OBG Management

Did posthysterectomy hemorrhage cause woman’s brain damage?

A 42-year-old woman underwent elective subtotal hysterectomy to treat a large uterine fibroid. In the recovery unit, she had extremely low blood pressure and tachycardia and lost consciousness for 15 minutes. She was given a blood transfusion, but was not returned to the operating room for emergency exploratory laparotomy until 3 hours later. Surgery revealed a hemorrhage from the left uterine artery requiring ligation.

PATIENT’S CLAIM:

The hemorrhage caused hypoxia resulting in an anoxic brain injury with memory and concentration difficulties. The gynecologist and hospital staff were negligent in delaying emergency treatment.

DEFENDANTS’ DEFENSE:

Postoperative bleeding is a known complication of hysterectomy. The patient was at increased risk of bleeding because of the numerous blood vessels feeding the fibroid. A morphine reaction is believed to be the cause of her becoming unconscious. The patient had not sustained an anoxic or hypoxic brain damage because she was alert and oriented immediately after the damage allegedly occurred.

VERDICT:

The Illinois jury deadlocked. The parties entered into a settlement agreement for a confidential sum before a mistrial was declared.

Related article:
7 Myomectomy myths debunked

Choriocarcinoma diagnosis missed

A 25-year-old woman had a miscarriage. A follow-up test to measure the patient’s human chorionic gonadotropin (hCG) hormone level test was not performed. The patient died from choriocarcinoma.

ESTATE’S CLAIM:

The ObGyn did not follow the standard of care: the patient’s hCG level should have been tested after the miscarriage. It is a well-known fact that an hCG level that does not return to zero after a miscarriage is cause for concern, especially from choriocarcinoma.

PHYSICIAN’S DEFENSE:

There was nothing that could have been done to save the woman’s life; choriocarcinoma is a quickly spreading cancer.

VERDICT:

A $1,800,000 Massachusetts settlement was reached.

Related article:
Manual vacuum aspiration: A safe and effective treatment for early miscarriage

Bowel perforation during hysterectomy: $860,000 verdict

A 58-year-old woman underwent laparoscopic hysterectomy and was discharged the next day although she had not urinated or defecated. After eating solid food that evening, she experienced immediate vomiting, nausea, and abdominal pain. When she saw her ObGyn the next morning, he immediately hospitalized her. During the next 8 days in the hospital, she was unable to pass gas, was febrile, and was given antibiotics. On postoperative day 11, a general surgeon transferred her to the intensive care unit due to shortness of breath and tachycardia. During exploratory abdominal surgery, several abscesses and a 1-cm injury to the rectosigmoid colon were discovered necessitating a colostomy. The patient underwent 5 additional abdominal washout procedures and was hospitalized for 40 days. Colostomy reversal surgery occurred 8 months later.

PATIENT’S CLAIM:

The ObGyn never provided an explanation of what went wrong; the patient was told the hysterectomy was accomplished without incident. An expert colorectal surgeon stated that the perforation likely occurred within 24 hours of surgery and was probably caused by the electromechanical device used during surgery.

DEFENDANTS’ DEFENSE:

The perforation was caused by a sudden rupture of a diverticulum 10 days after hysterectomy. The injury was treated in a timely manner.

VERDICT:

An $860,000 Virginia verdict was returned.

Related article:
How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Did posthysterectomy hemorrhage cause woman’s brain damage?

A 42-year-old woman underwent elective subtotal hysterectomy to treat a large uterine fibroid. In the recovery unit, she had extremely low blood pressure and tachycardia and lost consciousness for 15 minutes. She was given a blood transfusion, but was not returned to the operating room for emergency exploratory laparotomy until 3 hours later. Surgery revealed a hemorrhage from the left uterine artery requiring ligation.

PATIENT’S CLAIM:

The hemorrhage caused hypoxia resulting in an anoxic brain injury with memory and concentration difficulties. The gynecologist and hospital staff were negligent in delaying emergency treatment.

DEFENDANTS’ DEFENSE:

Postoperative bleeding is a known complication of hysterectomy. The patient was at increased risk of bleeding because of the numerous blood vessels feeding the fibroid. A morphine reaction is believed to be the cause of her becoming unconscious. The patient had not sustained an anoxic or hypoxic brain damage because she was alert and oriented immediately after the damage allegedly occurred.

VERDICT:

The Illinois jury deadlocked. The parties entered into a settlement agreement for a confidential sum before a mistrial was declared.

Related article:
7 Myomectomy myths debunked

Choriocarcinoma diagnosis missed

A 25-year-old woman had a miscarriage. A follow-up test to measure the patient’s human chorionic gonadotropin (hCG) hormone level test was not performed. The patient died from choriocarcinoma.

ESTATE’S CLAIM:

The ObGyn did not follow the standard of care: the patient’s hCG level should have been tested after the miscarriage. It is a well-known fact that an hCG level that does not return to zero after a miscarriage is cause for concern, especially from choriocarcinoma.

PHYSICIAN’S DEFENSE:

There was nothing that could have been done to save the woman’s life; choriocarcinoma is a quickly spreading cancer.

VERDICT:

A $1,800,000 Massachusetts settlement was reached.

Related article:
Manual vacuum aspiration: A safe and effective treatment for early miscarriage

Bowel perforation during hysterectomy: $860,000 verdict

A 58-year-old woman underwent laparoscopic hysterectomy and was discharged the next day although she had not urinated or defecated. After eating solid food that evening, she experienced immediate vomiting, nausea, and abdominal pain. When she saw her ObGyn the next morning, he immediately hospitalized her. During the next 8 days in the hospital, she was unable to pass gas, was febrile, and was given antibiotics. On postoperative day 11, a general surgeon transferred her to the intensive care unit due to shortness of breath and tachycardia. During exploratory abdominal surgery, several abscesses and a 1-cm injury to the rectosigmoid colon were discovered necessitating a colostomy. The patient underwent 5 additional abdominal washout procedures and was hospitalized for 40 days. Colostomy reversal surgery occurred 8 months later.

PATIENT’S CLAIM:

The ObGyn never provided an explanation of what went wrong; the patient was told the hysterectomy was accomplished without incident. An expert colorectal surgeon stated that the perforation likely occurred within 24 hours of surgery and was probably caused by the electromechanical device used during surgery.

DEFENDANTS’ DEFENSE:

The perforation was caused by a sudden rupture of a diverticulum 10 days after hysterectomy. The injury was treated in a timely manner.

VERDICT:

An $860,000 Virginia verdict was returned.

Related article:
How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Did posthysterectomy hemorrhage cause woman’s brain damage?

A 42-year-old woman underwent elective subtotal hysterectomy to treat a large uterine fibroid. In the recovery unit, she had extremely low blood pressure and tachycardia and lost consciousness for 15 minutes. She was given a blood transfusion, but was not returned to the operating room for emergency exploratory laparotomy until 3 hours later. Surgery revealed a hemorrhage from the left uterine artery requiring ligation.

PATIENT’S CLAIM:

The hemorrhage caused hypoxia resulting in an anoxic brain injury with memory and concentration difficulties. The gynecologist and hospital staff were negligent in delaying emergency treatment.

DEFENDANTS’ DEFENSE:

Postoperative bleeding is a known complication of hysterectomy. The patient was at increased risk of bleeding because of the numerous blood vessels feeding the fibroid. A morphine reaction is believed to be the cause of her becoming unconscious. The patient had not sustained an anoxic or hypoxic brain damage because she was alert and oriented immediately after the damage allegedly occurred.

VERDICT:

The Illinois jury deadlocked. The parties entered into a settlement agreement for a confidential sum before a mistrial was declared.

Related article:
7 Myomectomy myths debunked

Choriocarcinoma diagnosis missed

A 25-year-old woman had a miscarriage. A follow-up test to measure the patient’s human chorionic gonadotropin (hCG) hormone level test was not performed. The patient died from choriocarcinoma.

ESTATE’S CLAIM:

The ObGyn did not follow the standard of care: the patient’s hCG level should have been tested after the miscarriage. It is a well-known fact that an hCG level that does not return to zero after a miscarriage is cause for concern, especially from choriocarcinoma.

PHYSICIAN’S DEFENSE:

There was nothing that could have been done to save the woman’s life; choriocarcinoma is a quickly spreading cancer.

VERDICT:

A $1,800,000 Massachusetts settlement was reached.

Related article:
Manual vacuum aspiration: A safe and effective treatment for early miscarriage

Bowel perforation during hysterectomy: $860,000 verdict

A 58-year-old woman underwent laparoscopic hysterectomy and was discharged the next day although she had not urinated or defecated. After eating solid food that evening, she experienced immediate vomiting, nausea, and abdominal pain. When she saw her ObGyn the next morning, he immediately hospitalized her. During the next 8 days in the hospital, she was unable to pass gas, was febrile, and was given antibiotics. On postoperative day 11, a general surgeon transferred her to the intensive care unit due to shortness of breath and tachycardia. During exploratory abdominal surgery, several abscesses and a 1-cm injury to the rectosigmoid colon were discovered necessitating a colostomy. The patient underwent 5 additional abdominal washout procedures and was hospitalized for 40 days. Colostomy reversal surgery occurred 8 months later.

PATIENT’S CLAIM:

The ObGyn never provided an explanation of what went wrong; the patient was told the hysterectomy was accomplished without incident. An expert colorectal surgeon stated that the perforation likely occurred within 24 hours of surgery and was probably caused by the electromechanical device used during surgery.

DEFENDANTS’ DEFENSE:

The perforation was caused by a sudden rupture of a diverticulum 10 days after hysterectomy. The injury was treated in a timely manner.

