OBG Management

In 1992, the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) published their first joint guidelines on the prevention of early-onset neonatal group B streptococcal (GBS) infection.¹ In this initial statement, the organizations recommended universal culturing of obstetric patients at 28 weeks’ gestation and treatment of colonized women during labor if they had a recognized risk factor for neonatal GBS infection.

In 1996, the Centers for Disease Control and Prevention (CDC) published its first set of official guidelines on the topic and suggested that both universal screening and a risk-factor–based approach were reasonable options.² The 2002 update of the CDC guidelines strongly recommended universal screening of all pregnant women at 35 to 37 weeks’ gestation and intrapartum prophylaxis for all colonized women regardless of risk factors.³

The third set of CDC guidelines was published in 2010.⁴ The key features of this version were the elimination of erythromycin as an alternative to penicillin in patients who are allergic to beta-lactam antibiotics and the establishment of 4 hours as the critical interval for administration of prophylaxis prior to delivery. The 2010 publication was the last such report from the CDC. Since then ACOG and AAP have been tasked with providing updated practice guidelines. To that end, ACOG recently issued a new Committee Opinion on “Prevention of Group B Streptococcal Early-Onset Disease in Newborns.”⁵ Here we will highlight the key features of our current strategy for preventing neonatal GBS infection.

CASE Pregnant patient presents with many questions about GBS

A 26-year-old primigravid woman presents for her first prenatal appointment at 9 weeks’ gestation. Her older sister recently delivered a term infant that died in the first week of life from GBS sepsis. Understandably, she has many questions.

1. Your patient first wants to know, “What is this streptococcal organism and how likely am I to have this infection?”

Streptococcus agalactiae, also known as GBS, is a gram-positive encapsulated bacterium that produces beta hemolysis when grown on blood agar. Approximately 25% of pregnant women harbor this organism in the lower genital tract and/or rectum.⁶

GBS is one of the most important causes of neonatal infection, particularly in preterm infants. The frequency of infection is now 0.23 per 1,000 live births in the US.⁵

Neonatal infection can be divided into early-onset infection (occurring within the first 7 days of life) and late-onset infection (occurring from after the first week until the third month of life). Approximately 80% to 85% of cases of neonatal GBS infections are early in onset. Virtually all of the early-onset infections result from vertical transmission during delivery from a colonized mother to her infant.^5-7

2. “How dangerous is this infection to my baby and me? Are there certain factors that increase the risk of my baby becoming infected?”

GBS is responsible for approximately 2% to 3% of cases of either asymptomatic bacteriuria or acute cystitis. Women with urinary tract infections caused by GBS are at increased risk for preterm premature rupture of membranes and preterm delivery. Genital tract colonization also increases a woman’s risk for chorioamnionitis and endometritis, particularly after cesarean delivery (CD). In addition, GBS can be part of the polymicrobial flora in women who have a wound (incisional site) infection following CD.^6,7

Continue to: In colonized women, several risk factors...

In colonized women, several risk factors have been identified that increase the probability of early-onset neonatal GBS infection. These factors include: preterm labor, especially when complicated by premature rupture of membranes; intrapartum maternal fever (usually due to chorioamnionitis); rupture of membranes greater than 18 hours before delivery; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. Approximately 25% of colonized women will have one of these risk factors.^5-7

These risk factors have a profound impact on neonatal attack rates and mortality. Without the interventions outlined below, the neonatal infection rate is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present, but is less than 5% when risk factors are absent.^5-7

3. “What will you do to determine if I am colonized with this organism?”

The current guidelines set forth in the ACOG Committee Opinion recommend that selected high-risk patients (patients with preterm labor or preterm premature rupture of membranes) be tested for GBS at the time of initial presentation. All other women should be tested for GBS during the interval 36 0/7 to 37 6/7 weeks’ gestation.⁵ Testing at this point in pregnancy is almost 90% sensitive for identifying patients who will be colonized at the time of admission for labor if no more than 5 weeks elapse between the time the culture is obtained and labor begins. The positive predictive value of this test is 87%, and the negative predictive value is 96%.⁸

ACOG’s previous guidelines provided for testing at 35 rather than 36 weeks. The change in the recommendations was based on 2 factors. First, all women with unknown GBS status who may deliver before 37 weeks already should be targeted for prophylaxis. Second, the new 5-week window now will include women who deliver up to 41 weeks’ gestation. Given current obstetric practice in the US, delivery beyond 41 weeks is unlikely.⁵

At the present time, the best test for identification of GBS colonization is bacteriologic culture. A cotton swab is placed into the lower third of the vagina, streaked along the perineum, and then placed into the rectum. The swab is withdrawn, placed in a culturette tube, and transported to the laboratory. In the laboratory, the swab is cultured for approximately 24 hours in a nutrient broth and then subcultured on a selective blood agar plate. Failure to sample both the vagina and rectum or failure to use selective broth and selective blood agar will reduce the yield of positive cultures by approximately 50%.^5-7

In recent years, researchers have become interested in the use of rapid nucleic acid amplification tests for the identification of GBS. These tests perform well if the test protocol provides for an 18- to 24-hour incubation in nutrient broth prior to application of the nucleic acid probe. When the tests are performed without this enrichment phase, sensitivities are inferior to those associated with bacteriologic culture. In addition, because the rapid tests do not isolate the organisms, they do not allow for antibiotic sensitivity testing.^5-7

Continue to: “If I test positive for GBS, how and when will you treat me?”...

4. “If I test positive for GBS, how and when will you treat me?”

The current ACOG guidelines recommend that all colonized women be treated intrapartum with prophylactic antibiotics regardless of whether risk factors are present. Treatment should be started at the time of admission and continued until the infant is delivered.⁵

The drugs of choice for intrapartum prophylaxis are intravenous penicillin or ampicillin. If the patient has a mild allergy to penicillin, cefazolin is the appropriate alternative. If the patient has a severe allergy to penicillin, the 2 options are vancomycin or clindamycin. If the latter drug is used, the laboratory must perform sensitivity testing because 13% to 20% of strains of GBS may be resistant to clindamycin. The frequency of resistance to erythromycin now ranges from 25% to 32%. Thus, erythromycin is no longer used for intrapartum prophylaxis.^5-7,9

The appropriate intravenous dosages of these antibiotics are listed in the TABLE.⁵ The new ACOG guidelines have revised the previous recommendations for dosing of penicillin, eliminating the 2.5 million-unit dose. They also have revised the dosing recommendations for vancomyin, eliminating the previous recommendation of 1 g every 12 hours.⁵ The new recommendations regarding vancomycin are particularly important and are based, at least in part, on an interesting report from Onwuchuruba and colleagues.¹⁰ These authors studied maternal and cord blood concentrations of vancomycin in mother-infant dyads receiving either the original recommended dosage of vancomycin (1 g every 12 hours) or a dosage of 15 to 20 mg/kg every 8 hours. With standard dosing, only 9% of neonates had therapeutic vancomycin serum concentrations at delivery. With the 20 mg/kg dose of vancomycin, the percent of neonates with therapeutic serum concentrations of vancomycin increased to 80%.

5. “For how long must I be treated in labor before my baby will be protected by the antibiotics?”

The current ACOG Committee Opinion stresses the importance of treating the colonized mother for at least 4 hours prior to delivery.⁵ This recommendation is based primarily on the landmark report by De Cueto and colleagues.¹¹ These authors evaluated colonized women who received intrapartum prophylaxis at varying times prior to delivery. Their primary endpoint was the percentage of newborns who were colonized with GBS. If the mothers had received antibiotics for less than 1 hour prior to delivery, 46% of neonates were colonized. This figure was equal to the rate of colonization in neonates whose mothers received no antibiotics. When the interval was 1 to 2 hours, the percentage was 29%. When mothers had received antibiotics for 2 to 4 hours, the neonatal colonization rate fell to 2.9%. When antibiotics had been administered for greater than 4 hours, the rate of neonatal colonization was only 1.2%.

Fairlie and colleagues recently reported the results of another interesting investigation comparing the effectiveness of prophylaxis based on duration of treatment and choice of individual antibiotics.¹² Prophylaxis with penicillin or ampicillin for 4 hours or more was 91% effective in preventing early-onset neonatal infection in term infants and 86% effective in preventing infection in preterm infants. These outcomes were superior to the outcomes in both term and preterm infants who received penicillin or ampicillin for less than 4 hours.

Continue to: “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”...

6. “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”

If a mother is scheduled to have a CD, for example because of a prior cesarean or because of a persistent fetal malpresentation, she should still have a GBS culture at 36 0/7 to 37 6/7 weeks’ gestation. The information obtained from this culture may be of value to both the obstetrician and pediatrician if the patient experiences labor or rupture of membranes prior to her scheduled surgery. If she does not experience spontaneous labor prior to her scheduled date of surgery, she does not require specific GBS prophylaxis at the time of her operation.⁵ Rather, she should receive prophylactic antibiotics to prevent post–cesarean infection, ideally, the combination of cefazolin (2 g IV) plus azithromycin (500 mg IV).¹⁴ Cefazolin, of course, provides excellent coverage of GBS.

7. “If I am colonized with GBS and I receive treatment during labor, will my baby be safe after delivery?”

The interventions outlined above will prevent almost 90% of early-onset GBS infections, but they are not foolproof.^5-7,15,16 Successful management of the neonate is dependent upon several factors, including:^5-7

• gestational age
• presence of maternal chorioamnionitis
• presence or absence of risk factors for early-onset infection
• duration (adequacy) of maternal treatment during labor
• presence of immediate clinical signs of infection in the neonate (such as fever, lethargy, hemodynamic instability, respiratory distress, or elevated or decreased white blood cell count).

If the mother is at term and receives intrapartum prophylaxis for at least 4 hours prior to delivery, the neonate usually will not require any special tests and simply will be observed for 24 to 48 hours for signs of infection.

If the mother delivers preterm and receives appropriate intrapartum prophylaxis, the pediatricians typically will obtain a complete blood count (CBC) and treat with prophylactic antibiotics (ampicillin plus gentamicin) for 48 hours if abnormalities are noted on the CBC or the baby exhibits signs of infection. If the CBC is normal and the baby shows no signs of infection, no treatment is indicated.

Regardless of gestational age, if the mother does not receive prophylaxis for at least 4 hours before delivery, the pediatricians usually will obtain a CBC and closely observe the baby in the hospital for signs of infection. If such signs develop or the CBC is abnormal, blood and cerebrospinal fluid cultures will be obtained. Antibiotic therapy (usually ampicillin plus gentamicin) is then initiated, and the drugs are continued until cultures return with no growth. If either culture is positive, antibiotics will then be continued for 7 to 10 days.

If the mother has documented chorioamnionitis and receives treatment intrapartum with appropriate antibiotics (usually ampicillin plus gentamicin), the pediatricians usually will obtain a CBC, C-reactive protein (CRP) level, and blood cultures and then start the infant on antibiotics, pending the result of the laboratory tests. If the CBC and CRP are reassuring, the cultures are negative after 48 hours, and the infant demonstrates no signs of clinical infection, many pediatricians will then discontinue antibiotics. Others may still continue the antibiotics for 7 to 10 days.

In 1992, the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) published their first joint guidelines on the prevention of early-onset neonatal group B streptococcal (GBS) infection.¹ In this initial statement, the organizations recommended universal culturing of obstetric patients at 28 weeks’ gestation and treatment of colonized women during labor if they had a recognized risk factor for neonatal GBS infection.

In 1996, the Centers for Disease Control and Prevention (CDC) published its first set of official guidelines on the topic and suggested that both universal screening and a risk-factor–based approach were reasonable options.² The 2002 update of the CDC guidelines strongly recommended universal screening of all pregnant women at 35 to 37 weeks’ gestation and intrapartum prophylaxis for all colonized women regardless of risk factors.³

The third set of CDC guidelines was published in 2010.⁴ The key features of this version were the elimination of erythromycin as an alternative to penicillin in patients who are allergic to beta-lactam antibiotics and the establishment of 4 hours as the critical interval for administration of prophylaxis prior to delivery. The 2010 publication was the last such report from the CDC. Since then ACOG and AAP have been tasked with providing updated practice guidelines. To that end, ACOG recently issued a new Committee Opinion on “Prevention of Group B Streptococcal Early-Onset Disease in Newborns.”⁵ Here we will highlight the key features of our current strategy for preventing neonatal GBS infection.

