is a risk of hepatitis flare, particularly postpartum.

  • Those with chronic hepB and a viral load of > 200,000 IU/mL should be on antiviral therapy in the third trimester to reduce risk of perinatal transmission.

    • Some patients with lower VL may also be on antivirals if indicated for their own risk/health.

  • Vertical transmission is low with amniocentesis and shared-decision making can be employed when making decisions on this.

  • There is insufficient evidence to suggest invasive obstetric procedures (FSE, episiotomy, operative delivery) increase transmission risk, but there are some reports of increased risk with neonate coming to contact with infected blood.

  • All neonates of individuals with HBsAg-positive status or unknown status should receive HBIG and hepatitis B vaccine within 12 hours of birth.

  • Breastfeeding can proceed unless there are other contraindications.

    • Tenofovir can be continued during breastfeeding.

Hepatitis C: Screening, Treatment, and Pregnancy Pearls

  • ACOG recommends pre-pregnancy screening for hepatitis C virus infection and treatment.

    • Ideally, pregnant folks will get screened for hepatitis C antibody at the first prenatal visit of each pregnancy.

      • If positive —> assess hepatitis C viral PCR testing to confirm active infection vs cleared infection or false positive.

    • There are no treatment options for hepatitis C diagnosed in pregnancy — but there are really successful treatment options outside of pregnancy.

      • OB/GYNs can help get these patients to successful treatment in the postpartum period with prenatal screening.

    • Ribavirin achieves virology cure in large proportion of patients.

      • If patients are taking prior to pregnancy, couples should wait 6 months after completion of therapy due to possible teratogenic effects.

  • In pregnancy, there are no known preventive measures to reduce risk of vertical transmission.

    • Risk is generally low for amniocentesis and CVS: use shared decision making in decision to proceed.

    • There is insufficient evidence to suggest routine invasive obstetric procedures should be avoided (internal monitoring, episiotomy, operative delivery) but can be considered/minimized when possible.

      • No evidence pre labor cesarean decreases transmission risk.

    • Breastfeeding is not discouraged in patients with active hepatitis C.

      • Not enough data on cracked/bleeding nipples.

Immunization in Pregnancy

  • Both hepatitis A and hepatitis B vaccination are safe in pregnancy!

    • Newer hepatitis B vaccines do not have sufficient data (HepBZ-CpG and Hepb Vaccine Recombinant) — so need to know your manufacturer.

    • There is a combination vaccination for adults that can be used in pregnancy as well!

Common Aneuploidies

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Additional episodes that might be helpful for today:

What is aneuploidy?

  • The occurrence of one or more extra or missing chromosomes leading to an unbalanced complement.

  • Screening for aneuploidy occurs with either serum screening or cell free DNA.

    • Diagnostic testing for aneuploidy is done with chorionic villus sampling or amniocentesis.

      • As we discussed on the screening 2 episode; fluorescent in situ hybridization (FISH) can evaluate initially for common aneuploidies.

      • Karyotypes are the confirmatory testing for common aneuploidy, as well as other ways to get aneuploidy we’ll review (triploidy, balanced translocations).

      • Microarray can find other major aneuploidies, but can’t find triploidy or balanced translocations.

How does aneuploidy occur?

  • Meiosis is the process of cell division that produces gametes – eggs and sperm. 

    • Goal is to create daughter cells with a haploid chromosome number (in humans – 23).

    • The two gametes generally fuse to create a diploid zygote with 46 chromosomes.

      • If there’s an issue in the cell division process for a gamete, they may come into this fusion with an extra or missing chromosome.

    • Remember in cell division, we have multiple phases: prophase, metaphase, anaphase, telophase.

      • We’ll break it down simply into the stages you need to remember to get those bonus points!

  • Meiosis is broken into two phases: meiosis I and meiosis II.

    • In meiosis I, the starting cell is diploid – but after replication, ends up with 4n chromatids (held in 2n chromosome pairs, or sister chromatids). 

      • In prophase I, each pair of chromosomes lines up and matches with a homologous partner. This allows for the phenomenon of crossing over, where homologous portions of the chromosomes can rearrange and exchange portions of their DNA.

