Recurrent Pregnancy Loss

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Today we discuss a fortunately uncommon problem, but a difficult one to workup appropriately. Recurrent pregnancy loss is defined the American Society of Reproductive Medicine (ASRM) as two or more failed clinical pregnancies; though ideally a threshold of three or more is utilized for research purposes. It is estimated that less than 5% of women will experience 2 consecutive miscarriages, and less than 1% will experience three or more consecutive miscarriages. That said, the live birth rates are still excellent overall for women experiencing recurrent miscarriages:

ASRM

Let’s review the most common causes of RPL.

Unexplained: About 50-75% of couples with RPL have no explanation, but the below should be evaluated and ruled out.

Cytogenetic: These are abnormalities in chromosome number or structure. This accounts for at least 50% of early pregnancy loss!

  • Aneuploidy: risk of aneuploidy increases with increasing number of miscarriages.

  • Chromosomal rearrangements: 3-5% of couples with RPL have a major chromosomal rearrangement (vs. 0.7% in general population).

Cytogetnetic abnormalities can be evaluated by karyotyping to review for balanced reciprocal translocations. Preimplantation genetic screening can be used if other genetic causes are identified.

Antiphospholipid syndrome (APLS): 5-15% of patients with RPL may have APLS. The diagnosis of APLS is challenging to make, and requires the following criteria:

One of two clinical criteria:

  1. Vascular thrombosis 

  2. Pregnancy morbidity, defined as:

    1. One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

    2. One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

    3. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

And one of the following laboratory criteria 

  1. Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

  2. Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

  3. Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

If your patient is found to have APLAS, treatment is with heparin and aspirin.

Anatomic:

  • Uterine: congenital uterine anomalies are present in 10-15% of women with RPL, vs 7% of the general population. Additionally uterine leiomyoma, polyps, or adhesions can also be at play. Saline sonohysterogram or hysterosalpingogram can be used to evaluate the cavity.

Hormonal or metabolic 

  • Poorly controlled DM - associated with early and late pregnancy loss; several studies have linked high hemoglobin A1c values early in pregnancy (>8%) to increased frequency of miscarriages and congenital malformation.

  • PCOS - mechanism unknown, but miscarriage rate is as high as 20-40%.

  • Thyroid antibodies and disease - some studies have reported an increased rate of fetal loss in women with high serum thyroid antibody concentrations; also related to unexplained infertility and implantation failure.

  • Hyperprolactinemia - may be associated with RPL through alterations in the HPO axis.

  • Thrombophilia - association between hereditary thrombophilia and fetal loss have been suggested, but prospective cohort studies have failed to confirm this 

Psychologic 

  • There was a nonrandomized trial that looked at cohorts of couples with 3 or more consecutive pregnancy losses and no other identifiable etiology. These were divided into “standard care” vs “tender-loving care” or TLC group, consisting of psychologic support with weekly medical and ultrasonographic exams and instructions to avoid heavy work, travel, and sex. There was a 36% livebirth rate in the control group and 85% in the TLC group! 

Personal habits: There is no clear association between RPL and obesity, smoky, alcohol use, and caffeine consumption. That said, these may have some dose-dependent effect.

An Initial Infertility Evaluation

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Infertility is a problem with many social, economic, and psychological ramifications for patients presenting to an OB-GYN’s office, so it’s important to be able to start this work up with confidence. We’re here today to help!

We know somewhere between 82-92% of couples will conceive within 12 months of regular, unprotected intercourse; of those that don’t conceive in the first year, an additional 5-15% of couples will achieve conception within 24 months. So the odds of success are high, but may take some time. The frequency of infertility does climb with age, though: 7.3-9.1% among 15-34 year olds; 25% of 35-39 year olds; and 30% of 40-44 year olds. Infertility is defined based on these incidences:

  • 12 months of regular, unprotected intercourse without conception in women under age 35, or

  • 6 months of regular, unprotected intercourse in women over age 35.

These time frames are also the indication for our workup. Ideally, the first infertility visit should involve both partners; up to 26% of all infertility is provably male-factor in origin, and 6% of infertility may be related to coital problems! A history & physical for both partners can suggest where the workup will be most beneficial:

Female: 

  • PMH & PSH (ie. history of cancer, previous treatment? Ovarian surgery, uterine surgery?) 

  • Menstrual history

  • History of any previous pregnancies 

  • Social history: extensive smoking, drug use, etc.

  • Exam should focus on features of hyperandrogegism (i.e., PCOS), hyperinsulinism (i.e., uncontrolled DM or metabolic syndrome) or thyroid dysfunction, as well as assuring anatomy is present.

Male: 

  • History of testicular trauma, cancer, exposure to cytotoxic drugs 

  • History of previous children? 

From couple:

  • Regularity & timing of intercourse.

  • Sometimes it’s as simple as… are they having intercourse when patient is ovulating? Is he ejaculating within the vagina? 