CASE Pregnant patient presents with many questions about GBS

A 26-year-old primigravid woman presents for her first prenatal appointment at 9 weeks’ gestation. Her older sister recently delivered a term infant that died in the first week of life from GBS sepsis. Understandably, she has many questions.

1. Your patient first wants to know, “What is this streptococcal organism and how likely am I to have this infection?”

Streptococcus agalactiae, also known as GBS, is a gram-positive encapsulated bacterium that produces beta hemolysis when grown on blood agar. Approximately 25% of pregnant women harbor this organism in the lower genital tract and/or rectum.⁶

GBS is one of the most important causes of neonatal infection, particularly in preterm infants. The frequency of infection is now 0.23 per 1,000 live births in the US.⁵

Neonatal infection can be divided into early-onset infection (occurring within the first 7 days of life) and late-onset infection (occurring from after the first week until the third month of life). Approximately 80% to 85% of cases of neonatal GBS infections are early in onset. Virtually all of the early-onset infections result from vertical transmission during delivery from a colonized mother to her infant.^5-7

2. “How dangerous is this infection to my baby and me? Are there certain factors that increase the risk of my baby becoming infected?”

GBS is responsible for approximately 2% to 3% of cases of either asymptomatic bacteriuria or acute cystitis. Women with urinary tract infections caused by GBS are at increased risk for preterm premature rupture of membranes and preterm delivery. Genital tract colonization also increases a woman’s risk for chorioamnionitis and endometritis, particularly after cesarean delivery (CD). In addition, GBS can be part of the polymicrobial flora in women who have a wound (incisional site) infection following CD.^6,7

Continue to: In colonized women, several risk factors...

In colonized women, several risk factors have been identified that increase the probability of early-onset neonatal GBS infection. These factors include: preterm labor, especially when complicated by premature rupture of membranes; intrapartum maternal fever (usually due to chorioamnionitis); rupture of membranes greater than 18 hours before delivery; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. Approximately 25% of colonized women will have one of these risk factors.^5-7

These risk factors have a profound impact on neonatal attack rates and mortality. Without the interventions outlined below, the neonatal infection rate is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present, but is less than 5% when risk factors are absent.^5-7

3. “What will you do to determine if I am colonized with this organism?”

The current guidelines set forth in the ACOG Committee Opinion recommend that selected high-risk patients (patients with preterm labor or preterm premature rupture of membranes) be tested for GBS at the time of initial presentation. All other women should be tested for GBS during the interval 36 0/7 to 37 6/7 weeks’ gestation.⁵ Testing at this point in pregnancy is almost 90% sensitive for identifying patients who will be colonized at the time of admission for labor if no more than 5 weeks elapse between the time the culture is obtained and labor begins. The positive predictive value of this test is 87%, and the negative predictive value is 96%.⁸

ACOG’s previous guidelines provided for testing at 35 rather than 36 weeks. The change in the recommendations was based on 2 factors. First, all women with unknown GBS status who may deliver before 37 weeks already should be targeted for prophylaxis. Second, the new 5-week window now will include women who deliver up to 41 weeks’ gestation. Given current obstetric practice in the US, delivery beyond 41 weeks is unlikely.⁵

At the present time, the best test for identification of GBS colonization is bacteriologic culture. A cotton swab is placed into the lower third of the vagina, streaked along the perineum, and then placed into the rectum. The swab is withdrawn, placed in a culturette tube, and transported to the laboratory. In the laboratory, the swab is cultured for approximately 24 hours in a nutrient broth and then subcultured on a selective blood agar plate. Failure to sample both the vagina and rectum or failure to use selective broth and selective blood agar will reduce the yield of positive cultures by approximately 50%.^5-7

In recent years, researchers have become interested in the use of rapid nucleic acid amplification tests for the identification of GBS. These tests perform well if the test protocol provides for an 18- to 24-hour incubation in nutrient broth prior to application of the nucleic acid probe. When the tests are performed without this enrichment phase, sensitivities are inferior to those associated with bacteriologic culture. In addition, because the rapid tests do not isolate the organisms, they do not allow for antibiotic sensitivity testing.^5-7

Continue to: “If I test positive for GBS, how and when will you treat me?”...

4. “If I test positive for GBS, how and when will you treat me?”

The current ACOG guidelines recommend that all colonized women be treated intrapartum with prophylactic antibiotics regardless of whether risk factors are present. Treatment should be started at the time of admission and continued until the infant is delivered.⁵

The drugs of choice for intrapartum prophylaxis are intravenous penicillin or ampicillin. If the patient has a mild allergy to penicillin, cefazolin is the appropriate alternative. If the patient has a severe allergy to penicillin, the 2 options are vancomycin or clindamycin. If the latter drug is used, the laboratory must perform sensitivity testing because 13% to 20% of strains of GBS may be resistant to clindamycin. The frequency of resistance to erythromycin now ranges from 25% to 32%. Thus, erythromycin is no longer used for intrapartum prophylaxis.^5-7,9

The appropriate intravenous dosages of these antibiotics are listed in the TABLE.⁵ The new ACOG guidelines have revised the previous recommendations for dosing of penicillin, eliminating the 2.5 million-unit dose. They also have revised the dosing recommendations for vancomyin, eliminating the previous recommendation of 1 g every 12 hours.⁵ The new recommendations regarding vancomycin are particularly important and are based, at least in part, on an interesting report from Onwuchuruba and colleagues.¹⁰ These authors studied maternal and cord blood concentrations of vancomycin in mother-infant dyads receiving either the original recommended dosage of vancomycin (1 g every 12 hours) or a dosage of 15 to 20 mg/kg every 8 hours. With standard dosing, only 9% of neonates had therapeutic vancomycin serum concentrations at delivery. With the 20 mg/kg dose of vancomycin, the percent of neonates with therapeutic serum concentrations of vancomycin increased to 80%.

5. “For how long must I be treated in labor before my baby will be protected by the antibiotics?”

The current ACOG Committee Opinion stresses the importance of treating the colonized mother for at least 4 hours prior to delivery.⁵ This recommendation is based primarily on the landmark report by De Cueto and colleagues.¹¹ These authors evaluated colonized women who received intrapartum prophylaxis at varying times prior to delivery. Their primary endpoint was the percentage of newborns who were colonized with GBS. If the mothers had received antibiotics for less than 1 hour prior to delivery, 46% of neonates were colonized. This figure was equal to the rate of colonization in neonates whose mothers received no antibiotics. When the interval was 1 to 2 hours, the percentage was 29%. When mothers had received antibiotics for 2 to 4 hours, the neonatal colonization rate fell to 2.9%. When antibiotics had been administered for greater than 4 hours, the rate of neonatal colonization was only 1.2%.

Fairlie and colleagues recently reported the results of another interesting investigation comparing the effectiveness of prophylaxis based on duration of treatment and choice of individual antibiotics.¹² Prophylaxis with penicillin or ampicillin for 4 hours or more was 91% effective in preventing early-onset neonatal infection in term infants and 86% effective in preventing infection in preterm infants. These outcomes were superior to the outcomes in both term and preterm infants who received penicillin or ampicillin for less than 4 hours.

Continue to: “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”...

6. “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”

If a mother is scheduled to have a CD, for example because of a prior cesarean or because of a persistent fetal malpresentation, she should still have a GBS culture at 36 0/7 to 37 6/7 weeks’ gestation. The information obtained from this culture may be of value to both the obstetrician and pediatrician if the patient experiences labor or rupture of membranes prior to her scheduled surgery. If she does not experience spontaneous labor prior to her scheduled date of surgery, she does not require specific GBS prophylaxis at the time of her operation.⁵ Rather, she should receive prophylactic antibiotics to prevent post–cesarean infection, ideally, the combination of cefazolin (2 g IV) plus azithromycin (500 mg IV).¹⁴ Cefazolin, of course, provides excellent coverage of GBS.

7. “If I am colonized with GBS and I receive treatment during labor, will my baby be safe after delivery?”

The interventions outlined above will prevent almost 90% of early-onset GBS infections, but they are not foolproof.^5-7,15,16 Successful management of the neonate is dependent upon several factors, including:^5-7

• gestational age
• presence of maternal chorioamnionitis
• presence or absence of risk factors for early-onset infection
• duration (adequacy) of maternal treatment during labor
• presence of immediate clinical signs of infection in the neonate (such as fever, lethargy, hemodynamic instability, respiratory distress, or elevated or decreased white blood cell count).

If the mother is at term and receives intrapartum prophylaxis for at least 4 hours prior to delivery, the neonate usually will not require any special tests and simply will be observed for 24 to 48 hours for signs of infection.

If the mother delivers preterm and receives appropriate intrapartum prophylaxis, the pediatricians typically will obtain a complete blood count (CBC) and treat with prophylactic antibiotics (ampicillin plus gentamicin) for 48 hours if abnormalities are noted on the CBC or the baby exhibits signs of infection. If the CBC is normal and the baby shows no signs of infection, no treatment is indicated.

Regardless of gestational age, if the mother does not receive prophylaxis for at least 4 hours before delivery, the pediatricians usually will obtain a CBC and closely observe the baby in the hospital for signs of infection. If such signs develop or the CBC is abnormal, blood and cerebrospinal fluid cultures will be obtained. Antibiotic therapy (usually ampicillin plus gentamicin) is then initiated, and the drugs are continued until cultures return with no growth. If either culture is positive, antibiotics will then be continued for 7 to 10 days.

If the mother has documented chorioamnionitis and receives treatment intrapartum with appropriate antibiotics (usually ampicillin plus gentamicin), the pediatricians usually will obtain a CBC, C-reactive protein (CRP) level, and blood cultures and then start the infant on antibiotics, pending the result of the laboratory tests. If the CBC and CRP are reassuring, the cultures are negative after 48 hours, and the infant demonstrates no signs of clinical infection, many pediatricians will then discontinue antibiotics. Others may still continue the antibiotics for 7 to 10 days.

In 1992, the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) published their first joint guidelines on the prevention of early-onset neonatal group B streptococcal (GBS) infection.¹ In this initial statement, the organizations recommended universal culturing of obstetric patients at 28 weeks’ gestation and treatment of colonized women during labor if they had a recognized risk factor for neonatal GBS infection.

In 1996, the Centers for Disease Control and Prevention (CDC) published its first set of official guidelines on the topic and suggested that both universal screening and a risk-factor–based approach were reasonable options.² The 2002 update of the CDC guidelines strongly recommended universal screening of all pregnant women at 35 to 37 weeks’ gestation and intrapartum prophylaxis for all colonized women regardless of risk factors.³

The third set of CDC guidelines was published in 2010.⁴ The key features of this version were the elimination of erythromycin as an alternative to penicillin in patients who are allergic to beta-lactam antibiotics and the establishment of 4 hours as the critical interval for administration of prophylaxis prior to delivery. The 2010 publication was the last such report from the CDC. Since then ACOG and AAP have been tasked with providing updated practice guidelines. To that end, ACOG recently issued a new Committee Opinion on “Prevention of Group B Streptococcal Early-Onset Disease in Newborns.”⁵ Here we will highlight the key features of our current strategy for preventing neonatal GBS infection.

CASE Pregnant patient presents with many questions about GBS

A 26-year-old primigravid woman presents for her first prenatal appointment at 9 weeks’ gestation. Her older sister recently delivered a term infant that died in the first week of life from GBS sepsis. Understandably, she has many questions.