VERDICT:

An $860,000 Virginia verdict was returned.

Related article:
How to avoid intestinal and urinary tract injuries during gynecologic laparoscopy

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Also from PAGS 2016:

• Dr. Tommaso Falcone offers Top 3 things I learned at the PAGS 2016 symposium
• Visit PAGS

Also from PAGS 2016:

• Dr. Tommaso Falcone offers Top 3 things I learned at the PAGS 2016 symposium
• Visit PAGS

Also from PAGS 2016:

• Dr. Tommaso Falcone offers Top 3 things I learned at the PAGS 2016 symposium
• Visit PAGS

Umbilical cord blood (cord) gas values can aid both in understanding the cause of an infant’s acidosis and in providing reassurance that acute acidosis or asphyxia is not responsible for a compromised infant with a low Apgar score. Together with other clinical measurements (including fetal heart rate [FHR] tracings, Apgar scores, newborn nucleated red cell counts, and neonatal imaging), cord gas analysis can be remarkably helpful in determining the cause for a depressed newborn. It can help us determine, for example, if infant compromise was a result of an asphyxial event, and we often can differentiate whether the event was acute, prolonged, or occurred prior to presentation in labor. We further can use cord gas values to assess whether a decision for operative intervention for nonreassuring fetal well-being was appropriate (see “Brain injury at birth: Cord gas values presented as evidence at trial”). In addition, cord gas analysis can complement methods for determining fetal acidosis changes during labor, enabling improved assessment of FHR tracings.¹⁻³

I recommend checking umbilical cord blood gas values on all operative vaginal deliveries, cesarean deliveries for fetal concern, abnormal FHR patterns, clinical chorioamnionitis, multifetal gestations, premature deliveries, and all infants with low Apgar scores at 1 or 5 minutes. If you think you may need a cord gas analysis, go ahead and obtain it. Cord gas analysis often will aid in justifying your management or provide insight into the infant’s status.

Controversy remains as to the benefit of universal cord gas analysis. Assuming a variable cost of $15 for 2 (artery and vein) blood gas samples per neonate,⁴ the annual cost in the United States would be approximately $60 million. This would likely be cost effective as a result of medicolegal and educational benefits as well as potential improvements in perinatal outcome⁵ and reductions in special care nursery admissions.⁴

CASE 1: A newborn with unexpected acidosis

A 29-year-old woman (G2P1) at 38 weeks’ gestation was admitted to the hospital following an office visit during which oligohydramnios (amniotic fluid index, 3.5 cm) was found. The patient had a history of a prior cesarean delivery for failure to progress, and she desired a repeat cesarean delivery. Fetal monitoring revealed a heart rate of 140 beats per minute with moderate variability and uterine contractions every 3 to 5 minutes associated with moderate variable decelerations. A decision was made to proceed with the surgery. Blood samples were drawn for laboratory analysis, monitoring was discontinued, and the patient was taken to the operating room. An epidural anesthetic was placed and the cesarean delivery proceeded.

On uterine incision, there was no evidence of abruption or uterine rupture, but thick meconium-stained amniotic fluid was observed. A depressed infant was delivered, the umbilical cord clamped, and the infant handed to the pediatric team. Cord samples were obtained and values from the umbilical artery were as follows: pH, 6.80; Pco₂, 120 mm Hg; Po₂, 6 mm Hg; and base deficit extracellular fluid (BD_ECF), 13.8 mmol/L. Values from the umbilical vein were: pH, 7.32; Pco₂, 38 mm Hg; Po₂, 22 mm Hg; and BD_ECF, 5.8 mmol/L. The infant’s Apgar scores were 1, 2, and 7 at 1, 5, and 10 minutes, respectively, and the infant demonstrated encephalopathy, requiring brain cooling.

What happened?

Read how to use cord gas values in practice

Using cord gas values in practice

Before analyzing the circumstances in Case 1,it is important to consider several key questions, including:

• What are the normal levels of cord pH, O₂, CO₂, and base deficit (BD)?
• How does cord gas indicate what happened during labor?
• What are the preventable errors in cord gas sampling or interpretation?

For a review of fetal cord gas physiology, see “Physiology of fetal cord gases: The basics”.

Normal values: The “20, 30, 40, 50 rule”

Among the values reported for umbilical blood gas, the pH, Pco₂, and Po₂ are measured, whereas BD is calculated. The normal values for umbilical pH and blood gases are often included with laboratory results, although typically with a broad, overlapping range of values that may make it difficult to determine which is umbilical artery or vein (TABLE 1).^6,7

I recommend using the “20, 30, 40, 50 rule” as a simple tool for remembering normal umbilical artery and vein Po₂ and Pco₂ values (TABLE 2):

• Po₂ values are lower than Pco₂ values; thus, the 20 and 30 represent Po₂ values
• as fetal umbilical artery Po₂ is lower than umbilical vein Po₂, 20 mm Hg represents the umbilical artery and 30 mm Hg represents the vein
• Pco₂ values are higher in the umbilical artery than in the vein; thus, 50 mm Hg represents the umbilical artery and 40 mm Hg represents the umbilical vein.

Umbilical cord BD values change in relation to labor and FHR decelerations.⁸ Prior to labor, the normal fetus has a slight degree of acidosis (BD, 2 mmol/L). During the latent phase of labor, fetal BD typically does not change. With the increased frequency of contractions, BD may increase 1 mmol/L for every 3 to 6 hours during the active phase and up to 1 mmol/L per hour during the second stage, depending on FHR responses. Thus, following vaginal delivery the average umbilical artery BD is approximately 5 mmol/L and the umbilical vein BD is approximately 4 mmol/L. As lactate crosses the placenta slowly, BD values are typically only 1 mmol/L less in the umbilical vein than in the artery, unless there has been an obstruction to placental flow (see Case 1).

For pH, the umbilical artery value is always lower than that of the vein, a result of both the higher umbilical artery Pco₂ as well as the slightly higher levels of lactic acid before placental clearance. Fetal pH levels typically decrease during labor associated with the increased BD described above. However, short-term effects of increased CO₂ (respiratory acidosis) or CO₂ clearance may cause fluctuations in pH that do not correlate with the degree of metabolic acidosis.

Possible causes of abnormal cord gas values

Because of the nearly fully saturated maternal hemoglobin under normal conditions, fetal arterial and venous Po₂ levels cannot be increased significantly above normal values. However, reduced fetal Po₂ and increased fetal Pco₂ may occur with poor gas exchange between the maternal and fetal compartments (eg, placental abruption) or maternal respiratory compromise.

In contrast, reduced fetal Pco₂ may occur under conditions of maternal hyperventilation and lower maternal Pco₂ values. Decreased pH levels may be due to respiratory or metabolic acidosis, the former of which is generally benign. Elevated BD typically is a result of fetal metabolic acidosis, and values approaching 12 mmol/L should be avoided, if possible, as this level may be associated with newborn neurologic injury.⁹

Effect of maternal oxygen administration on fetal oxygenation

Although maternal oxygen administration is commonly used during labor and delivery, controversy remains as to the benefit of oxygen supplementation.¹⁰ In a normal mother with oxygen saturation above 95%, the administration of oxygen will increase maternal arterial Po₂ levels and thus dissolved oxygen. Because maternal hemoglobin is normally almost fully saturated at room air Po₂ levels, there is little change in the bound oxygen and thus little change in the maternal arterial O₂ content or maternal uterine venous Po₂ levels. As fetal umbilical vein Po₂ levels equilibrate to maternal uterine vein Po₂ levels, there is minimal change in fetal oxygenation.

However, maternal oxygen supplementation may have marked benefit in cases in which maternal arterial Po₂ is low (respiratory compromise). In this case, the steep fetal oxygen saturation curve may produce a large increase in fetal umbilical vein oxygen content. Thus, strongly consider oxygen supplementation for mothers with impaired cardiorespiratory function, and recognize that maternal oxygen supplementation for normal mothers may result in nominal benefit for compromised fetuses.

How did the Case 1 circumstances lead to newborn acidosis?

Most noticeable in this case is the large difference in BD between the umbilical artery and vein and the high Pco₂in the artery. Under conditions without interruption of fetal placental flow, either the umbilical artery and/or vein will provide a similar assessment of fetal or newborn metabolic acidosis (that is, BD).

Whereas BD normally is only about 1 mmol/L greater in the umbilical artery versus in the vein, occasionally the arterial value is markedly greater than the vein value. This can occur when there is a cessation of blood flow through the placenta, as a result of complete umbilical cord obstruction, or when there is a uterine abruption. In these situations, the umbilical vein (which has not had blood flow) represents the fetal status prior to the occlusion event. In contrast, despite bradycardia, fetal heart pulsations mix blood within the umbilical artery and therefore the artery generally represents the fetal status at the time of birth.

In response to complete cord occlusion, fetal BD increases by approximately 1 mmol/L every 2 minutes. Consequently, an 8 mmol/L difference in BD between the umbilical artery and vein is consistent with a 16-minute period of umbilical occlusion or placental abruption. Also in response to complete umbilical cord occlusion, Pco₂ values rise by approximately 7 mm Hg per minute of the occlusion, although this may not be linear at higher levels. Thus, the BD difference suggests there was likely a complete cord occlusion for the 16 minutes prior to birth.

The umbilical vein BD is also elevated for early labor. This value suggests that repetitive, intermittent cord occlusions (evident on the initial fetal monitor tracing) likely resulted in this moderate acidosis prior to the complete cord occlusion in the final 16 minutes.

Thus, BD and Pco₂ levels can be used to time the onset of umbilical cord occlusion or abruption. Since pH is an inverse logarithmic function, it cannot be used to time the onset or duration of cord occlusion. Remember that BD values should be adjusted for extracellular fluid under conditions of markedly elevated Pco₂.