        • This is where things can get dicey for a particular type of uncommon aneuploidy, known as a translocation. 

          • That is, rather than recombining with a portion of the homologous chromosome, it attaches to a different chromosome.

          • These translocations can be:

            • Balanced, where the genetic information is not gained or lost, but just rearranged differently. 

              • So for example: A piece of chromosome 21 joins onto chromosome 14, and a piece of chromosome 14 joins onto the break at 21. 

                • The cell at this point still technically is diploid – but there can be problems with this later on!

            • Unbalanced, where the genetic information is split unequally.

              • In the same example: a piece of chromosome 21 joins onto 14, but the piece from 14 is lost.

          • A particular type of translocation is known as a Robertsonian translocation, which is where the full long arms of two acrocentric chromosomes are joined together.

            • The acrocentric chromosomes are where the short arms are extremely short - these are 13, 14, 15, 21, and 22 in humans.

            • One of the most discussed is a 14:21 translocation, which is responsible for some Down syndrome.

              • These translocations typically result in familial cases of aneuploidy, as a parent may be a balanced carrier of an abnormal chromosome – issues don’t arise for aneuploidy until they start trying to have children, and the chromosome complement ends up unbalanced in offspring.

      • In the female reproductive cycle, eggs arrest in the cell cycle at prophase I, and only complete the remainder of meiosis prior to that egg’s ovulation.

        • So an egg can be arrested for 30-40 years! 

        • Ultimately, with this extended pause, meiosis I in oocytes is where the majority of nondisjunction events occur.

      • To complete meiosis I:

        • Metaphase I: the homologous pair lines up across the metaphase plate (like a cell equator) to prepare for division

        • Anaphase I: the homologues are separated to the opposite ends of the cell

          • Or not, if they can’t be separated! – This is nondisjunction.

        • Telophase I: the new cells are haploid in chromosome pairs.

    • We then move to meiosis II, where the sister chromatids are split into haploid pairs:

      • Metaphase II: the sister chromatids line up across the metaphase plate.

      • Anaphase II: the sister chromatids are separated to the opposite ends of the cell.

        • This is another point where nondisjunction can occur (less common than in meiosis I, though)!

      • Telophase II: the new cells are haploid with 23 single chromosomes (no longer in pairs).

The robertsonian translocation and gamete production

Trisomy 21: Down Syndrome

  • Syndrome resulting from the addition of an extra chromosome 21. 

  • Most common aneuploidy: affects about 1 in 700 births in the USA.

  • Occurs via:

    • Nondisjunction event: 95% of occurrences

    • Robertsonian translocation: 5% of occurrences

    • Mosaicism: infrequent (~1-2% max)

      • This is where some cell lines have aneuploidy, and others do not. This occurs usually in early mitosis of the zygote, where the embryo during cell division recognizes the extra chromosome and tries to “kick it out” with aneuploidy rescue. We won’t spend too much time on that today! 

  • Prenatal testing characteristics of trisomy 21:

    • Cell free DNA: excellent test performance with 99% sensitivity and specificity.

      • However, false positives still occur frequently, particularly in low-prevalence populations (i.e., around 50% false-positive risk in women aged 25).

    • Serum screening: 

      • Low msAFP

      • Low estriol

      • High HCG

      • High inhibin A

    • Ultrasound:

      • 1st trimester: elevated NT (64-70%), absent/hypoplastic nasal bone.

      • 2nd trimester:

        • Various soft markers all have significance for T21: pyelectasis, echogenic bowel, echogenic cardiac focus, short femur.

        • Most significant soft marker: thickened nuchal fold (LR 11-18 for T21)

        • Practically pathognomonic findings:

          • “Double bubble sign” – duodenal atresia - familiarize yourself with this ultrasound as it’s very commonly tested!

          • Cardiac anomalies in ~50% – particularly significant / common are atrioventricular septal defects.

DOUBLE BUBBLE - RADIOPAEDIA

Trisomy 18: Edward syndrome 

  • Syndrome resulting from additional chromosome 18.

  • Frequency: about 1 in 2k - 6k live births in USA.