1. Your patient first wants to know, “What is this streptococcal organism and how likely am I to have this infection?”

Streptococcus agalactiae, also known as GBS, is a gram-positive encapsulated bacterium that produces beta hemolysis when grown on blood agar. Approximately 25% of pregnant women harbor this organism in the lower genital tract and/or rectum.⁶

GBS is one of the most important causes of neonatal infection, particularly in preterm infants. The frequency of infection is now 0.23 per 1,000 live births in the US.⁵

Neonatal infection can be divided into early-onset infection (occurring within the first 7 days of life) and late-onset infection (occurring from after the first week until the third month of life). Approximately 80% to 85% of cases of neonatal GBS infections are early in onset. Virtually all of the early-onset infections result from vertical transmission during delivery from a colonized mother to her infant.^5-7

2. “How dangerous is this infection to my baby and me? Are there certain factors that increase the risk of my baby becoming infected?”

GBS is responsible for approximately 2% to 3% of cases of either asymptomatic bacteriuria or acute cystitis. Women with urinary tract infections caused by GBS are at increased risk for preterm premature rupture of membranes and preterm delivery. Genital tract colonization also increases a woman’s risk for chorioamnionitis and endometritis, particularly after cesarean delivery (CD). In addition, GBS can be part of the polymicrobial flora in women who have a wound (incisional site) infection following CD.^6,7

Continue to: In colonized women, several risk factors...

In colonized women, several risk factors have been identified that increase the probability of early-onset neonatal GBS infection. These factors include: preterm labor, especially when complicated by premature rupture of membranes; intrapartum maternal fever (usually due to chorioamnionitis); rupture of membranes greater than 18 hours before delivery; previous delivery of an infected infant; young age; and black or Hispanic ethnicity. Approximately 25% of colonized women will have one of these risk factors.^5-7

These risk factors have a profound impact on neonatal attack rates and mortality. Without the interventions outlined below, the neonatal infection rate is 40% to 50% in the presence of a risk factor and less than 5% in the absence of a risk factor. In infected infants, neonatal mortality approaches 30% to 35% when a maternal risk factor is present, but is less than 5% when risk factors are absent.^5-7

3. “What will you do to determine if I am colonized with this organism?”

The current guidelines set forth in the ACOG Committee Opinion recommend that selected high-risk patients (patients with preterm labor or preterm premature rupture of membranes) be tested for GBS at the time of initial presentation. All other women should be tested for GBS during the interval 36 0/7 to 37 6/7 weeks’ gestation.⁵ Testing at this point in pregnancy is almost 90% sensitive for identifying patients who will be colonized at the time of admission for labor if no more than 5 weeks elapse between the time the culture is obtained and labor begins. The positive predictive value of this test is 87%, and the negative predictive value is 96%.⁸

ACOG’s previous guidelines provided for testing at 35 rather than 36 weeks. The change in the recommendations was based on 2 factors. First, all women with unknown GBS status who may deliver before 37 weeks already should be targeted for prophylaxis. Second, the new 5-week window now will include women who deliver up to 41 weeks’ gestation. Given current obstetric practice in the US, delivery beyond 41 weeks is unlikely.⁵

At the present time, the best test for identification of GBS colonization is bacteriologic culture. A cotton swab is placed into the lower third of the vagina, streaked along the perineum, and then placed into the rectum. The swab is withdrawn, placed in a culturette tube, and transported to the laboratory. In the laboratory, the swab is cultured for approximately 24 hours in a nutrient broth and then subcultured on a selective blood agar plate. Failure to sample both the vagina and rectum or failure to use selective broth and selective blood agar will reduce the yield of positive cultures by approximately 50%.^5-7

In recent years, researchers have become interested in the use of rapid nucleic acid amplification tests for the identification of GBS. These tests perform well if the test protocol provides for an 18- to 24-hour incubation in nutrient broth prior to application of the nucleic acid probe. When the tests are performed without this enrichment phase, sensitivities are inferior to those associated with bacteriologic culture. In addition, because the rapid tests do not isolate the organisms, they do not allow for antibiotic sensitivity testing.^5-7

Continue to: “If I test positive for GBS, how and when will you treat me?”...

4. “If I test positive for GBS, how and when will you treat me?”

The current ACOG guidelines recommend that all colonized women be treated intrapartum with prophylactic antibiotics regardless of whether risk factors are present. Treatment should be started at the time of admission and continued until the infant is delivered.⁵

The drugs of choice for intrapartum prophylaxis are intravenous penicillin or ampicillin. If the patient has a mild allergy to penicillin, cefazolin is the appropriate alternative. If the patient has a severe allergy to penicillin, the 2 options are vancomycin or clindamycin. If the latter drug is used, the laboratory must perform sensitivity testing because 13% to 20% of strains of GBS may be resistant to clindamycin. The frequency of resistance to erythromycin now ranges from 25% to 32%. Thus, erythromycin is no longer used for intrapartum prophylaxis.^5-7,9

The appropriate intravenous dosages of these antibiotics are listed in the TABLE.⁵ The new ACOG guidelines have revised the previous recommendations for dosing of penicillin, eliminating the 2.5 million-unit dose. They also have revised the dosing recommendations for vancomyin, eliminating the previous recommendation of 1 g every 12 hours.⁵ The new recommendations regarding vancomycin are particularly important and are based, at least in part, on an interesting report from Onwuchuruba and colleagues.¹⁰ These authors studied maternal and cord blood concentrations of vancomycin in mother-infant dyads receiving either the original recommended dosage of vancomycin (1 g every 12 hours) or a dosage of 15 to 20 mg/kg every 8 hours. With standard dosing, only 9% of neonates had therapeutic vancomycin serum concentrations at delivery. With the 20 mg/kg dose of vancomycin, the percent of neonates with therapeutic serum concentrations of vancomycin increased to 80%.

5. “For how long must I be treated in labor before my baby will be protected by the antibiotics?”

The current ACOG Committee Opinion stresses the importance of treating the colonized mother for at least 4 hours prior to delivery.⁵ This recommendation is based primarily on the landmark report by De Cueto and colleagues.¹¹ These authors evaluated colonized women who received intrapartum prophylaxis at varying times prior to delivery. Their primary endpoint was the percentage of newborns who were colonized with GBS. If the mothers had received antibiotics for less than 1 hour prior to delivery, 46% of neonates were colonized. This figure was equal to the rate of colonization in neonates whose mothers received no antibiotics. When the interval was 1 to 2 hours, the percentage was 29%. When mothers had received antibiotics for 2 to 4 hours, the neonatal colonization rate fell to 2.9%. When antibiotics had been administered for greater than 4 hours, the rate of neonatal colonization was only 1.2%.

Fairlie and colleagues recently reported the results of another interesting investigation comparing the effectiveness of prophylaxis based on duration of treatment and choice of individual antibiotics.¹² Prophylaxis with penicillin or ampicillin for 4 hours or more was 91% effective in preventing early-onset neonatal infection in term infants and 86% effective in preventing infection in preterm infants. These outcomes were superior to the outcomes in both term and preterm infants who received penicillin or ampicillin for less than 4 hours.

Continue to: “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”...

6. “If I were to have a scheduled CD before the onset of labor and/or ruptured membranes, would I still need to receive antibiotics?”

If a mother is scheduled to have a CD, for example because of a prior cesarean or because of a persistent fetal malpresentation, she should still have a GBS culture at 36 0/7 to 37 6/7 weeks’ gestation. The information obtained from this culture may be of value to both the obstetrician and pediatrician if the patient experiences labor or rupture of membranes prior to her scheduled surgery. If she does not experience spontaneous labor prior to her scheduled date of surgery, she does not require specific GBS prophylaxis at the time of her operation.⁵ Rather, she should receive prophylactic antibiotics to prevent post–cesarean infection, ideally, the combination of cefazolin (2 g IV) plus azithromycin (500 mg IV).¹⁴ Cefazolin, of course, provides excellent coverage of GBS.

7. “If I am colonized with GBS and I receive treatment during labor, will my baby be safe after delivery?”

The interventions outlined above will prevent almost 90% of early-onset GBS infections, but they are not foolproof.^5-7,15,16 Successful management of the neonate is dependent upon several factors, including:^5-7

• gestational age
• presence of maternal chorioamnionitis
• presence or absence of risk factors for early-onset infection
• duration (adequacy) of maternal treatment during labor
• presence of immediate clinical signs of infection in the neonate (such as fever, lethargy, hemodynamic instability, respiratory distress, or elevated or decreased white blood cell count).

If the mother is at term and receives intrapartum prophylaxis for at least 4 hours prior to delivery, the neonate usually will not require any special tests and simply will be observed for 24 to 48 hours for signs of infection.

If the mother delivers preterm and receives appropriate intrapartum prophylaxis, the pediatricians typically will obtain a complete blood count (CBC) and treat with prophylactic antibiotics (ampicillin plus gentamicin) for 48 hours if abnormalities are noted on the CBC or the baby exhibits signs of infection. If the CBC is normal and the baby shows no signs of infection, no treatment is indicated.

Regardless of gestational age, if the mother does not receive prophylaxis for at least 4 hours before delivery, the pediatricians usually will obtain a CBC and closely observe the baby in the hospital for signs of infection. If such signs develop or the CBC is abnormal, blood and cerebrospinal fluid cultures will be obtained. Antibiotic therapy (usually ampicillin plus gentamicin) is then initiated, and the drugs are continued until cultures return with no growth. If either culture is positive, antibiotics will then be continued for 7 to 10 days.

If the mother has documented chorioamnionitis and receives treatment intrapartum with appropriate antibiotics (usually ampicillin plus gentamicin), the pediatricians usually will obtain a CBC, C-reactive protein (CRP) level, and blood cultures and then start the infant on antibiotics, pending the result of the laboratory tests. If the CBC and CRP are reassuring, the cultures are negative after 48 hours, and the infant demonstrates no signs of clinical infection, many pediatricians will then discontinue antibiotics. Others may still continue the antibiotics for 7 to 10 days.

Gestational diabetes mellitus (GDM) generally is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.^1-14 The best approach and exact criteria to use for GDM screening and diagnosis are under worldwide debate. In TABLE 1 we present just some of the many differing suggestions by varying organizations.^{2,7-9,11,12,15-17} The American College of Obstetricians and Gynecologists, for instance, suggests a Two Step approach to diagnosis.¹⁵ We will make the argument in this article, however, that diagnosis should be defined universally as an abnormal result with the One Step 75-g glucose testing, as adopted by the World Health Organization, International Federation of Gynecology and Obstetrics, and others. Approximately 8% of all pregnancies are complicated by GDM by the One Step test in the United States.^18-22 The prevalence may range from 1% to 14% of all pregnancies, depending on the population studied and the diagnostic tests employed.^1,19

Diagnostic options

Different methods for screening and diagnosis of GDM have been proposed by international societies; there is controversy regarding the diagnosis of GDM by either the One Step or the Two Step approach.⁶

The One Step approach includes an oral glucose tolerance test with a 75-g glucose load with measurement of plasma glucose concentration at fasting state and 1 hour and 2 hours post–glucose administration. A positive result for the One Step approach is defined as at least 1 measurement higher than 92, 180, or 153 mg/dL at fasting, 1 hour, or 2 hours, respectively.

The Two Step approach includes a nonfasting oral 50-g glucose load, with a glucose blood measurement 1 hour later. A positive screening, defined often as a blood glucose value higher than 135 mg/dL (range, 130 to 140 mg/dL), is followed by a diagnostic test with a 100-g glucose load with measurements at fasting and 1, 2, and 3 hours post–glucose administration. A positive diagnostic test is defined as 2 measurements higher than the target value.

Why we support the One Step test

There are several reasons to prefer the One Step approach for the diagnosis of GDM, compared with the Two Step approach.

Women testing negative for GDM with Two Step still experience complications pregnancy. Women who test positive for GDM with the One Step test, but negative with the Two Step test, despite having therefore a milder degree of glucose intolerance, do have a higher risk of experiencing several complications.²³ For the mother, these complications include gestational hypertension, preeclampsia, and cesarean delivery. The baby also can experience problems at birth (TABLE 2).²³ Therefore, women who test positive for GDM with the One Step test deserve to be diagnosed with and treated for the condition, as not only are they at risk for these complications but also treatment of the GDM decreases the incidence of these complications.^18,19

Continue to: US guidelines should be reconsidered...