Read more cases plus procedures, equipment for cord sampling

Illustration: Kimberly Martens for OBG Management

CASE 2: An infant with unusual umbilical artery values

An infant born via vacuum delivery for a prolonged second stage of labor had 1- and 5-minute Apgar scores of 8 and 9, respectively. Cord gas values were obtained, and analysis revealed that for the umbilical artery, the pH was 7.29; Pco₂, 20 mm Hg; and Po₂, 60 mm Hg. For the umbilical vein, the pH was 7.32; Pco₂, 38 mm Hg; and Po₂, 22 mm Hg.

The resident asked, “How is the Po₂ higher in the artery than in the vein?”

The curious Case 2 values suggest an air bubble

Although it is possible that the aberrant values in Case 2 could have resulted from switching the artery and vein samples, the pH is lower in the artery, and both the artery Po₂ and Pco₂ levels do not appear physiologic. The likely explanation for these values is that an air bubble was contained in the syringe. Since normal room air (21% O₂) has a Po₂ of 159 mm Hg and a Pco₂ of less than 1 mm Hg, exposure of cord blood gases to air bubbles will significantly increase the Po₂ and markedly reduce the Pco₂ values of the sample. Take care to avoid air bubbles in the syringes used to obtain samples for analysis.

Related article:
Is neonatal injury more likely outside of a 30-minute decision-to-incision time interval for cesarean delivery?

CASE 3: A vigorous baby with significant acidosis

A baby with 1- and 5-minute Apgar scores of 9 and 9 was delivered by cesarean and remained vigorous. Umbilical cord analysis revealed an umbilical artery pH level of 7.15, with normal Po₂ and Pco₂ values. What could be the explanation?

Was there a collection error in Case 3?

On occasion, a falsely low pH level and, thus, a falsely elevated BD may result from excessive heparin in the collection syringe. Heparin is acidotic and should be used only to coat the syringe. Although syringes in current use are often pre-heparinized, if one is drawing up heparin into the syringe, it should be coated and then fully expelled.

Umbilical cord sampling: Procedures and equipment

Many issues remain regarding the optimal storage of cord samples. Ideally, a doubly clamped section of the cord promptly should be sampled into glass syringes that can be placed on ice and rapidly measured for cord values.

Stability of umbilical cord samples within the cord is within 20 to 30 minutes. Delayed sampling of clamped cord sections generally has minimal effect on pH and Pco₂ values.¹¹ The BD does not change to a clinically significant degree over 15 to 30 minutes despite the cord specimen remaining at room temperature. However, one report demonstrated an increase in lactate and BD by 20 minutes under these conditions; this likely was a result of metabolism from endothelial or blood cells.¹² I therefore recommend that clamped cord be sampled as soon as is feasible and ideally not beyond 20 to 30 minutes.

Plastic syringes can introduce interference. Several studies have demonstrated that collection of samples in plastic may result in an increase in Po₂ values, likely due to the high room air Po₂ diffusing through the plastic to the blood sample.

Use glass, and “ice” the sample if necessary. Although it has been suggested that placing samples on ice minimizes metabolism, the cooled plastic may in fact be more susceptible to oxygen diffusion. Thus, unless samples will be analyzed promptly, it is best to use glass syringes on ice.^13,14

Related article:
Protecting the newborn brain—the final frontier in obstetric and neonatal care

What if the umbilical cord is torn?

Sometimes the umbilical cord is torn and discarded or cannot be accessed for other reasons. A sample can still be obtained, however, by aspirating the placental surface artery and vein vessels. Although there is some potential variance in pH, Po₂, and Pco₂ levels, the BD values of placental vessels have a high correlation with those of umbilical vessels and therefore can be used when the cord is not available.¹⁵

How do you obtain cord analysis when delaying cord clamping?

The American College of Obstetricians and Gynecologists (ACOG) now advises delayed cord clamping in term and preterm deliveries, which raises the question of how you obtain a blood sample in this setting. Importantly, ACOG recommends delayed cord clamping only in vigorous infants,¹⁶ whereas potentially compromised infants should be transferred rapidly for newborn care. Although several studies have demonstrated some variation in cord gas values with delayed cord clamping,^17–21 clamping after pulsation has ceased or after the recommended 30 to 60 seconds following birth results in minimal change in BD values. Thus, do not hesitate to perform delayed cord clamping in vigorous infants.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Umbilical cord blood (cord) gas values can aid both in understanding the cause of an infant’s acidosis and in providing reassurance that acute acidosis or asphyxia is not responsible for a compromised infant with a low Apgar score. Together with other clinical measurements (including fetal heart rate [FHR] tracings, Apgar scores, newborn nucleated red cell counts, and neonatal imaging), cord gas analysis can be remarkably helpful in determining the cause for a depressed newborn. It can help us determine, for example, if infant compromise was a result of an asphyxial event, and we often can differentiate whether the event was acute, prolonged, or occurred prior to presentation in labor. We further can use cord gas values to assess whether a decision for operative intervention for nonreassuring fetal well-being was appropriate (see “Brain injury at birth: Cord gas values presented as evidence at trial”). In addition, cord gas analysis can complement methods for determining fetal acidosis changes during labor, enabling improved assessment of FHR tracings.¹⁻³

I recommend checking umbilical cord blood gas values on all operative vaginal deliveries, cesarean deliveries for fetal concern, abnormal FHR patterns, clinical chorioamnionitis, multifetal gestations, premature deliveries, and all infants with low Apgar scores at 1 or 5 minutes. If you think you may need a cord gas analysis, go ahead and obtain it. Cord gas analysis often will aid in justifying your management or provide insight into the infant’s status.

Controversy remains as to the benefit of universal cord gas analysis. Assuming a variable cost of $15 for 2 (artery and vein) blood gas samples per neonate,⁴ the annual cost in the United States would be approximately $60 million. This would likely be cost effective as a result of medicolegal and educational benefits as well as potential improvements in perinatal outcome⁵ and reductions in special care nursery admissions.⁴

CASE 1: A newborn with unexpected acidosis

A 29-year-old woman (G2P1) at 38 weeks’ gestation was admitted to the hospital following an office visit during which oligohydramnios (amniotic fluid index, 3.5 cm) was found. The patient had a history of a prior cesarean delivery for failure to progress, and she desired a repeat cesarean delivery. Fetal monitoring revealed a heart rate of 140 beats per minute with moderate variability and uterine contractions every 3 to 5 minutes associated with moderate variable decelerations. A decision was made to proceed with the surgery. Blood samples were drawn for laboratory analysis, monitoring was discontinued, and the patient was taken to the operating room. An epidural anesthetic was placed and the cesarean delivery proceeded.

On uterine incision, there was no evidence of abruption or uterine rupture, but thick meconium-stained amniotic fluid was observed. A depressed infant was delivered, the umbilical cord clamped, and the infant handed to the pediatric team. Cord samples were obtained and values from the umbilical artery were as follows: pH, 6.80; Pco₂, 120 mm Hg; Po₂, 6 mm Hg; and base deficit extracellular fluid (BD_ECF), 13.8 mmol/L. Values from the umbilical vein were: pH, 7.32; Pco₂, 38 mm Hg; Po₂, 22 mm Hg; and BD_ECF, 5.8 mmol/L. The infant’s Apgar scores were 1, 2, and 7 at 1, 5, and 10 minutes, respectively, and the infant demonstrated encephalopathy, requiring brain cooling.

What happened?

Read how to use cord gas values in practice

Using cord gas values in practice

Before analyzing the circumstances in Case 1,it is important to consider several key questions, including:

• What are the normal levels of cord pH, O₂, CO₂, and base deficit (BD)?
• How does cord gas indicate what happened during labor?
• What are the preventable errors in cord gas sampling or interpretation?

For a review of fetal cord gas physiology, see “Physiology of fetal cord gases: The basics”.

Normal values: The “20, 30, 40, 50 rule”

Among the values reported for umbilical blood gas, the pH, Pco₂, and Po₂ are measured, whereas BD is calculated. The normal values for umbilical pH and blood gases are often included with laboratory results, although typically with a broad, overlapping range of values that may make it difficult to determine which is umbilical artery or vein (TABLE 1).^6,7

I recommend using the “20, 30, 40, 50 rule” as a simple tool for remembering normal umbilical artery and vein Po₂ and Pco₂ values (TABLE 2):

• Po₂ values are lower than Pco₂ values; thus, the 20 and 30 represent Po₂ values
• as fetal umbilical artery Po₂ is lower than umbilical vein Po₂, 20 mm Hg represents the umbilical artery and 30 mm Hg represents the vein
• Pco₂ values are higher in the umbilical artery than in the vein; thus, 50 mm Hg represents the umbilical artery and 40 mm Hg represents the umbilical vein.

Umbilical cord BD values change in relation to labor and FHR decelerations.⁸ Prior to labor, the normal fetus has a slight degree of acidosis (BD, 2 mmol/L). During the latent phase of labor, fetal BD typically does not change. With the increased frequency of contractions, BD may increase 1 mmol/L for every 3 to 6 hours during the active phase and up to 1 mmol/L per hour during the second stage, depending on FHR responses. Thus, following vaginal delivery the average umbilical artery BD is approximately 5 mmol/L and the umbilical vein BD is approximately 4 mmol/L. As lactate crosses the placenta slowly, BD values are typically only 1 mmol/L less in the umbilical vein than in the artery, unless there has been an obstruction to placental flow (see Case 1).