When considering a laboratory & imaging workup, cost can be a challenging factor. Sometimes insurances require certain tests, or a certain sequence of tests, in order for coverage to be assured. Others don’t cover this testing at all, and thus it’s up to you to make the appropriate decisions to work out the reason for infertility in a couple. Testing ideally includes the following:

  • Semen analysis - for assessing male factor 

  • Some assessment of ovarian reserve 

    • Day three FSH and estradiol level 

    • Anti-Mullerian hormone

    • Antral follicle count 

      • Early cycle count of antral follicles; done on day 3 of cycle. What is normal is different at each institution, but can be 3-8 per ovary.

  • Assessment of uterine cavity with hysterosalpingogram or sonohysterogram 

    • Can test tube patency as well, though with sonohyst, if there is spilling of fluid, that only confirms that at least 1 tube is patent.

  • TSH, A1c, PRL.

In deciding on your workup, keep in mind the most common causes of infertility: a semen analysis will almost always be indicated! These all add up to >100% because some couples will have multiple reasons.

  1. Unexplained: 28% 

  2. Male factor (ie. hypogonadism, post-testicular defects, seminiferous tubule dysfunction) = 26% 

  3. Ovulatory dysfunction: 21% 

  4. Tubal damage: 14% 

  5. Endometriosis: 6% 

  6. Coital problems: 6% 

Preventing the Primary Cesarean Section

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This mega-episode was inspired by a two-part Grand Rounds series written by our PGY-4 Brown OBGYN class. We’ll dive into some of the history of cesarean, the challenges and data with respect to deciding on cesarean delivery, and current evidence-based strategies to reduce the risk of primary cesarean in low-risk women.

Cesarean sections have been around for a long time, the very first of which was documented around 1750 BC. However, surgery was originally performed only on a dead or dying mom with the hope of saving the child, or so the infant could be buried separately from mom per religious edicts. And then for the first 3000 years of cesarean, the mortality rate for women was… 100%. And it stayed this way until the mid-18th century! Anesthesia was introduced in 1846 with the discovery of ether, and as the 19th century progressed sutures and antibiotics became live-saving measures that allowed women to survive cesarean.

With the urbanization of the western world through this time period, more women began to deliver in hospitals as cesarean became a viable alternative, rather than delivering at home. In the USA, by 1955, 99% of births occurred in hospital. The rate of cesarean in the US stayed low until the 1970s, which coincided with the introduction of electronic fetal monitoring. A cesarean rate of <10% prior to EFM increased to 17% by 1980, 25% by 1988, and 31.9% in 2016.

Now with the increased use of cesarean, we should expect some benefit to it. And there certainly are! There are life-saving implications for both mother and baby, and when needed, the surgery is absolutely a necessary tool for an obstetrician. That said, cesarean does not come without its own risks. For mothers, cesarean is associated with more risk of bleeding, infection, thrombosis, increased pain, worse satisfaction with the birth experience, and risks to future pregnancy such as increased risk of repeat cesarean and risk of placenta accreta spectrum (PAS) disorders. For infants, cesarean carries slightly higher risks of respiratory difficulty during the transition, breastfeeding difficulty, and intracranial hemorrhage (if laboring prior to cesarean; rates of IVH between SVD and non-laboring cesarean are about equal).

One of the criticisms of cesarean delivery are that its use does not seem standardized. There is a high level of variation between countries, and in the US, there is high variation between states, cities, and even hospitals in the same city! As an example, here are the nulliparous term singleton vertex (NTSV) cesarean rates between US states for 2016:

While no rate of cesarean has proven to be the “optimal” or “ideal” amount, some observational data may provide some clues. The WHO has compared countries’ rates of cesarean with respect to both maternal and neonatal mortality, and also attempted to normalize these countries’ resources by demonstrating their relative wealth. For both maternal and neonatal mortality benefit, the rate seems to sit around 20% — you can see these graphs from the WHO below.

In order to safely choose our use of cesarean delivery, there are evidence-based guidelines to recall. The ACOG/SMFM Obstetric Care Consensus #1 on safe prevention of the primary cesarean delivery is one such tool. In this document, there are three important thresholds to remember. This is nicely outlined in checklist format by the folks at the California Maternal Health Quality Collaborative (CMQCC):

The use of partographs also has some limited data to support their use to help monitor labor progress. While one version over another hasn’t been shown to be superior, in a before-and-after study, the presence of their use helped to reduce cesarean rates, likely because of the closer attention to normal labor progress that was effected by them.

We additionally came across some other exciting ways to try to help reduce cesarean rates or examine cesarean utilization. Some of these things include:

  • Open Access to Cesarean Data 

    • Beth Israel Deaconess’ NTSV rate was a target of a large, stepwise quality project, with a decrease from 35% to 21% over 8 years. However, their single best year of improvement was from 2014-2015, when cesarean data was fully unmasked and shared amongst all physicians who practiced there. Similar findings have been demonstrated in the CMQCC hospitals. Simply put, no one likes to be an outlier amongst their peers!

  • Cesarean Audit Committees

    • These committees meet to review all unplanned cesarean delivery, prepare and interpret data, and look for opportunities for improvement in terms of physician/midwife, nurse, or patient education.

      • These committees offer the advantage of individualized feedback for improvement of practice based on more nuanced classifications that adjust for risk in population than just “NTSV.” 