  • Occurs via:

    • Nondisjunction event: over 95% of cases

    • Mosaicism: around 4-5% of cases

    • Translocations: rare, but has been reported.

  • Prenatal testing characteristics:

    • Cell free DNA: good, with over 96% sensitivity and over 99% specificity.

      • However, given its infrequency, the positive-predictive value can still be low – 40% PPV in a woman at age 35. 

    • Serum screening:

      • All analytes decrease (though inhibin A can be normal).

    • Ultrasound:

      • 1st trimester: elevated NT, absent / hypoplastic nasal bone.

      • 2nd trimester: multiple characteristic signs:

        • Choroid plexus cysts are the most common soft-marker (though non-specific)

        • “Strawberry skull” – flattened occiput, pointed frontal bones

        • Clenched hands with overlapping fingers

        • Rocker-bottom feet

        • Cardiac anomalies

        • Esophageal atresia, diaphragmatic hernias

        • Growth restriction

STRAWBERRY SKULL

Trisomy 13: Patau syndrome

  • Syndrome resulting from additional chromosome 13

  • Frequency: about 1 in 10k-16k live births in USA

  • Occurs via:

    • Nondisjunction event: most common

    • Chromosome 13 is one of the acrocentric chromosomes so Robertsonian translocation can occur and familial forms have been reported.

    • Mosaicism is also possible.

  • Prenatal testing characteristics:

    • Cell free DNA: similar story to trisomy 18. Sensitivity is around 91% and specificity over 99%.

      • Given the low prevalence, positive-predictive values can still be low – around 20% for a woman at age 35. 

    • Serum screening:

      • No well-defined pattern, but elevated msAFP may be present given common CNS and other anomalies present in this syndrome.

    • Ultrasound:

      • 1st trimester: elevated NT, absent / hypoplastic nasal bone

      • 2nd trimester: multiple characteristic signs, but remember: midline and CNS are classic:

        • Holoprosencephaly: failure to divide brain into cerebral hemispheres (so no midline falx cerebri)

        • Facial anomalies: cleft lip/palate, proboscis, micropthalmia/anopthalmia or cyclops eye

        • Cardiac abnormalities - up to 80%

        • Omphalocele

        • Enlarged echogenic kidneys or horseshoe kidney

ALOBAR HOLOPROSENCEPALY - RADIOPAEDIA

Monosomy X: Turner Syndrome

  • Syndrome results from a missing sex chromosome - so 45, XO.

    • 80% of the time this is paternally derived – one of the few circumstances this is the case!

  • Frequency: 1 in 2k-5k live births

  • Occurs via:

    • Nondisjunction event: most common

      • On the paternal side, given the mismatch of X and Y, the Y chromosome can be subject to “getting lost” in meiosis.

    • Mosaicism can also occur with Turner syndrome in about 50% of individuals

      • Cell lines are able to be mixed as 45, XO/46, XX, or 45, XO / 46, XY most commonly

        • If Y chromosome is detected, gonadectomy is advised to reduce risk of gonadoblastoma in later life. 

  • Prenatal testing characteristics:

    • Cell free DNA: overall has about 90% sensitivity and over 99% specificity.

      • Similarly: PPV is limited by prevalence

      • cfDNA also has difficulty with mosaicism and delineating this specifically. 

    • Ultrasound:

      • The most commonly tested finding: cystic hygroma

        • Present in 1st and/or 2nd trimester

        • Can also present with more generalized edema

      • Horseshoe kidney, cardiac abnormalities may also be present.

CYSTIC HYGROMA - RADIOPAEDIA

Constipation

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What is constipation?

  • Infrequent and difficult defection.

    • Formally, constipation gets defined as three or fewer bowel movements per week.

  • In North America, chronic constipation is quite prevalent: estimated around 15%.

  • Chronic constipation is more prevalent in females, and in those over age 65.

    • However, pregnancy is another common time period for constipation to occur.

  • Before we get too deep into a discussion on stool, know we’ll be making mention today of the Bristol stool chart. 

    • Many of the diagnoses and considerations surrounding constipation, diarrhea, and IBS use this scale. It’s worth reviewing – probably the last time you looked was medical school! We’ll have one on the website.