For pH, the umbilical artery value is always lower than that of the vein, a result of both the higher umbilical artery Pco₂ as well as the slightly higher levels of lactic acid before placental clearance. Fetal pH levels typically decrease during labor associated with the increased BD described above. However, short-term effects of increased CO₂ (respiratory acidosis) or CO₂ clearance may cause fluctuations in pH that do not correlate with the degree of metabolic acidosis.

Possible causes of abnormal cord gas values

Because of the nearly fully saturated maternal hemoglobin under normal conditions, fetal arterial and venous Po₂ levels cannot be increased significantly above normal values. However, reduced fetal Po₂ and increased fetal Pco₂ may occur with poor gas exchange between the maternal and fetal compartments (eg, placental abruption) or maternal respiratory compromise.

In contrast, reduced fetal Pco₂ may occur under conditions of maternal hyperventilation and lower maternal Pco₂ values. Decreased pH levels may be due to respiratory or metabolic acidosis, the former of which is generally benign. Elevated BD typically is a result of fetal metabolic acidosis, and values approaching 12 mmol/L should be avoided, if possible, as this level may be associated with newborn neurologic injury.⁹

Effect of maternal oxygen administration on fetal oxygenation

Although maternal oxygen administration is commonly used during labor and delivery, controversy remains as to the benefit of oxygen supplementation.¹⁰ In a normal mother with oxygen saturation above 95%, the administration of oxygen will increase maternal arterial Po₂ levels and thus dissolved oxygen. Because maternal hemoglobin is normally almost fully saturated at room air Po₂ levels, there is little change in the bound oxygen and thus little change in the maternal arterial O₂ content or maternal uterine venous Po₂ levels. As fetal umbilical vein Po₂ levels equilibrate to maternal uterine vein Po₂ levels, there is minimal change in fetal oxygenation.

However, maternal oxygen supplementation may have marked benefit in cases in which maternal arterial Po₂ is low (respiratory compromise). In this case, the steep fetal oxygen saturation curve may produce a large increase in fetal umbilical vein oxygen content. Thus, strongly consider oxygen supplementation for mothers with impaired cardiorespiratory function, and recognize that maternal oxygen supplementation for normal mothers may result in nominal benefit for compromised fetuses.

How did the Case 1 circumstances lead to newborn acidosis?

Most noticeable in this case is the large difference in BD between the umbilical artery and vein and the high Pco₂in the artery. Under conditions without interruption of fetal placental flow, either the umbilical artery and/or vein will provide a similar assessment of fetal or newborn metabolic acidosis (that is, BD).

Whereas BD normally is only about 1 mmol/L greater in the umbilical artery versus in the vein, occasionally the arterial value is markedly greater than the vein value. This can occur when there is a cessation of blood flow through the placenta, as a result of complete umbilical cord obstruction, or when there is a uterine abruption. In these situations, the umbilical vein (which has not had blood flow) represents the fetal status prior to the occlusion event. In contrast, despite bradycardia, fetal heart pulsations mix blood within the umbilical artery and therefore the artery generally represents the fetal status at the time of birth.

In response to complete cord occlusion, fetal BD increases by approximately 1 mmol/L every 2 minutes. Consequently, an 8 mmol/L difference in BD between the umbilical artery and vein is consistent with a 16-minute period of umbilical occlusion or placental abruption. Also in response to complete umbilical cord occlusion, Pco₂ values rise by approximately 7 mm Hg per minute of the occlusion, although this may not be linear at higher levels. Thus, the BD difference suggests there was likely a complete cord occlusion for the 16 minutes prior to birth.

The umbilical vein BD is also elevated for early labor. This value suggests that repetitive, intermittent cord occlusions (evident on the initial fetal monitor tracing) likely resulted in this moderate acidosis prior to the complete cord occlusion in the final 16 minutes.

Thus, BD and Pco₂ levels can be used to time the onset of umbilical cord occlusion or abruption. Since pH is an inverse logarithmic function, it cannot be used to time the onset or duration of cord occlusion. Remember that BD values should be adjusted for extracellular fluid under conditions of markedly elevated Pco₂.

Read more cases plus procedures, equipment for cord sampling

Illustration: Kimberly Martens for OBG Management

CASE 2: An infant with unusual umbilical artery values

An infant born via vacuum delivery for a prolonged second stage of labor had 1- and 5-minute Apgar scores of 8 and 9, respectively. Cord gas values were obtained, and analysis revealed that for the umbilical artery, the pH was 7.29; Pco₂, 20 mm Hg; and Po₂, 60 mm Hg. For the umbilical vein, the pH was 7.32; Pco₂, 38 mm Hg; and Po₂, 22 mm Hg.

The resident asked, “How is the Po₂ higher in the artery than in the vein?”

The curious Case 2 values suggest an air bubble

Although it is possible that the aberrant values in Case 2 could have resulted from switching the artery and vein samples, the pH is lower in the artery, and both the artery Po₂ and Pco₂ levels do not appear physiologic. The likely explanation for these values is that an air bubble was contained in the syringe. Since normal room air (21% O₂) has a Po₂ of 159 mm Hg and a Pco₂ of less than 1 mm Hg, exposure of cord blood gases to air bubbles will significantly increase the Po₂ and markedly reduce the Pco₂ values of the sample. Take care to avoid air bubbles in the syringes used to obtain samples for analysis.

Related article:
Is neonatal injury more likely outside of a 30-minute decision-to-incision time interval for cesarean delivery?

CASE 3: A vigorous baby with significant acidosis

A baby with 1- and 5-minute Apgar scores of 9 and 9 was delivered by cesarean and remained vigorous. Umbilical cord analysis revealed an umbilical artery pH level of 7.15, with normal Po₂ and Pco₂ values. What could be the explanation?

Was there a collection error in Case 3?

On occasion, a falsely low pH level and, thus, a falsely elevated BD may result from excessive heparin in the collection syringe. Heparin is acidotic and should be used only to coat the syringe. Although syringes in current use are often pre-heparinized, if one is drawing up heparin into the syringe, it should be coated and then fully expelled.

Umbilical cord sampling: Procedures and equipment

Many issues remain regarding the optimal storage of cord samples. Ideally, a doubly clamped section of the cord promptly should be sampled into glass syringes that can be placed on ice and rapidly measured for cord values.

Stability of umbilical cord samples within the cord is within 20 to 30 minutes. Delayed sampling of clamped cord sections generally has minimal effect on pH and Pco₂ values.¹¹ The BD does not change to a clinically significant degree over 15 to 30 minutes despite the cord specimen remaining at room temperature. However, one report demonstrated an increase in lactate and BD by 20 minutes under these conditions; this likely was a result of metabolism from endothelial or blood cells.¹² I therefore recommend that clamped cord be sampled as soon as is feasible and ideally not beyond 20 to 30 minutes.

Plastic syringes can introduce interference. Several studies have demonstrated that collection of samples in plastic may result in an increase in Po₂ values, likely due to the high room air Po₂ diffusing through the plastic to the blood sample.

Use glass, and “ice” the sample if necessary. Although it has been suggested that placing samples on ice minimizes metabolism, the cooled plastic may in fact be more susceptible to oxygen diffusion. Thus, unless samples will be analyzed promptly, it is best to use glass syringes on ice.^13,14

Related article:
Protecting the newborn brain—the final frontier in obstetric and neonatal care

What if the umbilical cord is torn?

Sometimes the umbilical cord is torn and discarded or cannot be accessed for other reasons. A sample can still be obtained, however, by aspirating the placental surface artery and vein vessels. Although there is some potential variance in pH, Po₂, and Pco₂ levels, the BD values of placental vessels have a high correlation with those of umbilical vessels and therefore can be used when the cord is not available.¹⁵

How do you obtain cord analysis when delaying cord clamping?

The American College of Obstetricians and Gynecologists (ACOG) now advises delayed cord clamping in term and preterm deliveries, which raises the question of how you obtain a blood sample in this setting. Importantly, ACOG recommends delayed cord clamping only in vigorous infants,¹⁶ whereas potentially compromised infants should be transferred rapidly for newborn care. Although several studies have demonstrated some variation in cord gas values with delayed cord clamping,^17–21 clamping after pulsation has ceased or after the recommended 30 to 60 seconds following birth results in minimal change in BD values. Thus, do not hesitate to perform delayed cord clamping in vigorous infants.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Umbilical cord blood (cord) gas values can aid both in understanding the cause of an infant’s acidosis and in providing reassurance that acute acidosis or asphyxia is not responsible for a compromised infant with a low Apgar score. Together with other clinical measurements (including fetal heart rate [FHR] tracings, Apgar scores, newborn nucleated red cell counts, and neonatal imaging), cord gas analysis can be remarkably helpful in determining the cause for a depressed newborn. It can help us determine, for example, if infant compromise was a result of an asphyxial event, and we often can differentiate whether the event was acute, prolonged, or occurred prior to presentation in labor. We further can use cord gas values to assess whether a decision for operative intervention for nonreassuring fetal well-being was appropriate (see “Brain injury at birth: Cord gas values presented as evidence at trial”). In addition, cord gas analysis can complement methods for determining fetal acidosis changes during labor, enabling improved assessment of FHR tracings.¹⁻³

I recommend checking umbilical cord blood gas values on all operative vaginal deliveries, cesarean deliveries for fetal concern, abnormal FHR patterns, clinical chorioamnionitis, multifetal gestations, premature deliveries, and all infants with low Apgar scores at 1 or 5 minutes. If you think you may need a cord gas analysis, go ahead and obtain it. Cord gas analysis often will aid in justifying your management or provide insight into the infant’s status.