US guidelines should be reconsidered

The One Step, 75-g, 2-hour oral glucose tolerance test is universally used to diagnose diabetes mellitus outside of pregnancy. Given our many noted reasons (TABLE 3), we recommend universal screening of GDM by using the One Step approach. It is time, indeed, for the United States to reconsider its guidelines for screening for GDM.

Gestational diabetes mellitus (GDM) generally is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.^1-14 The best approach and exact criteria to use for GDM screening and diagnosis are under worldwide debate. In TABLE 1 we present just some of the many differing suggestions by varying organizations.^{2,7-9,11,12,15-17} The American College of Obstetricians and Gynecologists, for instance, suggests a Two Step approach to diagnosis.¹⁵ We will make the argument in this article, however, that diagnosis should be defined universally as an abnormal result with the One Step 75-g glucose testing, as adopted by the World Health Organization, International Federation of Gynecology and Obstetrics, and others. Approximately 8% of all pregnancies are complicated by GDM by the One Step test in the United States.^18-22 The prevalence may range from 1% to 14% of all pregnancies, depending on the population studied and the diagnostic tests employed.^1,19

Diagnostic options

Different methods for screening and diagnosis of GDM have been proposed by international societies; there is controversy regarding the diagnosis of GDM by either the One Step or the Two Step approach.⁶

The One Step approach includes an oral glucose tolerance test with a 75-g glucose load with measurement of plasma glucose concentration at fasting state and 1 hour and 2 hours post–glucose administration. A positive result for the One Step approach is defined as at least 1 measurement higher than 92, 180, or 153 mg/dL at fasting, 1 hour, or 2 hours, respectively.

The Two Step approach includes a nonfasting oral 50-g glucose load, with a glucose blood measurement 1 hour later. A positive screening, defined often as a blood glucose value higher than 135 mg/dL (range, 130 to 140 mg/dL), is followed by a diagnostic test with a 100-g glucose load with measurements at fasting and 1, 2, and 3 hours post–glucose administration. A positive diagnostic test is defined as 2 measurements higher than the target value.

Why we support the One Step test

There are several reasons to prefer the One Step approach for the diagnosis of GDM, compared with the Two Step approach.

Women testing negative for GDM with Two Step still experience complications pregnancy. Women who test positive for GDM with the One Step test, but negative with the Two Step test, despite having therefore a milder degree of glucose intolerance, do have a higher risk of experiencing several complications.²³ For the mother, these complications include gestational hypertension, preeclampsia, and cesarean delivery. The baby also can experience problems at birth (TABLE 2).²³ Therefore, women who test positive for GDM with the One Step test deserve to be diagnosed with and treated for the condition, as not only are they at risk for these complications but also treatment of the GDM decreases the incidence of these complications.^18,19

Continue to: US guidelines should be reconsidered...

US guidelines should be reconsidered

The One Step, 75-g, 2-hour oral glucose tolerance test is universally used to diagnose diabetes mellitus outside of pregnancy. Given our many noted reasons (TABLE 3), we recommend universal screening of GDM by using the One Step approach. It is time, indeed, for the United States to reconsider its guidelines for screening for GDM.

Gestational diabetes mellitus (GDM) generally is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.^1-14 The best approach and exact criteria to use for GDM screening and diagnosis are under worldwide debate. In TABLE 1 we present just some of the many differing suggestions by varying organizations.^{2,7-9,11,12,15-17} The American College of Obstetricians and Gynecologists, for instance, suggests a Two Step approach to diagnosis.¹⁵ We will make the argument in this article, however, that diagnosis should be defined universally as an abnormal result with the One Step 75-g glucose testing, as adopted by the World Health Organization, International Federation of Gynecology and Obstetrics, and others. Approximately 8% of all pregnancies are complicated by GDM by the One Step test in the United States.^18-22 The prevalence may range from 1% to 14% of all pregnancies, depending on the population studied and the diagnostic tests employed.^1,19

Diagnostic options

Different methods for screening and diagnosis of GDM have been proposed by international societies; there is controversy regarding the diagnosis of GDM by either the One Step or the Two Step approach.⁶

The One Step approach includes an oral glucose tolerance test with a 75-g glucose load with measurement of plasma glucose concentration at fasting state and 1 hour and 2 hours post–glucose administration. A positive result for the One Step approach is defined as at least 1 measurement higher than 92, 180, or 153 mg/dL at fasting, 1 hour, or 2 hours, respectively.

The Two Step approach includes a nonfasting oral 50-g glucose load, with a glucose blood measurement 1 hour later. A positive screening, defined often as a blood glucose value higher than 135 mg/dL (range, 130 to 140 mg/dL), is followed by a diagnostic test with a 100-g glucose load with measurements at fasting and 1, 2, and 3 hours post–glucose administration. A positive diagnostic test is defined as 2 measurements higher than the target value.

Why we support the One Step test

There are several reasons to prefer the One Step approach for the diagnosis of GDM, compared with the Two Step approach.

Women testing negative for GDM with Two Step still experience complications pregnancy. Women who test positive for GDM with the One Step test, but negative with the Two Step test, despite having therefore a milder degree of glucose intolerance, do have a higher risk of experiencing several complications.²³ For the mother, these complications include gestational hypertension, preeclampsia, and cesarean delivery. The baby also can experience problems at birth (TABLE 2).²³ Therefore, women who test positive for GDM with the One Step test deserve to be diagnosed with and treated for the condition, as not only are they at risk for these complications but also treatment of the GDM decreases the incidence of these complications.^18,19

Continue to: US guidelines should be reconsidered...

US guidelines should be reconsidered

The One Step, 75-g, 2-hour oral glucose tolerance test is universally used to diagnose diabetes mellitus outside of pregnancy. Given our many noted reasons (TABLE 3), we recommend universal screening of GDM by using the One Step approach. It is time, indeed, for the United States to reconsider its guidelines for screening for GDM.

Chappell LC, Brocklehurst P, Green ME, et al; PHOENIX Study Group. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394:1181-1190.

EXPERT COMMENTARY

Preeclampsia is a common hypertensive disorder of pregnancy. Among women who develop the disease at late preterm gestation, the question remains, “What is the optimal timing for delivery?” The American College of Obstetricians and Gynecologists (ACOG) categorizes preeclampsia as “with and without severe features.”¹ Delivery is recommended for women with preeclampsia with severe features at or beyond 34 weeks’ gestation, and for women with preeclampsia without severe features at or beyond 37 weeks’ gestation.¹ For patients with fetal growth restriction and preeclampsia, ACOG also recommends delivery between 34 and 37 weeks’ gestation.

Details of the study

Chappell and colleagues conducted a randomized controlled trial among women with singleton or dichorionic diamniotic twin pregnancy between 34 and 36.6 weeks’ gestation. Women were assigned to either planned delivery within 48 hours of randomization or expectant management until 37 weeks or earlier with clinical deterioration.

Among the 901 women included in the study, 450 were allocated to planned delivery and 451 to expectant management.

Study outcomes. The co-primary short-term maternal outcome was a composite of maternal morbidity with the addition of recorded systolic blood pressure of at least 160 mm Hg postrandomization (on any occasion). The co-primary short-term perinatal outcome was a composite of neonatal deaths within 7 days of delivery and perinatal deaths or neonatal unit admissions.

Participant details. At baseline, the average gestational age at randomization was 35.6 weeks, with equal distribution through the 3 weeks (34 through 36 weeks). About 37% of the women had severe hypertension (≥ 160 mm Hg) in the previous 48 hours prior to randomization, and approximately 22% had fetal growth restriction. The authors did not categorize the women based on severe features of preeclampsia.

Results. The investigators found that the proportion of women with the maternal co-primary outcome was significantly lower in the planned delivery group compared with the expectant management group (65% vs 75%), and the proportion of infants with the perinatal co-primary outcome was significantly higher in the planned delivery group compared with the expectant management group (42% vs 34%). The fact that early delivery led to more neonatal unit admissions for the infant, principally for a listed indication of prematurity and without an excess of respiratory or other morbidity, intensity of care, or length of stay, is very reassuring.

Study strengths and limitations

This is the largest study of women in this group allocated, randomized, and multicenter investigation addressing a very important clinical question. The patient population was mostly white, with only 13% black women, and had an average body mass index of 29 kg/m² (which is low compared with many practices in the United States). The average difference between the 2 study groups was the additional prolongation of pregnancy from enrollment to delivery of only 3 days, which may not be clinically relevant. More than half of the women in the expectant management group had medically indicated delivery before 37 weeks’ gestation.

Continue to: A limitation of this study...

A limitation of this study is that all women with preeclampsia were considered the same—that is, no distinction was made between severe and nonsevere preeclampsia, and a significant proportion of women had severe hypertension at enrollment, which would make them ineligible for expectant management anyway.

The maternal composite outcome was driven mostly by severe hypertension and progression to severe preeclampsia (likely driven by severe hypertension). All other maternal outcomes were very rare or did not happen; however, the incidence of delivery indications for various preeclampsia-related complications was higher in the expectant management group.

The takeaway

In the absence of biomarkers for risk stratification and treatment of preeclampsia, delivering women who have a diagnosis of preeclampsia at or beyond 34 weeks’ gestation may be a viable option for preventing maternal complications.

Chappell LC, Brocklehurst P, Green ME, et al; PHOENIX Study Group. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394:1181-1190.

EXPERT COMMENTARY

Preeclampsia is a common hypertensive disorder of pregnancy. Among women who develop the disease at late preterm gestation, the question remains, “What is the optimal timing for delivery?” The American College of Obstetricians and Gynecologists (ACOG) categorizes preeclampsia as “with and without severe features.”¹ Delivery is recommended for women with preeclampsia with severe features at or beyond 34 weeks’ gestation, and for women with preeclampsia without severe features at or beyond 37 weeks’ gestation.¹ For patients with fetal growth restriction and preeclampsia, ACOG also recommends delivery between 34 and 37 weeks’ gestation.

Details of the study

Chappell and colleagues conducted a randomized controlled trial among women with singleton or dichorionic diamniotic twin pregnancy between 34 and 36.6 weeks’ gestation. Women were assigned to either planned delivery within 48 hours of randomization or expectant management until 37 weeks or earlier with clinical deterioration.

Among the 901 women included in the study, 450 were allocated to planned delivery and 451 to expectant management.

Study outcomes. The co-primary short-term maternal outcome was a composite of maternal morbidity with the addition of recorded systolic blood pressure of at least 160 mm Hg postrandomization (on any occasion). The co-primary short-term perinatal outcome was a composite of neonatal deaths within 7 days of delivery and perinatal deaths or neonatal unit admissions.

Participant details. At baseline, the average gestational age at randomization was 35.6 weeks, with equal distribution through the 3 weeks (34 through 36 weeks). About 37% of the women had severe hypertension (≥ 160 mm Hg) in the previous 48 hours prior to randomization, and approximately 22% had fetal growth restriction. The authors did not categorize the women based on severe features of preeclampsia.

Results. The investigators found that the proportion of women with the maternal co-primary outcome was significantly lower in the planned delivery group compared with the expectant management group (65% vs 75%), and the proportion of infants with the perinatal co-primary outcome was significantly higher in the planned delivery group compared with the expectant management group (42% vs 34%). The fact that early delivery led to more neonatal unit admissions for the infant, principally for a listed indication of prematurity and without an excess of respiratory or other morbidity, intensity of care, or length of stay, is very reassuring.

Study strengths and limitations

This is the largest study of women in this group allocated, randomized, and multicenter investigation addressing a very important clinical question. The patient population was mostly white, with only 13% black women, and had an average body mass index of 29 kg/m² (which is low compared with many practices in the United States). The average difference between the 2 study groups was the additional prolongation of pregnancy from enrollment to delivery of only 3 days, which may not be clinically relevant. More than half of the women in the expectant management group had medically indicated delivery before 37 weeks’ gestation.