WIKIPEDIA

Here are actual criteria to make a diagnosis of functional constipation known as the Rome IV criteria:

  • Functional constipation must be three months with:

    • 1) Loose stools rarely present without the use of laxatives

    • 2) Insufficient criteria to diagnose irritable bowel syndrome (IBS)

    • 3) Two or more of the following symptoms:

      • Straining during more than 25% of defecations

      • Lumpy or hard stools (Bristol scale 1 or 2) in more than 25% of defecations

      • Sensation of incomplete evacuation for more than 25% of defecations.

      • Sensation of anorectal obstruction/blockage for more than 25% of defecations.

      • Manual maneuvers to facilitate more than 25% of defecations (i.e., splinting or digital evacuation)

      • Fewer than three spontaneous bowel movements per week.

  • In terms of causes, there are three broad categories:

    • Normal transit constipation, which includes functional chronic constipation and IBS. 

    • Slow transit constipation, which can be due to a variety of factors like: 

      • medications that slow colonic transit (i.e., opioids) or 

      • medical disorders or conditions such as different systemic or neuromuscular diseases (i.e., severe diabetes, anorexia nervosa, pregnancy) or diseases of the colon (i.e., colorectal cancer, Hirschsprung’s disease)

    • Pelvic floor disorders, such as pelvic floor dysfunction after injury or trauma, or pelvic organ prolapse.

  • Constipation is usually not a life-threatening issue.

    • It is a major quality of life issue though!

    • Severe constipation can lead to colonic dilatation and perforation.

How to approach the patient with constipation

  • Start with history:

    • Get a sense of the problem, and whether there might be any major red flags:

      • Evaluate medications that may slow colonic transit.

        • Common meds that slow transit include:

          • Opioids, 

          • Antihistamines, 

          • Certain antidepressants and antipsychotics, 

          • Iron supplements,

          • Aluminum-based antacids, 

          • Serotonin antagonists (i.e., ondansetron/Zofran), 

          • and some antihypertensives like calcium channel blockers (i.e., nifedipine).

      • Ask about major red flags for colon cancer:

        • Presence of hematochezia, or positive fecal occult blood tests

        • Weight loss of > 10 lbs

        • Family history of colon cancer or inflammatory bowel disease

        • Acute onset of constipation particularly in older adults

      • Consider other medical conditions that may contribute to constipation, depending on the patient’s age and medical status:

        • Diabetes mellitus or other neuropathic disorders

        • Multiple sclerosis, Parkinson disease

        • Spinal cord injuries

        • Hypothyroidism

        • Pregnancy

        • Panhypopituitarism (i.e., Sheehan syndrome after postpartum hemorrhage)

        • Irritable bowel syndrome

          • IBS specifically encompasses abdominal pain that is recurrent, and can be associated with changes in stool (diarrhea or constipation).

          • The Rome IV criteria for IBS are having > 1 day per week of recurrent abdominal pain for at least three months, along with two or more of the following:

            • The pain is related to defecation (either increasing or relieving pain)

            • The pain is associated with a change in stool frequency

            • The pain is associated with a change in stool form (appearance on Bristol scale)

  • Consider a physical exam:

    • In most patients, a general physical exam is not super helpful.

    • A pelvic and rectal exam may be quite useful in those with chronic constipation:

      • Can identify evidence of chronic constipation, such as skin tags, fissures, hemorrhoids, or a fistula near the anus.

      • Can evaluate for prolapse and pelvic floor dysfunction.

        • Inspecting the anus, can ask the patient to squeeze like they’re holding a bowel movement to look for contraction of the sphincter and gluteal muscles.

        • Check for anal wink reflex to make sure sacral nerves intact.

        • Digital rectal exam to assess rectal tone, tenderness, and relaxation when finger is expelled.

  • In most patients with new complaints of constipation and no red flag symptoms, a trial of laxatives is appropriate before other major diagnostic workup.

    • Talk more about laxatives and treatments later!

  • If your patient needs some additional testing, others to consider (though probably with our GI colleagues!)