Controversy remains as to the benefit of universal cord gas analysis. Assuming a variable cost of $15 for 2 (artery and vein) blood gas samples per neonate,⁴ the annual cost in the United States would be approximately $60 million. This would likely be cost effective as a result of medicolegal and educational benefits as well as potential improvements in perinatal outcome⁵ and reductions in special care nursery admissions.⁴

CASE 1: A newborn with unexpected acidosis

A 29-year-old woman (G2P1) at 38 weeks’ gestation was admitted to the hospital following an office visit during which oligohydramnios (amniotic fluid index, 3.5 cm) was found. The patient had a history of a prior cesarean delivery for failure to progress, and she desired a repeat cesarean delivery. Fetal monitoring revealed a heart rate of 140 beats per minute with moderate variability and uterine contractions every 3 to 5 minutes associated with moderate variable decelerations. A decision was made to proceed with the surgery. Blood samples were drawn for laboratory analysis, monitoring was discontinued, and the patient was taken to the operating room. An epidural anesthetic was placed and the cesarean delivery proceeded.

On uterine incision, there was no evidence of abruption or uterine rupture, but thick meconium-stained amniotic fluid was observed. A depressed infant was delivered, the umbilical cord clamped, and the infant handed to the pediatric team. Cord samples were obtained and values from the umbilical artery were as follows: pH, 6.80; Pco₂, 120 mm Hg; Po₂, 6 mm Hg; and base deficit extracellular fluid (BD_ECF), 13.8 mmol/L. Values from the umbilical vein were: pH, 7.32; Pco₂, 38 mm Hg; Po₂, 22 mm Hg; and BD_ECF, 5.8 mmol/L. The infant’s Apgar scores were 1, 2, and 7 at 1, 5, and 10 minutes, respectively, and the infant demonstrated encephalopathy, requiring brain cooling.

What happened?

Read how to use cord gas values in practice

Using cord gas values in practice

Before analyzing the circumstances in Case 1,it is important to consider several key questions, including:

• What are the normal levels of cord pH, O₂, CO₂, and base deficit (BD)?
• How does cord gas indicate what happened during labor?
• What are the preventable errors in cord gas sampling or interpretation?

For a review of fetal cord gas physiology, see “Physiology of fetal cord gases: The basics”.

Normal values: The “20, 30, 40, 50 rule”

Among the values reported for umbilical blood gas, the pH, Pco₂, and Po₂ are measured, whereas BD is calculated. The normal values for umbilical pH and blood gases are often included with laboratory results, although typically with a broad, overlapping range of values that may make it difficult to determine which is umbilical artery or vein (TABLE 1).^6,7

I recommend using the “20, 30, 40, 50 rule” as a simple tool for remembering normal umbilical artery and vein Po₂ and Pco₂ values (TABLE 2):

• Po₂ values are lower than Pco₂ values; thus, the 20 and 30 represent Po₂ values
• as fetal umbilical artery Po₂ is lower than umbilical vein Po₂, 20 mm Hg represents the umbilical artery and 30 mm Hg represents the vein
• Pco₂ values are higher in the umbilical artery than in the vein; thus, 50 mm Hg represents the umbilical artery and 40 mm Hg represents the umbilical vein.

Umbilical cord BD values change in relation to labor and FHR decelerations.⁸ Prior to labor, the normal fetus has a slight degree of acidosis (BD, 2 mmol/L). During the latent phase of labor, fetal BD typically does not change. With the increased frequency of contractions, BD may increase 1 mmol/L for every 3 to 6 hours during the active phase and up to 1 mmol/L per hour during the second stage, depending on FHR responses. Thus, following vaginal delivery the average umbilical artery BD is approximately 5 mmol/L and the umbilical vein BD is approximately 4 mmol/L. As lactate crosses the placenta slowly, BD values are typically only 1 mmol/L less in the umbilical vein than in the artery, unless there has been an obstruction to placental flow (see Case 1).

For pH, the umbilical artery value is always lower than that of the vein, a result of both the higher umbilical artery Pco₂ as well as the slightly higher levels of lactic acid before placental clearance. Fetal pH levels typically decrease during labor associated with the increased BD described above. However, short-term effects of increased CO₂ (respiratory acidosis) or CO₂ clearance may cause fluctuations in pH that do not correlate with the degree of metabolic acidosis.

Possible causes of abnormal cord gas values

Because of the nearly fully saturated maternal hemoglobin under normal conditions, fetal arterial and venous Po₂ levels cannot be increased significantly above normal values. However, reduced fetal Po₂ and increased fetal Pco₂ may occur with poor gas exchange between the maternal and fetal compartments (eg, placental abruption) or maternal respiratory compromise.

In contrast, reduced fetal Pco₂ may occur under conditions of maternal hyperventilation and lower maternal Pco₂ values. Decreased pH levels may be due to respiratory or metabolic acidosis, the former of which is generally benign. Elevated BD typically is a result of fetal metabolic acidosis, and values approaching 12 mmol/L should be avoided, if possible, as this level may be associated with newborn neurologic injury.⁹

Effect of maternal oxygen administration on fetal oxygenation

Although maternal oxygen administration is commonly used during labor and delivery, controversy remains as to the benefit of oxygen supplementation.¹⁰ In a normal mother with oxygen saturation above 95%, the administration of oxygen will increase maternal arterial Po₂ levels and thus dissolved oxygen. Because maternal hemoglobin is normally almost fully saturated at room air Po₂ levels, there is little change in the bound oxygen and thus little change in the maternal arterial O₂ content or maternal uterine venous Po₂ levels. As fetal umbilical vein Po₂ levels equilibrate to maternal uterine vein Po₂ levels, there is minimal change in fetal oxygenation.

However, maternal oxygen supplementation may have marked benefit in cases in which maternal arterial Po₂ is low (respiratory compromise). In this case, the steep fetal oxygen saturation curve may produce a large increase in fetal umbilical vein oxygen content. Thus, strongly consider oxygen supplementation for mothers with impaired cardiorespiratory function, and recognize that maternal oxygen supplementation for normal mothers may result in nominal benefit for compromised fetuses.

How did the Case 1 circumstances lead to newborn acidosis?

Most noticeable in this case is the large difference in BD between the umbilical artery and vein and the high Pco₂in the artery. Under conditions without interruption of fetal placental flow, either the umbilical artery and/or vein will provide a similar assessment of fetal or newborn metabolic acidosis (that is, BD).

Whereas BD normally is only about 1 mmol/L greater in the umbilical artery versus in the vein, occasionally the arterial value is markedly greater than the vein value. This can occur when there is a cessation of blood flow through the placenta, as a result of complete umbilical cord obstruction, or when there is a uterine abruption. In these situations, the umbilical vein (which has not had blood flow) represents the fetal status prior to the occlusion event. In contrast, despite bradycardia, fetal heart pulsations mix blood within the umbilical artery and therefore the artery generally represents the fetal status at the time of birth.

In response to complete cord occlusion, fetal BD increases by approximately 1 mmol/L every 2 minutes. Consequently, an 8 mmol/L difference in BD between the umbilical artery and vein is consistent with a 16-minute period of umbilical occlusion or placental abruption. Also in response to complete umbilical cord occlusion, Pco₂ values rise by approximately 7 mm Hg per minute of the occlusion, although this may not be linear at higher levels. Thus, the BD difference suggests there was likely a complete cord occlusion for the 16 minutes prior to birth.

The umbilical vein BD is also elevated for early labor. This value suggests that repetitive, intermittent cord occlusions (evident on the initial fetal monitor tracing) likely resulted in this moderate acidosis prior to the complete cord occlusion in the final 16 minutes.

Thus, BD and Pco₂ levels can be used to time the onset of umbilical cord occlusion or abruption. Since pH is an inverse logarithmic function, it cannot be used to time the onset or duration of cord occlusion. Remember that BD values should be adjusted for extracellular fluid under conditions of markedly elevated Pco₂.

Read more cases plus procedures, equipment for cord sampling

Illustration: Kimberly Martens for OBG Management

CASE 2: An infant with unusual umbilical artery values

An infant born via vacuum delivery for a prolonged second stage of labor had 1- and 5-minute Apgar scores of 8 and 9, respectively. Cord gas values were obtained, and analysis revealed that for the umbilical artery, the pH was 7.29; Pco₂, 20 mm Hg; and Po₂, 60 mm Hg. For the umbilical vein, the pH was 7.32; Pco₂, 38 mm Hg; and Po₂, 22 mm Hg.

The resident asked, “How is the Po₂ higher in the artery than in the vein?”

The curious Case 2 values suggest an air bubble

Although it is possible that the aberrant values in Case 2 could have resulted from switching the artery and vein samples, the pH is lower in the artery, and both the artery Po₂ and Pco₂ levels do not appear physiologic. The likely explanation for these values is that an air bubble was contained in the syringe. Since normal room air (21% O₂) has a Po₂ of 159 mm Hg and a Pco₂ of less than 1 mm Hg, exposure of cord blood gases to air bubbles will significantly increase the Po₂ and markedly reduce the Pco₂ values of the sample. Take care to avoid air bubbles in the syringes used to obtain samples for analysis.

Related article:
Is neonatal injury more likely outside of a 30-minute decision-to-incision time interval for cesarean delivery?

CASE 3: A vigorous baby with significant acidosis

A baby with 1- and 5-minute Apgar scores of 9 and 9 was delivered by cesarean and remained vigorous. Umbilical cord analysis revealed an umbilical artery pH level of 7.15, with normal Po₂ and Pco₂ values. What could be the explanation?

Was there a collection error in Case 3?

On occasion, a falsely low pH level and, thus, a falsely elevated BD may result from excessive heparin in the collection syringe. Heparin is acidotic and should be used only to coat the syringe. Although syringes in current use are often pre-heparinized, if one is drawing up heparin into the syringe, it should be coated and then fully expelled.