Continue to: A limitation of this study...

A limitation of this study is that all women with preeclampsia were considered the same—that is, no distinction was made between severe and nonsevere preeclampsia, and a significant proportion of women had severe hypertension at enrollment, which would make them ineligible for expectant management anyway.

The maternal composite outcome was driven mostly by severe hypertension and progression to severe preeclampsia (likely driven by severe hypertension). All other maternal outcomes were very rare or did not happen; however, the incidence of delivery indications for various preeclampsia-related complications was higher in the expectant management group.

The takeaway

In the absence of biomarkers for risk stratification and treatment of preeclampsia, delivering women who have a diagnosis of preeclampsia at or beyond 34 weeks’ gestation may be a viable option for preventing maternal complications.

Chappell LC, Brocklehurst P, Green ME, et al; PHOENIX Study Group. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019;394:1181-1190.

EXPERT COMMENTARY

Preeclampsia is a common hypertensive disorder of pregnancy. Among women who develop the disease at late preterm gestation, the question remains, “What is the optimal timing for delivery?” The American College of Obstetricians and Gynecologists (ACOG) categorizes preeclampsia as “with and without severe features.”¹ Delivery is recommended for women with preeclampsia with severe features at or beyond 34 weeks’ gestation, and for women with preeclampsia without severe features at or beyond 37 weeks’ gestation.¹ For patients with fetal growth restriction and preeclampsia, ACOG also recommends delivery between 34 and 37 weeks’ gestation.

Details of the study

Chappell and colleagues conducted a randomized controlled trial among women with singleton or dichorionic diamniotic twin pregnancy between 34 and 36.6 weeks’ gestation. Women were assigned to either planned delivery within 48 hours of randomization or expectant management until 37 weeks or earlier with clinical deterioration.

Among the 901 women included in the study, 450 were allocated to planned delivery and 451 to expectant management.

Study outcomes. The co-primary short-term maternal outcome was a composite of maternal morbidity with the addition of recorded systolic blood pressure of at least 160 mm Hg postrandomization (on any occasion). The co-primary short-term perinatal outcome was a composite of neonatal deaths within 7 days of delivery and perinatal deaths or neonatal unit admissions.

Participant details. At baseline, the average gestational age at randomization was 35.6 weeks, with equal distribution through the 3 weeks (34 through 36 weeks). About 37% of the women had severe hypertension (≥ 160 mm Hg) in the previous 48 hours prior to randomization, and approximately 22% had fetal growth restriction. The authors did not categorize the women based on severe features of preeclampsia.

Results. The investigators found that the proportion of women with the maternal co-primary outcome was significantly lower in the planned delivery group compared with the expectant management group (65% vs 75%), and the proportion of infants with the perinatal co-primary outcome was significantly higher in the planned delivery group compared with the expectant management group (42% vs 34%). The fact that early delivery led to more neonatal unit admissions for the infant, principally for a listed indication of prematurity and without an excess of respiratory or other morbidity, intensity of care, or length of stay, is very reassuring.

Study strengths and limitations

This is the largest study of women in this group allocated, randomized, and multicenter investigation addressing a very important clinical question. The patient population was mostly white, with only 13% black women, and had an average body mass index of 29 kg/m² (which is low compared with many practices in the United States). The average difference between the 2 study groups was the additional prolongation of pregnancy from enrollment to delivery of only 3 days, which may not be clinically relevant. More than half of the women in the expectant management group had medically indicated delivery before 37 weeks’ gestation.

Continue to: A limitation of this study...

A limitation of this study is that all women with preeclampsia were considered the same—that is, no distinction was made between severe and nonsevere preeclampsia, and a significant proportion of women had severe hypertension at enrollment, which would make them ineligible for expectant management anyway.

The maternal composite outcome was driven mostly by severe hypertension and progression to severe preeclampsia (likely driven by severe hypertension). All other maternal outcomes were very rare or did not happen; however, the incidence of delivery indications for various preeclampsia-related complications was higher in the expectant management group.

The takeaway

In the absence of biomarkers for risk stratification and treatment of preeclampsia, delivering women who have a diagnosis of preeclampsia at or beyond 34 weeks’ gestation may be a viable option for preventing maternal complications.

CASE Pregnant woman with chronic opioid use and HIV, recently diagnosed with HCV 

A 34-year-old primigravid woman at 35 weeks' gestation has a history of chronic opioid use. She previously was diagnosed with human immunodeficiency virus (HIV) infection and has been treated with a 3-drug combination antiretroviral regimen. Her most recent HIV viral load was 750 copies/mL. Three weeks ago, she tested positive for hepatitis C virus (HCV) infection. Liver function tests showed mild elevations in transaminase levels. The viral genotype is 1, and the viral load is 2.6 million copies/mL. 
 

How should this patient be delivered? Should she be encouraged to breastfeed her neonate? 

The scope of HCV infection 

Hepatitis C virus is a positive-sense, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family.¹ There are 7 confirmed major genotypes of HCV and 67 confirmed subtypes.² HCV possesses several important virulence factors. First, the virus's replication is prone to frequent mutations because its RNA polymerase lacks proofreading activity, resulting in significant genetic diversity. The great degree of heterogeneity among HCV leads to high antigenic variability, which is one of the main reasons there is not yet a vaccine for HCV.³ Additionally, HCV's genomic plasticity plays a role in the emergence of drug-resistant variants.⁴ 

Virus transmission. Worldwide, approximately 130 to 170 million people are infected with HCV.⁵ HCV infections are caused primarily by exposure to infected blood, through sharing needles for intravenous drug injection and through receiving a blood transfusion.⁶ Other routes of transmission include exposure through sexual contact, occupational injury, and perinatal acquisition. 

The risk of acquiring HCV varies for each of these transmission mechanisms. Blood transfusion is no longer a common mechanism of transmission in places where blood donations are screened for HCV antibodies and viral RNA. Additionally, unintentional needle-stick injury is the only occupational risk factor associated with HCV infection, and health care workers do not have a greater prevalence of HCV than the general population. Moreover, sexual transmission is not a particularly efficient mechanism for spread of HCV.⁷ Therefore, unsafe intravenous injections are now the leading cause of HCV infection.⁶ 

Consequences of HCV infection. Once infected with HCV, about 25% of people spontaneously clear the virus and approximately 75% progress to chronic HCV infection.⁵ The consequences of long-term infection with HCV include end-stage liver disease, cirrhosis, and hepatocellular carcinoma. 

Approximately 30% of people infected with HCV will develop cirrhosis and another 2% will develop hepatocellular carcinoma.⁸ Liver transplant is the only treatment option for patients with decompensated cirrhosis or hepatocellular carcinoma as a result of HCV infection. Currently, HCV infection is the leading indication for liver transplant in the United States.⁹ 

Continue to: Risk of perinatal HCV transmission...

Risk of perinatal HCV transmission 

Approximately 1% to 8% of pregnant women worldwide are infected with HCV.¹⁰ In the United States, 1% to 2.5% of pregnant women are infected.¹¹ Of these, about 6% transmit the infection to their offspring. The risk of HCV vertical transmission increases to about 11% if the mother is co-infected with HIV.¹² Vertical transmission is the primary method by which children become infected with HCV.¹³ 

Several risk factors increase the likelihood of HCV transmission from mother to child, including HIV co-infection, internal fetal monitoring, and longer duration of membrane rupture.¹⁴ The effect that mode of delivery has on vertical transmission rates, however, is still debated, and a Cochrane Review found that there were no randomized controlled trials assessing the effect of mode of delivery on mother-to-infant HCV transmission.¹⁵ 

Serology and genotyping used in diagnosis 

The serological enzyme immunoassay is the first test used in screening for HCV infection. Currently, third- and fourth-generation enzyme immunoassays are used in the United States.¹⁶ However, even these newer serological assays cannot consistently and precisely distinguish between acute and chronic HCV infections.¹⁷ After the initial diagnosis is made with serology, it usually is confirmed by assays that detect the virus's genomic RNA in the patient's serum or plasma. 

The patient's HCV genotype should be identified so that the best treatment options can be determined. HCV genotyping can be accomplished using reverse transcription quantitative polymerase chain reaction (RT-qPCR) amplification. Three different RT-qPCR assessments usually are performed using different primers and probes specific to different genotypes of HCV. While direct sequencing of the HCV genome also can be performed, this method is usually not used clinically due to its technical complexity.¹⁶ 

Modern treatments are effective 

Introduced in 2011, direct-acting antiviral therapies are now the recommended treatment for HCV infection. These drugs inhibit the virus's replication by targeting different proteins involved in the HCV replication cycle. They are remarkably successful and have achieved sustained virologic response (SVR) rates greater than 90%.¹¹ The World Health Organization recommends several pangenotypic (that is, agents that work against all genotypes) direct-acting antiviral regimens for the treatment of chronic HCV infection in adults without cirrhosis (TABLE 1).^18,19 

Unfortunately, experience with these drugs in pregnant women is lacking. Many direct-acting antiviral agents have not been tested systematically in pregnant women, and, accordingly, most information about their effects in pregnant women comes from animal models.¹¹ 

Continue to: Perinatal transmission rates and effect of mode of delivery...

Perinatal transmission rates and effect of mode of delivery 

We compiled data from 11 studies that reported the perinatal transmission rate of HCV associated with various modes of delivery. These studies were selected from a MEDLINE literature review from 1999 to 2019. The studies were screened first by title and, subsequently, by abstract. Inclusion was restricted to randomized controlled trials, cohort studies, and case-control studies written in English. Study quality was assessed as good, fair, or poor based on the study design, sample size, and statistical analyses performed. The results from the total population of each study are reported in TABLE 2.^14,20-29 

Three studies separated data based on the mother's HIV status. The perinatal transmission rates of HCV for mothers co-infected with HIV are reported in TABLE 3.^23,27 The results for HIV-negative mothers are reported in TABLE 4.^14,23 

Finally, 2 studies grouped mothers according to their HCV viral load. All of the mothers in these studies were anti-HCV antibody positive, and the perinatal transmission rates for the total study populations were reported previously in TABLE 2. The results for mothers who had detectable HCV RNA are reported in TABLE 5.^20,21 High viral load was defined as 
≥ 2.5 x 10⁶ Eq/mL in the study by Okamoto and colleagues, which is equivalent to ≥ 6.0 x 10⁵ IU/mL in the study by Murakami and colleagues due to the different assays that were used.^20,21 The perinatal transmission rates for mothers with a high viral load are presented in TABLE 6.^20,21

Continue to: For most, CD does not reduce HCV transmission...

For most, CD does not reduce HCV transmission 

Nine of the 11 studies found that the mode of delivery did not have a statistically significant impact on the vertical transmission rate of HCV in the total study populations.^14,22-29 The remaining 2 studies found that the perinatal transmission rate of HCV was lower with cesarean delivery (CD) than with vaginal delivery.^20,21 When considered together, the results of these 11 studies indicate that CD does not provide a significant reduction in the HCV transmission rate in the general population. 

Our review confirms the findings of others, including a systematic review by the US Preventive Services Task Force.30 That investigation also failed to demonstrate any measurable increase in risk of HCV transmission as a result of breastfeeding. 

Cesarean delivery may benefit 2 groups. Careful assessment of these studies, however, suggests that 2 select groups of patients with HCV may benefit from CD: 

• mothers co-infected with HIV, and 
• mothers with high viral loads of HCV. 

In both of these populations, the vertical transmission rate of HCV was significantly reduced with CD compared with vaginal delivery. Therefore, CD should be strongly considered in mothers with HCV who are co-infected with HIV and/or in mothers who have a high viral load of HCV. 

CASE Our recommendation for mode of delivery 

The patient in our case scenario has both HIV infection and a very high HCV viral load. We would therefore recommend a planned CD at 38 to 39 weeks' gestation, prior to the onset of labor or membrane rupture. Although HCV infection is not a contraindication to breastfeeding, the mother's HIV infection is a distinct contraindication. 