    • Anorectal manometry: a probe with sensors in the rectum to measure rectal and anal pressure, and the gradient with evacuation and squeeze. Similar in principle to urodynamics in urogynecology.

      • Can be accompanied with various tests such as a balloon expulsion test or balloon rectal sensitivity test, which can provide additional information.

    • Defecography: a radiocontrast study to evaluate what occurs during evacuation of rectal content to look for signs of prolapse or obstruction.

    • Sitz marker study or Nuclear medicine scintigraphy: radioopaque markers or tracers are swallowed and radiographs taken at certain intervals to evaluate transit within the bowel and colon.

Treating Constipation

  • There are loads of treatment options for constipation, so we’ll break them down mechanistically.

  • Fiber

    • First line treatment, and soluble fibers are recommended (beans, psyllium, oat bran, barley)

      • Soluble fibers attract water and turn to a gel-substance during digestion.

      • Insoluble fibers (wheat bran, vegetables, whole grain) add bulk to stool and help food pass more quickly.

        • Soluble fibers are generally preferred for constipation and are what are sold as supplements (i.e., psyllium is Metamucil and Benefiber). 

        • Soluble fibers can increase gas production though, and so in those with IBS and slow-transit constipation, it can be difficult to encourage compliance.

          • This can be modulated by starting with small amounts and slowly titrating upwards.

    • Recommended daily intake is >25g/day for women, and >35g/day for men.

  • Osmotic laxatives

    • These laxatives act as hyperosmolar solutions that are not systemically absorbed, and thus add water into the stool in order to increase stool frequency.

      • Examples: polyethylene glycol (GoLytely, MiraLax); lactulose; sorbitol; milk of magnesia, magnesium citrate.

    • They are highly effective and titratable to effect.

    • Excess use in patients with renal and cardiac dysfunction can lead to electrolyte abnormalities.

  • Stimulant laxatives

    • These alter electrolyte transport mechanisms in the intestinal mucosa, thus increasing their motor activity.

      • Examples: bisacodyl (Dulcolax), senna, sodium picosulfate

    • They are generally well-tolerated, but can produce abdominal discomfort in some patients due to the “irritation” effect on the intestines.

      • Some of these can be associated with developing hypokalemia, salt depletion, and significant enteric protein-wasting, so are not encouraged to be used chronically.

    • Some folks can develop tolerance to these medications, so are also not encouraged to be used chronically so that tolerance does not develop.

  • Biofeedback and Pelvic Floor Treatment

    • Pelvic floor PT, biofeedback training, and pelvic floor therapies with colorectal surgeons or urogynecologists can also be effective, especially if patients have symptoms of rectocele.

    • Other positioning tools for pelvic floor dysfunction include things like the “squatty potty” to encourage puborectalis muscle / sphincter relaxation.

  • Suppositories, Enemas, and Disimpaction

    • Bisacodyl suppositories are easy to use and can be considered first.

      • They can effectively liquefy stool and clear impaction in the rectum.

    • Various enemas exist: tap water, mineral oil, soap suds, phosphate, milk & molasses)

      • It is most important to focus on side effects - i.e., fleets enemas (phosphate) can lead to hyperphosphatemia, particularly in patients with kidney disease.

    • Manual disimpaction

      • Never fun, and not a lot of guidance on the best method – break stool up with your well-lubricated finger, and extract it, until the hardened stool is cleared.

      • Best followed up with a mineral oil enema or milk and molasses enema – will soften stool and provide lubrication.

        • If disimpaction is not successful, water-soluble contrast enema should be considered with fluoroscopy to evaluate for obstruction and rarely GI may need to be consulted for flexible or rigid sigmoidoscopy to evacuate stool.

  • What about docusate (Colace)?

    • Not the best evidence… likely no impact.

    • Journal of Hospital Medicine 2019: Things We Do For No Reason: Prescribing Colace for Constipation in Hospitalized Adults

      • Potentially over $100 million spent on colace annually across North America in hospitalized populations.

      • Multiple negative studies in randomized trials show that it does not improve or prevent constipation.

      • Recommend de-implementing it from order sets and hospital formularies.