Umbilical cord sampling: Procedures and equipment

Many issues remain regarding the optimal storage of cord samples. Ideally, a doubly clamped section of the cord promptly should be sampled into glass syringes that can be placed on ice and rapidly measured for cord values.

Stability of umbilical cord samples within the cord is within 20 to 30 minutes. Delayed sampling of clamped cord sections generally has minimal effect on pH and Pco₂ values.¹¹ The BD does not change to a clinically significant degree over 15 to 30 minutes despite the cord specimen remaining at room temperature. However, one report demonstrated an increase in lactate and BD by 20 minutes under these conditions; this likely was a result of metabolism from endothelial or blood cells.¹² I therefore recommend that clamped cord be sampled as soon as is feasible and ideally not beyond 20 to 30 minutes.

Plastic syringes can introduce interference. Several studies have demonstrated that collection of samples in plastic may result in an increase in Po₂ values, likely due to the high room air Po₂ diffusing through the plastic to the blood sample.

Use glass, and “ice” the sample if necessary. Although it has been suggested that placing samples on ice minimizes metabolism, the cooled plastic may in fact be more susceptible to oxygen diffusion. Thus, unless samples will be analyzed promptly, it is best to use glass syringes on ice.^13,14

Related article:
Protecting the newborn brain—the final frontier in obstetric and neonatal care

What if the umbilical cord is torn?

Sometimes the umbilical cord is torn and discarded or cannot be accessed for other reasons. A sample can still be obtained, however, by aspirating the placental surface artery and vein vessels. Although there is some potential variance in pH, Po₂, and Pco₂ levels, the BD values of placental vessels have a high correlation with those of umbilical vessels and therefore can be used when the cord is not available.¹⁵

How do you obtain cord analysis when delaying cord clamping?

The American College of Obstetricians and Gynecologists (ACOG) now advises delayed cord clamping in term and preterm deliveries, which raises the question of how you obtain a blood sample in this setting. Importantly, ACOG recommends delayed cord clamping only in vigorous infants,¹⁶ whereas potentially compromised infants should be transferred rapidly for newborn care. Although several studies have demonstrated some variation in cord gas values with delayed cord clamping,^17–21 clamping after pulsation has ceased or after the recommended 30 to 60 seconds following birth results in minimal change in BD values. Thus, do not hesitate to perform delayed cord clamping in vigorous infants.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In 2017, an estimated 22,240 women will be diagnosed with ovarian cancer, and 14,080 women will die of the disease.¹ The high mortality associated with ovarian cancer is due largely to the inability to detect the disease early and the lack of effective therapeutics for women with recurrent disease. In this Update, we review important advances in the diagnosis and treatment of ovarian cancer.

Development of an effective screening tool for women at average risk has been an elusive challenge. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) examined the efficacy of transvaginal ultrasound and cancer antigen 125 (CA 125) monitoring for ovarian cancer in a large cohort of women.

For women diagnosed with ovarian cancer, treatment paradigms for the initial management of the disease have shifted dramatically. Based on data from multiple randomized controlled trials, neoadjuvant chemotherapy (NACT) is being used more frequently. The American Society of Clinical Oncology and the Society of Gynecologic Oncology developed consensus recommendations for the appropriate use of NACT and primary cytoreductive surgery for women with ovarian cancer.

Finally, all of oncology has moved toward incorporating molecularly targeted therapeutics directed toward individual genetic abnormalities in tumors, so-called precision medicine. In ovarian cancer, poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) has emerged as an important target, particularly for women with BRCA gene pathway mutations. We describe a recently published randomized controlled trial of the PARP inhibitor niraparib.

Read about ovarian cancer screening tests

Is CA 125 or ultrasound screening appropriate for the general population?

Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-956.

In the United States, the overall ovarian cancer 5-year survival rate is 46.2%, resulting in more than 14,000 deaths annually.² The poor prognosis associated with this malignancy is largely attributable to the fact that almost 75% of women have stage III or stage IV disease at the time of diagnosis.² Ovarian cancer is usually associated with vague, nonspecific symptoms as it progresses, which contributes to delayed diagnosis and increased mortality. 

Multiple studies have examined pelvic ultrasonography and tumor markers, such as CA 125, as possible screening tools to increase early detection in asymptomatic women. However, neither modality alone or in combination has sufficient sensitivity or specificity to recommend it for use in the general population.^3,4 Nevertheless, the search for an appropriate screening tool continues, and the UKCTOCS trial results have reinvigorated this discussion.⁵ 

Photo: © Steve Gschmeissner / Science Source

The UKCTOCS findings 

The UKCTOCS was a multicenter, randomized controlled trial in the United Kingdom in which researchers allocated 202,638 women aged 50 to 74 years to 1 of 3 groups: annual multimodal screening (MMS) with serum CA 125 interpreted with the use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening. The median follow-up was more than 11 years. 

The investigators found that equivalent rates of ovarian cancer were diagnosed in each group: 0.7% in the MMS group, 0.6% in the USS group, and 0.6% in the no-screening group. Overall, there was no significant reduction in the mortality rate from ovarian cancer in either of the 2 screening groups compared with the no-screening group.⁵ 

An important subset discovery

However, in a prespecified subset analysis excluding "prevalent cases" (women with ovarian cancer thought to be present prior to randomization and subsequent screening), ovarian cancer mortality was significantly lower in the MMS group compared with the no-screening group (P = .021). Compared with no screening, MMS was associated with a 20% reduction in mortality rate from ovarian cancer over time, with the most pronounced effects occurring at years 7 to 14 of follow-up, suggesting the possible increased effectiveness of screening over time.⁵

Related article:
Can CA 125 screening reduce mortality from ovarian cancer?

Concordance with other screening trials

While impressive in study magnitude and scope, the UKCTOCS results did not demonstrate a significant mortality benefit associated with MMS or USS when compared with no screening. Although the screening complications were low (<1% in both screening groups), the authors did note a false-positive surgery rate of 14 per 10,000 screens for the MMS group and 50 per 10,000 screens for the USS group. Based on the performance of screening in this trial, 641 women would need to be screened annually using MMS for 14 years to prevent 1 ovarian cancer death.

Like the UKCTOCS, the ovarian cancer-screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial in the United States was also unable to demonstrate a reduction in mortality rate with screening with CA 125 and transvaginal ultrasound. Importantly, more than one-third of women with a false-positive screen underwent surgery and 15% of them experienced a major complication.6 Based on these findings, the US Preventive Services Task Force grades screening for ovarian cancer as D, suggesting that the harms of screening may outweigh the benefits.⁷

Read about patient selection for neoadjuvant chemotherapy

New clinical practice guideline advises neoadjuvant chemotherapy for certain women with ovarian cancer

Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(28):3460-3473.

It has long been held as a central dogma that primary cytoreductive surgery (PCS) is the preferred initial treatment for women with newly diagnosed ovarian cancer.⁸ However, PCS is associated with substantial morbidity, and the ability to achieve optimal cytoreduction (<1 cm of residual disease), an important prognostic factor, is often compromised in women with significant tumor burden.^9,10

Neoadjuvant chemotherapy, in which chemotherapy is administered prior to surgical cytoreduction, challenges the traditional treatment paradigm for advanced-stage ovarian cancer. Several randomized controlled trials have reported equivalent survival for primary surgical cytoreduction and NACT. Importantly, women who received NACT had fewer complications and were more likely to have optimal cytoreduction at the time of surgery.^11,12 These studies have limitations, however, and the role of NACT remains uncertain.

To help guide clinicians, the Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an expert panel to provide recommendations and guidance on the evaluation of women for and the use of NACT in the setting of advanced ovarian cancer.¹³

Related article:
2015 Update on cancer

Recommendation: Clinical evaluation and patient selection

Strong clinical evidence supports that all women with suspected stage IIIC or stage IV ovarian cancer should be evaluated by a gynecologic oncologist prior to the initiation of therapy. The evaluation should include at least a computed tomography scan of the chest, abdomen, and pelvis to assess the extent of disease and resectability. A preoperative risk assessment should be performed to assess risk factors for increased morbidity and mortality.

Women who have a high perioperative risk profile or a low likelihood of achieving cytoreduction to 1 cm or less of residual tumor should receive NACT. Prior to the initiation of NACT, histologic confirmation of ovarian cancer should be obtained.¹³ 

Outcomes for neoadjuvant chemotherapy versus primary cytoreduction

Four phase 3 randomized controlled trials (EORTC 55971, CHORUS, JCOG0602, and SCORPION) suggest that NACT is noninferior to PCS with regard to progression-free survival and overall survival. NACT is associated with less perioperative and postoperative morbidity and mortality and is associated with shorter hospital stays.

To date, complete data are available only from the EORTC and CHORUS trials, which both demonstrated similar progression-free survival and overall survival for NACT and PCS. Critics have noted, however, that both trials have shorter median overall survival for the PCS groups than were previously reported in other phase 3 studies in the United States, suggesting the possibility of different patient populations or less aggressive "surgical effort." Thus, PCS remains the preferred management strategy for women with advanced-stage ovarian cancer in whom there is a high likelihood of optimal cytoreduction.¹³

Recommendation: Use of neoadjuvant chemotherapy

Patients who are appropriate candidates for NACT should be treated with a platinum and taxane doublet and should receive interval cytoreduction following 3 to 4 cycles of therapy if a favorable response is noted. Patients whose disease progresses despite NACT have a poor prognosis, and there is little role for surgical treatment with the exception of palliative purposes.¹³  

Read about a new PARP inhibitor for maintenance therapy

Niraparib is promising as maintenance therapy in ovarian cancer 

Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.