      • Meta-analyses have demonstrated reduced cesarean rates stemming from a cesarean audit in concert with multifaceted programs to reduce cesarean delivery.

  • Utilizing Labor Dystocia Checklists

    • Several quality collaborative groups use checklists, such as the one from CMQCC above; these are evidence-based, objective, and don’t call into question a provider’s interpretation of labor progress. 

      • Overall decrease PCS by preventing premature C/S for indications of labor dystocia. 

      • Some institutions have gone as far as to institute “double doctor” reviews for cesarean for labor arrest, allowing for a second opinion, particularly regarding the feasibility of operative vaginal delivery.

  • Improved, transparent team communication 

    • Improved communication between physician or midwife, bedside nurse, patient, and support persons allows for appropriate expectations for labor or induction, and allows all members of the team to “be on the same page.”

    • At our institution, we are trialing using a whiteboard to document the partograph in the labor room; this allows the patient to compare patient to where they are on partograph compared to “standard labor progress.”

Have a technique you’re using at your hospital to help reduce primary cesarean delivery? Share it with us! We’d love to hear from you via email or the comments section of the website.

Chorioamnionitis and Endometritis

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Today we dive into intraamniotic infection (IAI), more commonly known as chorioamnionitis or endometritis. CO 712 reviews a lot of the surprisingly limited evidence on the management of IAI, and the essentials you need to know for your labor floor and for CREOGs.

IAI is an important topic because of its morbidity. 2-5% of term deliveries are complicated by chorioamnionitis. It is associated with acute neonatal morbidity, including things such as pneumonia, meningitis, sepsis, and death. Treatment intrapartum is associated with an over 10-fold decrease in GBS-neonatal sepsis. Maternal morbidities include dysfunctional labor curves that lead to further intervention, increased risk of postpartum hemorrhage due to atony, and peritonitis, sepsis, ARDS, and rarely death.

Risk factors for IAI include a longer length of labor and longer length of ROM. Additionally, it is thought that multiple digital vaginal exams in the setting of ROM  can increase risk. Other, less obvious risk factors include cervical insufficiency, nulliparity, meconium-stained fluid, use of internal fetal or uterine contraction monitoring, presence of genital tract pathogens (ie. STIs, GBS, BV), alcohol and tobacco use, and of course previous history of chorioamnionitis.

The gold standard diagnosis is made off of a gram stain or culture of amniotic fluid, but this is obviously problematic! So in reality, there are three categories of IAI or IAI-risk that help guide clinicians into deciding therapy:

  1. Isolated Maternal Fever: Single oral temperature of 39 C or greater OR an oral temperature of 38-38.9 C that persists when the temp is repeated after 30 minutes.

  2. Suspected intraamniotic infection: Based on clinical criteria, which includes maternal fever PLUS one of maternal leukocytosis, fetal tachycardia, or purulent or malodorous amniotic fluid. 

  3. Confirmed intraamniotic infection: Based on the gold standard of culture/gram stain.

Does every fever intrapartum need to be treated?

There are lots of things that can cause fever intrapartum or immediately postpartum other than chorioamnionitis, such as:

  • Misoprostol use and other types of drug fevers.

  • Epidural use.

  • Other sources of infection (ie. UTI, respiratory infection).

  • Also… being in a hot room (girl, labor is hard work)!

For isolated maternal fever of 38-38.9, CO 712 states that without other clinical criteria indicating infection and with/without persistent temperature elevation: 

  1. Few data exist to guide appropriate management of women with isolated intrapartum fever in absence of other clinical signs suggesting intra-amniotic infection.

  2. Consider antibiotics, but should definitely still communicate to pediatric team.

Our tendency is to treat persistent temperatures in this range in most cases.

Antibiotic Therapy: from CO 712:

ACOG CO 712

Once postpartum, antibiotics should not need to continue based on principle. Instead, antimicrobial therapy should be based on risk factors for postpartum endometritis:

  • Women who deliver vaginally may NOT require antibiotics postpartum as they are less likely to develop endometritis.

    1. However, give an additional dose if bacteremia or persistent fever are present.

  • Women undergoing cesarean deliveries should receive at least one additional dose of antimicrobial agents after delivery is recommended.

    1. One additional dose of chosen regimen + clindamycin 900 mg IV or metronidazole 500 mg IV.

Postpartum endometritis occurs when infection is not totally cleared out after delivery and affects the endometrium. Risk factors include chorioamnionitis, cesarean delivery, prolonged labor or ROM, manual placental removal, and all the chorioamnionitis risk factors above.

The diagnosis is based on the presence of postpartum fever, along with tachycardia, uterine tenderness, foul smelling lochia, and/or leukocytosis.

Treating endometritis occurs most commonly with clindamycin and gentamicin, with the addition of ampicillin (“triple therapy”) for GBS-positive patients. The patient should be treated until 24-48 hours afebrile. Additional oral antibiotic therapy after successful IV therapy is not required as RCTs have demonstrated no improved outcomes. And of course if someone isn’t looking better, consider source control measures (i.e., D&C for retained POCs) or a different source of infection.