CASE Pregnant woman with chronic opioid use and HIV, recently diagnosed with HCV 

A 34-year-old primigravid woman at 35 weeks' gestation has a history of chronic opioid use. She previously was diagnosed with human immunodeficiency virus (HIV) infection and has been treated with a 3-drug combination antiretroviral regimen. Her most recent HIV viral load was 750 copies/mL. Three weeks ago, she tested positive for hepatitis C virus (HCV) infection. Liver function tests showed mild elevations in transaminase levels. The viral genotype is 1, and the viral load is 2.6 million copies/mL. 
 

How should this patient be delivered? Should she be encouraged to breastfeed her neonate? 

The scope of HCV infection 

Hepatitis C virus is a positive-sense, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family.¹ There are 7 confirmed major genotypes of HCV and 67 confirmed subtypes.² HCV possesses several important virulence factors. First, the virus's replication is prone to frequent mutations because its RNA polymerase lacks proofreading activity, resulting in significant genetic diversity. The great degree of heterogeneity among HCV leads to high antigenic variability, which is one of the main reasons there is not yet a vaccine for HCV.³ Additionally, HCV's genomic plasticity plays a role in the emergence of drug-resistant variants.⁴ 

Virus transmission. Worldwide, approximately 130 to 170 million people are infected with HCV.⁵ HCV infections are caused primarily by exposure to infected blood, through sharing needles for intravenous drug injection and through receiving a blood transfusion.⁶ Other routes of transmission include exposure through sexual contact, occupational injury, and perinatal acquisition. 

The risk of acquiring HCV varies for each of these transmission mechanisms. Blood transfusion is no longer a common mechanism of transmission in places where blood donations are screened for HCV antibodies and viral RNA. Additionally, unintentional needle-stick injury is the only occupational risk factor associated with HCV infection, and health care workers do not have a greater prevalence of HCV than the general population. Moreover, sexual transmission is not a particularly efficient mechanism for spread of HCV.⁷ Therefore, unsafe intravenous injections are now the leading cause of HCV infection.⁶ 

Consequences of HCV infection. Once infected with HCV, about 25% of people spontaneously clear the virus and approximately 75% progress to chronic HCV infection.⁵ The consequences of long-term infection with HCV include end-stage liver disease, cirrhosis, and hepatocellular carcinoma. 

Approximately 30% of people infected with HCV will develop cirrhosis and another 2% will develop hepatocellular carcinoma.⁸ Liver transplant is the only treatment option for patients with decompensated cirrhosis or hepatocellular carcinoma as a result of HCV infection. Currently, HCV infection is the leading indication for liver transplant in the United States.⁹ 

Continue to: Risk of perinatal HCV transmission...

Risk of perinatal HCV transmission 

Approximately 1% to 8% of pregnant women worldwide are infected with HCV.¹⁰ In the United States, 1% to 2.5% of pregnant women are infected.¹¹ Of these, about 6% transmit the infection to their offspring. The risk of HCV vertical transmission increases to about 11% if the mother is co-infected with HIV.¹² Vertical transmission is the primary method by which children become infected with HCV.¹³ 

Several risk factors increase the likelihood of HCV transmission from mother to child, including HIV co-infection, internal fetal monitoring, and longer duration of membrane rupture.¹⁴ The effect that mode of delivery has on vertical transmission rates, however, is still debated, and a Cochrane Review found that there were no randomized controlled trials assessing the effect of mode of delivery on mother-to-infant HCV transmission.¹⁵ 

Serology and genotyping used in diagnosis 

The serological enzyme immunoassay is the first test used in screening for HCV infection. Currently, third- and fourth-generation enzyme immunoassays are used in the United States.¹⁶ However, even these newer serological assays cannot consistently and precisely distinguish between acute and chronic HCV infections.¹⁷ After the initial diagnosis is made with serology, it usually is confirmed by assays that detect the virus's genomic RNA in the patient's serum or plasma. 

The patient's HCV genotype should be identified so that the best treatment options can be determined. HCV genotyping can be accomplished using reverse transcription quantitative polymerase chain reaction (RT-qPCR) amplification. Three different RT-qPCR assessments usually are performed using different primers and probes specific to different genotypes of HCV. While direct sequencing of the HCV genome also can be performed, this method is usually not used clinically due to its technical complexity.¹⁶ 

Modern treatments are effective 

Introduced in 2011, direct-acting antiviral therapies are now the recommended treatment for HCV infection. These drugs inhibit the virus's replication by targeting different proteins involved in the HCV replication cycle. They are remarkably successful and have achieved sustained virologic response (SVR) rates greater than 90%.¹¹ The World Health Organization recommends several pangenotypic (that is, agents that work against all genotypes) direct-acting antiviral regimens for the treatment of chronic HCV infection in adults without cirrhosis (TABLE 1).^18,19 

Unfortunately, experience with these drugs in pregnant women is lacking. Many direct-acting antiviral agents have not been tested systematically in pregnant women, and, accordingly, most information about their effects in pregnant women comes from animal models.¹¹ 

Continue to: Perinatal transmission rates and effect of mode of delivery...

Perinatal transmission rates and effect of mode of delivery 

We compiled data from 11 studies that reported the perinatal transmission rate of HCV associated with various modes of delivery. These studies were selected from a MEDLINE literature review from 1999 to 2019. The studies were screened first by title and, subsequently, by abstract. Inclusion was restricted to randomized controlled trials, cohort studies, and case-control studies written in English. Study quality was assessed as good, fair, or poor based on the study design, sample size, and statistical analyses performed. The results from the total population of each study are reported in TABLE 2.^14,20-29 

Three studies separated data based on the mother's HIV status. The perinatal transmission rates of HCV for mothers co-infected with HIV are reported in TABLE 3.^23,27 The results for HIV-negative mothers are reported in TABLE 4.^14,23 

Finally, 2 studies grouped mothers according to their HCV viral load. All of the mothers in these studies were anti-HCV antibody positive, and the perinatal transmission rates for the total study populations were reported previously in TABLE 2. The results for mothers who had detectable HCV RNA are reported in TABLE 5.^20,21 High viral load was defined as 
≥ 2.5 x 10⁶ Eq/mL in the study by Okamoto and colleagues, which is equivalent to ≥ 6.0 x 10⁵ IU/mL in the study by Murakami and colleagues due to the different assays that were used.^20,21 The perinatal transmission rates for mothers with a high viral load are presented in TABLE 6.^20,21

Continue to: For most, CD does not reduce HCV transmission...

For most, CD does not reduce HCV transmission 

Nine of the 11 studies found that the mode of delivery did not have a statistically significant impact on the vertical transmission rate of HCV in the total study populations.^14,22-29 The remaining 2 studies found that the perinatal transmission rate of HCV was lower with cesarean delivery (CD) than with vaginal delivery.^20,21 When considered together, the results of these 11 studies indicate that CD does not provide a significant reduction in the HCV transmission rate in the general population. 

Our review confirms the findings of others, including a systematic review by the US Preventive Services Task Force.30 That investigation also failed to demonstrate any measurable increase in risk of HCV transmission as a result of breastfeeding. 

Cesarean delivery may benefit 2 groups. Careful assessment of these studies, however, suggests that 2 select groups of patients with HCV may benefit from CD: 

• mothers co-infected with HIV, and 
• mothers with high viral loads of HCV. 

In both of these populations, the vertical transmission rate of HCV was significantly reduced with CD compared with vaginal delivery. Therefore, CD should be strongly considered in mothers with HCV who are co-infected with HIV and/or in mothers who have a high viral load of HCV. 

CASE Our recommendation for mode of delivery 

The patient in our case scenario has both HIV infection and a very high HCV viral load. We would therefore recommend a planned CD at 38 to 39 weeks' gestation, prior to the onset of labor or membrane rupture. Although HCV infection is not a contraindication to breastfeeding, the mother's HIV infection is a distinct contraindication. 

CASE Pregnant woman with chronic opioid use and HIV, recently diagnosed with HCV 

A 34-year-old primigravid woman at 35 weeks' gestation has a history of chronic opioid use. She previously was diagnosed with human immunodeficiency virus (HIV) infection and has been treated with a 3-drug combination antiretroviral regimen. Her most recent HIV viral load was 750 copies/mL. Three weeks ago, she tested positive for hepatitis C virus (HCV) infection. Liver function tests showed mild elevations in transaminase levels. The viral genotype is 1, and the viral load is 2.6 million copies/mL. 
 

How should this patient be delivered? Should she be encouraged to breastfeed her neonate? 

The scope of HCV infection 

Hepatitis C virus is a positive-sense, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family.¹ There are 7 confirmed major genotypes of HCV and 67 confirmed subtypes.² HCV possesses several important virulence factors. First, the virus's replication is prone to frequent mutations because its RNA polymerase lacks proofreading activity, resulting in significant genetic diversity. The great degree of heterogeneity among HCV leads to high antigenic variability, which is one of the main reasons there is not yet a vaccine for HCV.³ Additionally, HCV's genomic plasticity plays a role in the emergence of drug-resistant variants.⁴ 

Virus transmission. Worldwide, approximately 130 to 170 million people are infected with HCV.⁵ HCV infections are caused primarily by exposure to infected blood, through sharing needles for intravenous drug injection and through receiving a blood transfusion.⁶ Other routes of transmission include exposure through sexual contact, occupational injury, and perinatal acquisition. 

The risk of acquiring HCV varies for each of these transmission mechanisms. Blood transfusion is no longer a common mechanism of transmission in places where blood donations are screened for HCV antibodies and viral RNA. Additionally, unintentional needle-stick injury is the only occupational risk factor associated with HCV infection, and health care workers do not have a greater prevalence of HCV than the general population. Moreover, sexual transmission is not a particularly efficient mechanism for spread of HCV.⁷ Therefore, unsafe intravenous injections are now the leading cause of HCV infection.⁶ 

Consequences of HCV infection. Once infected with HCV, about 25% of people spontaneously clear the virus and approximately 75% progress to chronic HCV infection.⁵ The consequences of long-term infection with HCV include end-stage liver disease, cirrhosis, and hepatocellular carcinoma. 

Approximately 30% of people infected with HCV will develop cirrhosis and another 2% will develop hepatocellular carcinoma.⁸ Liver transplant is the only treatment option for patients with decompensated cirrhosis or hepatocellular carcinoma as a result of HCV infection. Currently, HCV infection is the leading indication for liver transplant in the United States.⁹ 

Continue to: Risk of perinatal HCV transmission...

Risk of perinatal HCV transmission 

Approximately 1% to 8% of pregnant women worldwide are infected with HCV.¹⁰ In the United States, 1% to 2.5% of pregnant women are infected.¹¹ Of these, about 6% transmit the infection to their offspring. The risk of HCV vertical transmission increases to about 11% if the mother is co-infected with HIV.¹² Vertical transmission is the primary method by which children become infected with HCV.¹³ 

Several risk factors increase the likelihood of HCV transmission from mother to child, including HIV co-infection, internal fetal monitoring, and longer duration of membrane rupture.¹⁴ The effect that mode of delivery has on vertical transmission rates, however, is still debated, and a Cochrane Review found that there were no randomized controlled trials assessing the effect of mode of delivery on mother-to-infant HCV transmission.¹⁵ 

Serology and genotyping used in diagnosis 

The serological enzyme immunoassay is the first test used in screening for HCV infection. Currently, third- and fourth-generation enzyme immunoassays are used in the United States.¹⁶ However, even these newer serological assays cannot consistently and precisely distinguish between acute and chronic HCV infections.¹⁷ After the initial diagnosis is made with serology, it usually is confirmed by assays that detect the virus's genomic RNA in the patient's serum or plasma. 