Approximately 85% of women with ovarian cancer will develop recurrent disease. Women with ovarian cancer are commonly treated with a range of antineoplastic agents over the course of their lifetime. As such, there is a great need for additional active therapeutic agents in this setting. Recently, substantial effort has been directed toward "precision" or "personalized medicine" in oncology.

Precision medicine, targeted therapies in oncology

Precision medicine refers to the customization of medical therapy based on the genetic characterization of the individual patient or the molecular profile of the patient's tumor. As a result of large-scale molecular profiling from projects such as the International Cancer Genome Consortium and The Cancer Genome Atlas, an abundance of molecular data has been generated through the characterization of multiple tumor types. This has led to the discovery of key cancer drivers, alterations, and specific molecular profiles that have distinct prognostic and treatment implications. These data, in combination with the commercial availability of molecular profiling tests, has made precision medicine a reality for women with ovarian cancer.

This wealth of new information has led to development of targeted therapeutics that block the growth and spread of cancer by acting on specific molecules or molecular pathways. Targeted therapies approved for cancer treatment include hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, and immunotherapies.¹⁴ 

How PARP inhibitors work

PARP inhibitors are a class of agents that are emerging as important therapies for ovarian cancer. These agents block the nuclear protein PARP, which functions to detect and repair single-strand DNA breaks with the resulting accumulation of double-stranded DNA breaks.¹⁵ In the setting of DNA damage, the homologous recombination repair pathway is activated for repair. However, homologous recombination deficiencies (HRD) can arise as a result of BRCA1 or BRCA2 mutations or BRCA-independent pathways, which effectively disable this DNA repair pathway. As a result, when PARP inhibitors are used in patients with HRD, the cell cannot repair double-stranded DNA breaks and this leads to "synthetic lethality."¹⁶

Understanding this molecular mechanism of PARP inhibitors as well as the frequent abnormalities in the BRCA genes and HRD pathways in ovarian cancer has provided an important potential therapeutic target in ovarian cancer. A number of PARP inhibitors are now commercially available and are undergoing testing in ovarian cancer.

Related article:
Is a minimally invasive approach to hysterectomy for Gyn cancer utilized equally in all racial and income groups?

Niraparib for ovarian cancer

In a randomized, double-blind, phase 3 trial by Mizra and colleagues, 553 women with platinum-sensitive recurrent ovarian cancer who responded to therapy were divided according to the presence or absence of a germline BRCA (gBRCA) mutation and randomly assigned to niraparib 300 mg or placebo once daily. Women in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group. This was most pronounced in women in the gBRCA cohort (21.0 vs 5.5 months). Importantly, niraparib was associated with improved progression-free survival in HRD-positive patients without gBRCA mutations (12.9 vs 3.8 months) as well as in the HRD-negative subgroup (6.9 vs 3.8 months).¹⁷

Overall, niraparib was well tolerated. About 15% of women discontinued the drug due to toxicity. Significant (grade 3 or 4) adverse events were seen in three-quarters of women treated with niraparib, and they most commonly consisted of hematologic toxicities. Patient-reported outcomes were similar for both groups, indicating no significant effect from niraparib on quality of life.¹⁷   

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In 2017, an estimated 22,240 women will be diagnosed with ovarian cancer, and 14,080 women will die of the disease.¹ The high mortality associated with ovarian cancer is due largely to the inability to detect the disease early and the lack of effective therapeutics for women with recurrent disease. In this Update, we review important advances in the diagnosis and treatment of ovarian cancer.

Development of an effective screening tool for women at average risk has been an elusive challenge. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) examined the efficacy of transvaginal ultrasound and cancer antigen 125 (CA 125) monitoring for ovarian cancer in a large cohort of women.

For women diagnosed with ovarian cancer, treatment paradigms for the initial management of the disease have shifted dramatically. Based on data from multiple randomized controlled trials, neoadjuvant chemotherapy (NACT) is being used more frequently. The American Society of Clinical Oncology and the Society of Gynecologic Oncology developed consensus recommendations for the appropriate use of NACT and primary cytoreductive surgery for women with ovarian cancer.

Finally, all of oncology has moved toward incorporating molecularly targeted therapeutics directed toward individual genetic abnormalities in tumors, so-called precision medicine. In ovarian cancer, poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) has emerged as an important target, particularly for women with BRCA gene pathway mutations. We describe a recently published randomized controlled trial of the PARP inhibitor niraparib.

Read about ovarian cancer screening tests

Is CA 125 or ultrasound screening appropriate for the general population?

Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-956.

In the United States, the overall ovarian cancer 5-year survival rate is 46.2%, resulting in more than 14,000 deaths annually.² The poor prognosis associated with this malignancy is largely attributable to the fact that almost 75% of women have stage III or stage IV disease at the time of diagnosis.² Ovarian cancer is usually associated with vague, nonspecific symptoms as it progresses, which contributes to delayed diagnosis and increased mortality. 

Multiple studies have examined pelvic ultrasonography and tumor markers, such as CA 125, as possible screening tools to increase early detection in asymptomatic women. However, neither modality alone or in combination has sufficient sensitivity or specificity to recommend it for use in the general population.^3,4 Nevertheless, the search for an appropriate screening tool continues, and the UKCTOCS trial results have reinvigorated this discussion.⁵ 

Photo: © Steve Gschmeissner / Science Source

The UKCTOCS findings 

The UKCTOCS was a multicenter, randomized controlled trial in the United Kingdom in which researchers allocated 202,638 women aged 50 to 74 years to 1 of 3 groups: annual multimodal screening (MMS) with serum CA 125 interpreted with the use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening. The median follow-up was more than 11 years. 

The investigators found that equivalent rates of ovarian cancer were diagnosed in each group: 0.7% in the MMS group, 0.6% in the USS group, and 0.6% in the no-screening group. Overall, there was no significant reduction in the mortality rate from ovarian cancer in either of the 2 screening groups compared with the no-screening group.⁵ 

An important subset discovery

However, in a prespecified subset analysis excluding "prevalent cases" (women with ovarian cancer thought to be present prior to randomization and subsequent screening), ovarian cancer mortality was significantly lower in the MMS group compared with the no-screening group (P = .021). Compared with no screening, MMS was associated with a 20% reduction in mortality rate from ovarian cancer over time, with the most pronounced effects occurring at years 7 to 14 of follow-up, suggesting the possible increased effectiveness of screening over time.⁵

Related article:
Can CA 125 screening reduce mortality from ovarian cancer?

Concordance with other screening trials

While impressive in study magnitude and scope, the UKCTOCS results did not demonstrate a significant mortality benefit associated with MMS or USS when compared with no screening. Although the screening complications were low (<1% in both screening groups), the authors did note a false-positive surgery rate of 14 per 10,000 screens for the MMS group and 50 per 10,000 screens for the USS group. Based on the performance of screening in this trial, 641 women would need to be screened annually using MMS for 14 years to prevent 1 ovarian cancer death.

Like the UKCTOCS, the ovarian cancer-screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial in the United States was also unable to demonstrate a reduction in mortality rate with screening with CA 125 and transvaginal ultrasound. Importantly, more than one-third of women with a false-positive screen underwent surgery and 15% of them experienced a major complication.6 Based on these findings, the US Preventive Services Task Force grades screening for ovarian cancer as D, suggesting that the harms of screening may outweigh the benefits.⁷

Read about patient selection for neoadjuvant chemotherapy

New clinical practice guideline advises neoadjuvant chemotherapy for certain women with ovarian cancer

Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(28):3460-3473.

It has long been held as a central dogma that primary cytoreductive surgery (PCS) is the preferred initial treatment for women with newly diagnosed ovarian cancer.⁸ However, PCS is associated with substantial morbidity, and the ability to achieve optimal cytoreduction (<1 cm of residual disease), an important prognostic factor, is often compromised in women with significant tumor burden.^9,10

Neoadjuvant chemotherapy, in which chemotherapy is administered prior to surgical cytoreduction, challenges the traditional treatment paradigm for advanced-stage ovarian cancer. Several randomized controlled trials have reported equivalent survival for primary surgical cytoreduction and NACT. Importantly, women who received NACT had fewer complications and were more likely to have optimal cytoreduction at the time of surgery.^11,12 These studies have limitations, however, and the role of NACT remains uncertain.

To help guide clinicians, the Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an expert panel to provide recommendations and guidance on the evaluation of women for and the use of NACT in the setting of advanced ovarian cancer.¹³

Related article:
2015 Update on cancer

Recommendation: Clinical evaluation and patient selection

Strong clinical evidence supports that all women with suspected stage IIIC or stage IV ovarian cancer should be evaluated by a gynecologic oncologist prior to the initiation of therapy. The evaluation should include at least a computed tomography scan of the chest, abdomen, and pelvis to assess the extent of disease and resectability. A preoperative risk assessment should be performed to assess risk factors for increased morbidity and mortality.

Women who have a high perioperative risk profile or a low likelihood of achieving cytoreduction to 1 cm or less of residual tumor should receive NACT. Prior to the initiation of NACT, histologic confirmation of ovarian cancer should be obtained.¹³ 

Outcomes for neoadjuvant chemotherapy versus primary cytoreduction

Four phase 3 randomized controlled trials (EORTC 55971, CHORUS, JCOG0602, and SCORPION) suggest that NACT is noninferior to PCS with regard to progression-free survival and overall survival. NACT is associated with less perioperative and postoperative morbidity and mortality and is associated with shorter hospital stays.