The patient's HCV genotype should be identified so that the best treatment options can be determined. HCV genotyping can be accomplished using reverse transcription quantitative polymerase chain reaction (RT-qPCR) amplification. Three different RT-qPCR assessments usually are performed using different primers and probes specific to different genotypes of HCV. While direct sequencing of the HCV genome also can be performed, this method is usually not used clinically due to its technical complexity.¹⁶ 

Modern treatments are effective 

Introduced in 2011, direct-acting antiviral therapies are now the recommended treatment for HCV infection. These drugs inhibit the virus's replication by targeting different proteins involved in the HCV replication cycle. They are remarkably successful and have achieved sustained virologic response (SVR) rates greater than 90%.¹¹ The World Health Organization recommends several pangenotypic (that is, agents that work against all genotypes) direct-acting antiviral regimens for the treatment of chronic HCV infection in adults without cirrhosis (TABLE 1).^18,19 

Unfortunately, experience with these drugs in pregnant women is lacking. Many direct-acting antiviral agents have not been tested systematically in pregnant women, and, accordingly, most information about their effects in pregnant women comes from animal models.¹¹ 

Continue to: Perinatal transmission rates and effect of mode of delivery...

Perinatal transmission rates and effect of mode of delivery 

We compiled data from 11 studies that reported the perinatal transmission rate of HCV associated with various modes of delivery. These studies were selected from a MEDLINE literature review from 1999 to 2019. The studies were screened first by title and, subsequently, by abstract. Inclusion was restricted to randomized controlled trials, cohort studies, and case-control studies written in English. Study quality was assessed as good, fair, or poor based on the study design, sample size, and statistical analyses performed. The results from the total population of each study are reported in TABLE 2.^14,20-29 

Three studies separated data based on the mother's HIV status. The perinatal transmission rates of HCV for mothers co-infected with HIV are reported in TABLE 3.^23,27 The results for HIV-negative mothers are reported in TABLE 4.^14,23 

Finally, 2 studies grouped mothers according to their HCV viral load. All of the mothers in these studies were anti-HCV antibody positive, and the perinatal transmission rates for the total study populations were reported previously in TABLE 2. The results for mothers who had detectable HCV RNA are reported in TABLE 5.^20,21 High viral load was defined as 
≥ 2.5 x 10⁶ Eq/mL in the study by Okamoto and colleagues, which is equivalent to ≥ 6.0 x 10⁵ IU/mL in the study by Murakami and colleagues due to the different assays that were used.^20,21 The perinatal transmission rates for mothers with a high viral load are presented in TABLE 6.^20,21

Continue to: For most, CD does not reduce HCV transmission...

For most, CD does not reduce HCV transmission 

Nine of the 11 studies found that the mode of delivery did not have a statistically significant impact on the vertical transmission rate of HCV in the total study populations.^14,22-29 The remaining 2 studies found that the perinatal transmission rate of HCV was lower with cesarean delivery (CD) than with vaginal delivery.^20,21 When considered together, the results of these 11 studies indicate that CD does not provide a significant reduction in the HCV transmission rate in the general population. 

Our review confirms the findings of others, including a systematic review by the US Preventive Services Task Force.30 That investigation also failed to demonstrate any measurable increase in risk of HCV transmission as a result of breastfeeding. 

Cesarean delivery may benefit 2 groups. Careful assessment of these studies, however, suggests that 2 select groups of patients with HCV may benefit from CD: 

• mothers co-infected with HIV, and 
• mothers with high viral loads of HCV. 

In both of these populations, the vertical transmission rate of HCV was significantly reduced with CD compared with vaginal delivery. Therefore, CD should be strongly considered in mothers with HCV who are co-infected with HIV and/or in mothers who have a high viral load of HCV. 

CASE Our recommendation for mode of delivery 

The patient in our case scenario has both HIV infection and a very high HCV viral load. We would therefore recommend a planned CD at 38 to 39 weeks' gestation, prior to the onset of labor or membrane rupture. Although HCV infection is not a contraindication to breastfeeding, the mother's HIV infection is a distinct contraindication. 

A new American College of Obstetricians and Gynecologists (ACOG) committee opinion addresses how contraception access can be improved through over-the-counter (OTC) hormonal contraception for people of all ages—including oral contraceptive pills (OCPs), progesterone-only pills, the patch, vaginal rings, and depot medroxyprogesterone acetate (DMPA). Although ACOG endorses OTC contraception, some health care providers may be hesitant to support the increase in accessibility for a variety of reasons. We are hopeful that we address these concerns and that all clinicians can move to support ACOG’s position.

Easing access to hormonal contraception is a first step

OCPs are the most widely used contraception among teens and women of reproductive age in the United States.¹ Although the Affordable Care Act (ACA) mandated health insurance coverage for contraception, many barriers continue to exist, including obtaining a prescription. Only 13 states have made it legal to obtain hormonal contraception through a pharmacist.² There also has been an increase in the number of telemedicine and online services that deliver contraceptives to individuals’ homes. While these efforts have helped to decrease barriers to hormonal contraception access for some patients, they only reach a small segment of the population. As clinicians, we should strive to make contraception universally accessible and affordable to everyone who desires to use it. OTC provision can bring us closer to this goal.

Addressing the misconceptions about contraception

Adverse events with hormonal contraception are rarer than one may think. There are few risks associated with hormonal contraception. Venous thromboembolus (VTE) is a serious, although rare, adverse effect (AE) of hormonal contraception. The rate of VTE with combined oral contraception is estimated at 3 to 8 events per 10,000 patient-years, and VTE is even less common with progestin-only contraception (1 to 5 per 10,000 patient-years). For both types of hormonal contraception, the risk of VTE is smaller than with pregnancy, which is 5 to 20 per 10,000 patient-years.³ There are comorbidities that increase the risk of VTE and other AEs of hormonal contraception. In the setting of OTC hormonal contraception, individuals would self-screen for contraindications in order to reduce these complications.

Patients have the aptitude to self-screen for contraindications. Studies looking at the ability of patients over the age of 18 to self-screen for contraindications to hormonal contraception have found that patients do appropriately screen themselves. In fact, they are often more conservative than a physician in avoiding hormonal contraceptive methods.⁴ Patients younger than age 18 rarely have contraindications to hormonal contraception, but limited studies have shown that they too are able to successfully self-screen.⁵ ACOG recommends self-screening tools be provided with all OTC combined hormonal contraceptive methods to aid an individual’s contraceptive choice.

Most patients continue their well person care. Some opponents to ACOG’s position also have expressed concern that people who access their contraception OTC will forego their annual exam with their provider. However, studies have shown that the majority of people will continue to make their preventative health care visits.^6,7

We need to invest in preventing unplanned pregnancy

Currently, hormonal contraception is covered by health insurance under the ACA, with some caveats. Without a prescription, patients may have to pay full price for their contraception. However, one can find generic OCPs for less than $10 per pack out of pocket. Any cost can be prohibitive to many patients; thus, transition to OTC access to contraception also should ensure limiting the cost to the patient. One possible solution to mitigate costs is to require insurance companies to cover the cost of OTC hormonal contraceptives. (See action item below.)

Reduction in unplanned pregnancies improves public health and public expense, and broadening access to effective forms of contraception is imperative in reducing unplanned pregnancies. Every $1 invested in contraception access realizes $7.09 in savings.⁸ By making hormonal contraception widely available OTC, access could be improved dramatically—although pharmacist provision of hormonal contraception may be a necessary intermediate step. ACOG’s most recent committee opinion encourages all reproductive health care providers to be strong advocates for this improvement in access. As women’s health providers, we should work to decrease access barriers for our patients; working toward OTC contraception is a critical step in equal access to birth control methods for all of our patients.

Action items

Remember, before a pill can move to OTC access, the manufacturing (pharmaceutical) company must submit an application to the US Food and Drug Administration to obtain this status. Once submitted, the process may take 3 to 4 years to be completed. Currently, no company has submitted an OTC application and no hormonal birth control is available OTC. Find resources for OTC birth control access here: http://ocsotc.org/ and www.freethepill.org.

• Talk to your state representatives about why both OTC birth control access and direct pharmacy availability are important to increasing access and decreasing disparities in reproductive health care. Find your local and federal representatives here and check the status of OCP access in your state here.
• Representative Ayanna Pressley (D-MA) and Senator Patty Murray (D-WA) both have introduced legislation—the Affordability is Access Act (HR 3296/S1847)—to ensure insurance coverage for OTC contraception. Call your representative and ask them to cosponsor this legislation.
• Be mindful of legislation that promotes OTC OCPs but limits access to some populations (minors) and increases cost sharing to the patient. This type of legislation can create harmful barriers to access for some of our patients

A new American College of Obstetricians and Gynecologists (ACOG) committee opinion addresses how contraception access can be improved through over-the-counter (OTC) hormonal contraception for people of all ages—including oral contraceptive pills (OCPs), progesterone-only pills, the patch, vaginal rings, and depot medroxyprogesterone acetate (DMPA). Although ACOG endorses OTC contraception, some health care providers may be hesitant to support the increase in accessibility for a variety of reasons. We are hopeful that we address these concerns and that all clinicians can move to support ACOG’s position.

Easing access to hormonal contraception is a first step

OCPs are the most widely used contraception among teens and women of reproductive age in the United States.¹ Although the Affordable Care Act (ACA) mandated health insurance coverage for contraception, many barriers continue to exist, including obtaining a prescription. Only 13 states have made it legal to obtain hormonal contraception through a pharmacist.² There also has been an increase in the number of telemedicine and online services that deliver contraceptives to individuals’ homes. While these efforts have helped to decrease barriers to hormonal contraception access for some patients, they only reach a small segment of the population. As clinicians, we should strive to make contraception universally accessible and affordable to everyone who desires to use it. OTC provision can bring us closer to this goal.

Addressing the misconceptions about contraception

Adverse events with hormonal contraception are rarer than one may think. There are few risks associated with hormonal contraception. Venous thromboembolus (VTE) is a serious, although rare, adverse effect (AE) of hormonal contraception. The rate of VTE with combined oral contraception is estimated at 3 to 8 events per 10,000 patient-years, and VTE is even less common with progestin-only contraception (1 to 5 per 10,000 patient-years). For both types of hormonal contraception, the risk of VTE is smaller than with pregnancy, which is 5 to 20 per 10,000 patient-years.³ There are comorbidities that increase the risk of VTE and other AEs of hormonal contraception. In the setting of OTC hormonal contraception, individuals would self-screen for contraindications in order to reduce these complications.

Patients have the aptitude to self-screen for contraindications. Studies looking at the ability of patients over the age of 18 to self-screen for contraindications to hormonal contraception have found that patients do appropriately screen themselves. In fact, they are often more conservative than a physician in avoiding hormonal contraceptive methods.⁴ Patients younger than age 18 rarely have contraindications to hormonal contraception, but limited studies have shown that they too are able to successfully self-screen.⁵ ACOG recommends self-screening tools be provided with all OTC combined hormonal contraceptive methods to aid an individual’s contraceptive choice.

Most patients continue their well person care. Some opponents to ACOG’s position also have expressed concern that people who access their contraception OTC will forego their annual exam with their provider. However, studies have shown that the majority of people will continue to make their preventative health care visits.^6,7

We need to invest in preventing unplanned pregnancy

Currently, hormonal contraception is covered by health insurance under the ACA, with some caveats. Without a prescription, patients may have to pay full price for their contraception. However, one can find generic OCPs for less than $10 per pack out of pocket. Any cost can be prohibitive to many patients; thus, transition to OTC access to contraception also should ensure limiting the cost to the patient. One possible solution to mitigate costs is to require insurance companies to cover the cost of OTC hormonal contraceptives. (See action item below.)

Reduction in unplanned pregnancies improves public health and public expense, and broadening access to effective forms of contraception is imperative in reducing unplanned pregnancies. Every $1 invested in contraception access realizes $7.09 in savings.⁸ By making hormonal contraception widely available OTC, access could be improved dramatically—although pharmacist provision of hormonal contraception may be a necessary intermediate step. ACOG’s most recent committee opinion encourages all reproductive health care providers to be strong advocates for this improvement in access. As women’s health providers, we should work to decrease access barriers for our patients; working toward OTC contraception is a critical step in equal access to birth control methods for all of our patients.

Action items

Remember, before a pill can move to OTC access, the manufacturing (pharmaceutical) company must submit an application to the US Food and Drug Administration to obtain this status. Once submitted, the process may take 3 to 4 years to be completed. Currently, no company has submitted an OTC application and no hormonal birth control is available OTC. Find resources for OTC birth control access here: http://ocsotc.org/ and www.freethepill.org.

• Talk to your state representatives about why both OTC birth control access and direct pharmacy availability are important to increasing access and decreasing disparities in reproductive health care. Find your local and federal representatives here and check the status of OCP access in your state here.
• Representative Ayanna Pressley (D-MA) and Senator Patty Murray (D-WA) both have introduced legislation—the Affordability is Access Act (HR 3296/S1847)—to ensure insurance coverage for OTC contraception. Call your representative and ask them to cosponsor this legislation.
• Be mindful of legislation that promotes OTC OCPs but limits access to some populations (minors) and increases cost sharing to the patient. This type of legislation can create harmful barriers to access for some of our patients

A new American College of Obstetricians and Gynecologists (ACOG) committee opinion addresses how contraception access can be improved through over-the-counter (OTC) hormonal contraception for people of all ages—including oral contraceptive pills (OCPs), progesterone-only pills, the patch, vaginal rings, and depot medroxyprogesterone acetate (DMPA). Although ACOG endorses OTC contraception, some health care providers may be hesitant to support the increase in accessibility for a variety of reasons. We are hopeful that we address these concerns and that all clinicians can move to support ACOG’s position.

Easing access to hormonal contraception is a first step

OCPs are the most widely used contraception among teens and women of reproductive age in the United States.¹ Although the Affordable Care Act (ACA) mandated health insurance coverage for contraception, many barriers continue to exist, including obtaining a prescription. Only 13 states have made it legal to obtain hormonal contraception through a pharmacist.² There also has been an increase in the number of telemedicine and online services that deliver contraceptives to individuals’ homes. While these efforts have helped to decrease barriers to hormonal contraception access for some patients, they only reach a small segment of the population. As clinicians, we should strive to make contraception universally accessible and affordable to everyone who desires to use it. OTC provision can bring us closer to this goal.

Addressing the misconceptions about contraception

Adverse events with hormonal contraception are rarer than one may think. There are few risks associated with hormonal contraception. Venous thromboembolus (VTE) is a serious, although rare, adverse effect (AE) of hormonal contraception. The rate of VTE with combined oral contraception is estimated at 3 to 8 events per 10,000 patient-years, and VTE is even less common with progestin-only contraception (1 to 5 per 10,000 patient-years). For both types of hormonal contraception, the risk of VTE is smaller than with pregnancy, which is 5 to 20 per 10,000 patient-years.³ There are comorbidities that increase the risk of VTE and other AEs of hormonal contraception. In the setting of OTC hormonal contraception, individuals would self-screen for contraindications in order to reduce these complications.

Patients have the aptitude to self-screen for contraindications. Studies looking at the ability of patients over the age of 18 to self-screen for contraindications to hormonal contraception have found that patients do appropriately screen themselves. In fact, they are often more conservative than a physician in avoiding hormonal contraceptive methods.⁴ Patients younger than age 18 rarely have contraindications to hormonal contraception, but limited studies have shown that they too are able to successfully self-screen.⁵ ACOG recommends self-screening tools be provided with all OTC combined hormonal contraceptive methods to aid an individual’s contraceptive choice.

Most patients continue their well person care. Some opponents to ACOG’s position also have expressed concern that people who access their contraception OTC will forego their annual exam with their provider. However, studies have shown that the majority of people will continue to make their preventative health care visits.^6,7

We need to invest in preventing unplanned pregnancy

Currently, hormonal contraception is covered by health insurance under the ACA, with some caveats. Without a prescription, patients may have to pay full price for their contraception. However, one can find generic OCPs for less than $10 per pack out of pocket. Any cost can be prohibitive to many patients; thus, transition to OTC access to contraception also should ensure limiting the cost to the patient. One possible solution to mitigate costs is to require insurance companies to cover the cost of OTC hormonal contraceptives. (See action item below.)

Reduction in unplanned pregnancies improves public health and public expense, and broadening access to effective forms of contraception is imperative in reducing unplanned pregnancies. Every $1 invested in contraception access realizes $7.09 in savings.⁸ By making hormonal contraception widely available OTC, access could be improved dramatically—although pharmacist provision of hormonal contraception may be a necessary intermediate step. ACOG’s most recent committee opinion encourages all reproductive health care providers to be strong advocates for this improvement in access. As women’s health providers, we should work to decrease access barriers for our patients; working toward OTC contraception is a critical step in equal access to birth control methods for all of our patients.

Action items

Remember, before a pill can move to OTC access, the manufacturing (pharmaceutical) company must submit an application to the US Food and Drug Administration to obtain this status. Once submitted, the process may take 3 to 4 years to be completed. Currently, no company has submitted an OTC application and no hormonal birth control is available OTC. Find resources for OTC birth control access here: http://ocsotc.org/ and www.freethepill.org.

• Talk to your state representatives about why both OTC birth control access and direct pharmacy availability are important to increasing access and decreasing disparities in reproductive health care. Find your local and federal representatives here and check the status of OCP access in your state here.
• Representative Ayanna Pressley (D-MA) and Senator Patty Murray (D-WA) both have introduced legislation—the Affordability is Access Act (HR 3296/S1847)—to ensure insurance coverage for OTC contraception. Call your representative and ask them to cosponsor this legislation.
• Be mindful of legislation that promotes OTC OCPs but limits access to some populations (minors) and increases cost sharing to the patient. This type of legislation can create harmful barriers to access for some of our patients

Do health effects of menopausal estrogen therapy differ between women with bilateral oophorectomy versus those with conserved ovaries? To answer this question a group of investigators performed a subanalysis of the Women’s Health Initiative (WHI) Estrogen-Alone Trial,¹ which included 40 clinical centers across the United States. They examined estrogen therapy outcomes by bilateral salpingo-oophorectomy (BSO) status, with additional stratification by 10-year age groups in 9,939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status. In the WHI trial, women were randomly assigned to conjugated equine estrogens (CEE) 0.625 mg/d or placebo for a median of 7.2 years. Investigators assessed the incidence of coronary heart disease and invasive breast cancer (the trial’s 2 primary end points), all-cause mortality, and a “global index”—these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture—during the intervention phase and 18-year cumulative follow-up.

OBG Management caught up with lead author JoAnn E. Manson, MD, DrPH, NCMP, to discuss the study’s results.
 

OBG Management: How many women undergo BSO with their hysterectomy?

Dr. JoAnn E. Manson, MD, DrPH, NCMP: Of the 425,000 women who undergo hysterectomy in the United States for benign reasons each year,^2,3 about 40% of them undergo BSO—so between 150,000 and 200,000 women per year undergo BSO with their hysterectomy.^4,5
 

OBG Management: Although BSO is performed with hysterectomy to minimize patients’ future ovarian cancer risk, does BSO have health risks of its own, and how has estrogen been shown to affect these risks?

Dr. Manson: First, yes, BSO has been associated with health risks, especially when it is performed at a young age, such as before age 45. It has been linked to an increased risk of heart disease, osteoporosis, cognitive decline, and all-cause mortality. According to observational studies, estrogen therapy appears to offset many of these risks, particularly those related to heart disease and osteoporosis (the evidence is less clear on cognitive deficits).⁵
 

OBG Management: What did you find in your trial when you randomly assigned women in the age groups of 50 to 79 who underwent hysterectomy with and without BSO to estrogen therapy or placebo?

Dr. Manson: The WHI is the first study to be conducted in a randomized trial setting to analyze the health risks and benefits of estrogen therapy according to whether or not women had their ovaries removed. What we found was that the woman’s age had a strong influence on the effects of estrogen therapy among women who had BSO but only a negligible effect among women who had conserved ovaries. Overall, across the full age range, the effects of estrogen therapy did not differ substantially between women who had a BSO and those who had their ovaries conserved.

However, there were major differences by age group among the women who had BSO. A significant 32% reduction in all-cause mortality emerged during the 18-year follow-up period among the younger women (below age 60) who had BSO when they received estrogen therapy as compared with placebo. By contrast, the women who had conserved ovaries did not have this significant reduction in all-cause mortality, or in most of the other outcomes on estrogen compared with placebo. Overall, the effects of estrogen therapy tended to be relatively neutral in the women with conserved ovaries.

Now, the reduction in all-cause mortality with estrogen therapy was particularly pronounced among women who had BSO before age 45. They had a 40% statistically significant reduction in all-cause mortality with estrogen therapy compared with placebo. Also, among the women with BSO, there was a strong association between the timing of estrogen initiation and the magnitude of reduction in mortality. Women who started the estrogen therapy within 10 years of having the BSO had a 34% significant reduction in all-cause mortality, and those who started estrogen more than 20 years after having their ovaries removed had no reduction in mortality.
 

Continue to: OBG Management: Do your data give support to the timing hypothesis?

OBG Management: Do your data give support to the timing hypothesis?

Dr. Manson: Yes, our findings do support a timing hypothesis that was particularly pronounced for women who underwent BSO. It was the women who had early surgical menopause (before age 45) and those who started the estrogen therapy within 10 years of having their ovaries removed who had the greatest reduction in all-cause mortality and the most favorable benefit-risk profile from hormone therapy. So, the results do lend support to the timing hypothesis.

By contrast, women who had BSO at hysterectomy and began hormone therapy at age 70 or older had net adverse effects from hormone therapy. They posted a 40% increase in the global index—which is a summary measure of adverse effects on cardiovascular disease, cancer, and other major health outcomes. So, the women with BSO who were randomized in the trial at age 70 and older, had unfavorable results from estrogen therapy and an increase in the global index, in contrast to the women who were below age 60 or within 10 years of menopause.
 

OBG Management: Given your study findings, in which women would you recommend estrogen therapy? And are there groups of women in which you would advise avoiding estrogen therapy?

Dr. Manson: Current guidelines^6,7 recommend estrogen therapy for women who have early menopause, particularly an early surgical menopause and BSO prior to the average age at natural menopause. Unless the woman has contraindications to estrogen therapy, the recommendations are to treat with estrogen until the average age of menopause—until about age 50 to 51.

Our study findings provide reassurance that, if a woman continues to have indications for estrogen (vasomotor symptoms, or other indications for estrogen therapy), there is relative safety of continuing estrogen-alone therapy through her 50s, until age 60. For example, a woman who, after the average age of menopause continues to have vasomotor symptoms, or if she has bone health problems, our study would suggest that estrogen therapy would continue to have a favorable benefit-risk profile until at least the age of 60. Decisions would have to be individualized, especially after age 60, with shared decision-making particularly important for those decisions. (Some women, depending on their risk profile, may continue to be candidates for estrogen therapy past age 60.)

So, this study provides reassurance regarding use of estrogen therapy for women in their 50s if they have had BSO. Actually, the women who had conserved ovaries also had relative safety with estrogen therapy until age 60. They just didn’t show the significant benefits for all-cause mortality. Overall, their pattern of health-related benefits and risks was neutral. Thus, if vasomotor symptom management, quality of life benefits, or bone health effects are sought, taking hormone therapy is a quite reasonable choice for these women.

By contrast, women who have had a BSO and are age 70 or older should really avoid initiating estrogen therapy because it would follow a prolonged period of estrogen deficiency, or very low estrogen levels, and these women appeared to have a net adverse effect from initiating hormone therapy (with increases in the global index found).

Continue to: OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

OBG Management: Did taking estrogen therapy prior to trial enrollment make a difference when it came to study outcomes?

Dr. Manson: We found minimal if any effect in our analyses. In fact, even the women who did not have prior (pre-randomization) use of estrogen therapy tended to do well on estrogen-alone therapy if they were younger than age 60. This was particularly true for the women who had BSO. Even if they had not used estrogen previously, and they were many years past the BSO, they still did well on estrogen therapy if they were below age 60.