To date, complete data are available only from the EORTC and CHORUS trials, which both demonstrated similar progression-free survival and overall survival for NACT and PCS. Critics have noted, however, that both trials have shorter median overall survival for the PCS groups than were previously reported in other phase 3 studies in the United States, suggesting the possibility of different patient populations or less aggressive "surgical effort." Thus, PCS remains the preferred management strategy for women with advanced-stage ovarian cancer in whom there is a high likelihood of optimal cytoreduction.¹³

Recommendation: Use of neoadjuvant chemotherapy

Patients who are appropriate candidates for NACT should be treated with a platinum and taxane doublet and should receive interval cytoreduction following 3 to 4 cycles of therapy if a favorable response is noted. Patients whose disease progresses despite NACT have a poor prognosis, and there is little role for surgical treatment with the exception of palliative purposes.¹³  

Read about a new PARP inhibitor for maintenance therapy

Niraparib is promising as maintenance therapy in ovarian cancer 

Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.

Approximately 85% of women with ovarian cancer will develop recurrent disease. Women with ovarian cancer are commonly treated with a range of antineoplastic agents over the course of their lifetime. As such, there is a great need for additional active therapeutic agents in this setting. Recently, substantial effort has been directed toward "precision" or "personalized medicine" in oncology.

Precision medicine, targeted therapies in oncology

Precision medicine refers to the customization of medical therapy based on the genetic characterization of the individual patient or the molecular profile of the patient's tumor. As a result of large-scale molecular profiling from projects such as the International Cancer Genome Consortium and The Cancer Genome Atlas, an abundance of molecular data has been generated through the characterization of multiple tumor types. This has led to the discovery of key cancer drivers, alterations, and specific molecular profiles that have distinct prognostic and treatment implications. These data, in combination with the commercial availability of molecular profiling tests, has made precision medicine a reality for women with ovarian cancer.

This wealth of new information has led to development of targeted therapeutics that block the growth and spread of cancer by acting on specific molecules or molecular pathways. Targeted therapies approved for cancer treatment include hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, and immunotherapies.¹⁴ 

How PARP inhibitors work

PARP inhibitors are a class of agents that are emerging as important therapies for ovarian cancer. These agents block the nuclear protein PARP, which functions to detect and repair single-strand DNA breaks with the resulting accumulation of double-stranded DNA breaks.¹⁵ In the setting of DNA damage, the homologous recombination repair pathway is activated for repair. However, homologous recombination deficiencies (HRD) can arise as a result of BRCA1 or BRCA2 mutations or BRCA-independent pathways, which effectively disable this DNA repair pathway. As a result, when PARP inhibitors are used in patients with HRD, the cell cannot repair double-stranded DNA breaks and this leads to "synthetic lethality."¹⁶

Understanding this molecular mechanism of PARP inhibitors as well as the frequent abnormalities in the BRCA genes and HRD pathways in ovarian cancer has provided an important potential therapeutic target in ovarian cancer. A number of PARP inhibitors are now commercially available and are undergoing testing in ovarian cancer.

Related article:
Is a minimally invasive approach to hysterectomy for Gyn cancer utilized equally in all racial and income groups?

Niraparib for ovarian cancer

In a randomized, double-blind, phase 3 trial by Mizra and colleagues, 553 women with platinum-sensitive recurrent ovarian cancer who responded to therapy were divided according to the presence or absence of a germline BRCA (gBRCA) mutation and randomly assigned to niraparib 300 mg or placebo once daily. Women in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group. This was most pronounced in women in the gBRCA cohort (21.0 vs 5.5 months). Importantly, niraparib was associated with improved progression-free survival in HRD-positive patients without gBRCA mutations (12.9 vs 3.8 months) as well as in the HRD-negative subgroup (6.9 vs 3.8 months).¹⁷

Overall, niraparib was well tolerated. About 15% of women discontinued the drug due to toxicity. Significant (grade 3 or 4) adverse events were seen in three-quarters of women treated with niraparib, and they most commonly consisted of hematologic toxicities. Patient-reported outcomes were similar for both groups, indicating no significant effect from niraparib on quality of life.¹⁷   

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In 2017, an estimated 22,240 women will be diagnosed with ovarian cancer, and 14,080 women will die of the disease.¹ The high mortality associated with ovarian cancer is due largely to the inability to detect the disease early and the lack of effective therapeutics for women with recurrent disease. In this Update, we review important advances in the diagnosis and treatment of ovarian cancer.

Development of an effective screening tool for women at average risk has been an elusive challenge. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) examined the efficacy of transvaginal ultrasound and cancer antigen 125 (CA 125) monitoring for ovarian cancer in a large cohort of women.

For women diagnosed with ovarian cancer, treatment paradigms for the initial management of the disease have shifted dramatically. Based on data from multiple randomized controlled trials, neoadjuvant chemotherapy (NACT) is being used more frequently. The American Society of Clinical Oncology and the Society of Gynecologic Oncology developed consensus recommendations for the appropriate use of NACT and primary cytoreductive surgery for women with ovarian cancer.

Finally, all of oncology has moved toward incorporating molecularly targeted therapeutics directed toward individual genetic abnormalities in tumors, so-called precision medicine. In ovarian cancer, poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) has emerged as an important target, particularly for women with BRCA gene pathway mutations. We describe a recently published randomized controlled trial of the PARP inhibitor niraparib.

Read about ovarian cancer screening tests

Is CA 125 or ultrasound screening appropriate for the general population?

Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-956.

In the United States, the overall ovarian cancer 5-year survival rate is 46.2%, resulting in more than 14,000 deaths annually.² The poor prognosis associated with this malignancy is largely attributable to the fact that almost 75% of women have stage III or stage IV disease at the time of diagnosis.² Ovarian cancer is usually associated with vague, nonspecific symptoms as it progresses, which contributes to delayed diagnosis and increased mortality. 

Multiple studies have examined pelvic ultrasonography and tumor markers, such as CA 125, as possible screening tools to increase early detection in asymptomatic women. However, neither modality alone or in combination has sufficient sensitivity or specificity to recommend it for use in the general population.^3,4 Nevertheless, the search for an appropriate screening tool continues, and the UKCTOCS trial results have reinvigorated this discussion.⁵ 

Photo: © Steve Gschmeissner / Science Source

The UKCTOCS findings 

The UKCTOCS was a multicenter, randomized controlled trial in the United Kingdom in which researchers allocated 202,638 women aged 50 to 74 years to 1 of 3 groups: annual multimodal screening (MMS) with serum CA 125 interpreted with the use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening. The median follow-up was more than 11 years. 

The investigators found that equivalent rates of ovarian cancer were diagnosed in each group: 0.7% in the MMS group, 0.6% in the USS group, and 0.6% in the no-screening group. Overall, there was no significant reduction in the mortality rate from ovarian cancer in either of the 2 screening groups compared with the no-screening group.⁵ 

An important subset discovery

However, in a prespecified subset analysis excluding "prevalent cases" (women with ovarian cancer thought to be present prior to randomization and subsequent screening), ovarian cancer mortality was significantly lower in the MMS group compared with the no-screening group (P = .021). Compared with no screening, MMS was associated with a 20% reduction in mortality rate from ovarian cancer over time, with the most pronounced effects occurring at years 7 to 14 of follow-up, suggesting the possible increased effectiveness of screening over time.⁵

Related article:
Can CA 125 screening reduce mortality from ovarian cancer?

Concordance with other screening trials

While impressive in study magnitude and scope, the UKCTOCS results did not demonstrate a significant mortality benefit associated with MMS or USS when compared with no screening. Although the screening complications were low (<1% in both screening groups), the authors did note a false-positive surgery rate of 14 per 10,000 screens for the MMS group and 50 per 10,000 screens for the USS group. Based on the performance of screening in this trial, 641 women would need to be screened annually using MMS for 14 years to prevent 1 ovarian cancer death.

Like the UKCTOCS, the ovarian cancer-screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial in the United States was also unable to demonstrate a reduction in mortality rate with screening with CA 125 and transvaginal ultrasound. Importantly, more than one-third of women with a false-positive screen underwent surgery and 15% of them experienced a major complication.6 Based on these findings, the US Preventive Services Task Force grades screening for ovarian cancer as D, suggesting that the harms of screening may outweigh the benefits.⁷

Read about patient selection for neoadjuvant chemotherapy

New clinical practice guideline advises neoadjuvant chemotherapy for certain women with ovarian cancer

Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(28):3460-3473.

It has long been held as a central dogma that primary cytoreductive surgery (PCS) is the preferred initial treatment for women with newly diagnosed ovarian cancer.⁸ However, PCS is associated with substantial morbidity, and the ability to achieve optimal cytoreduction (<1 cm of residual disease), an important prognostic factor, is often compromised in women with significant tumor burden.^9,10

Neoadjuvant chemotherapy, in which chemotherapy is administered prior to surgical cytoreduction, challenges the traditional treatment paradigm for advanced-stage ovarian cancer. Several randomized controlled trials have reported equivalent survival for primary surgical cytoreduction and NACT. Importantly, women who received NACT had fewer complications and were more likely to have optimal cytoreduction at the time of surgery.^11,12 These studies have limitations, however, and the role of NACT remains uncertain.

To help guide clinicians, the Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an expert panel to provide recommendations and guidance on the evaluation of women for and the use of NACT in the setting of advanced ovarian cancer.¹³

Related article:
2015 Update on cancer

Recommendation: Clinical evaluation and patient selection

Strong clinical evidence supports that all women with suspected stage IIIC or stage IV ovarian cancer should be evaluated by a gynecologic oncologist prior to the initiation of therapy. The evaluation should include at least a computed tomography scan of the chest, abdomen, and pelvis to assess the extent of disease and resectability. A preoperative risk assessment should be performed to assess risk factors for increased morbidity and mortality.

Women who have a high perioperative risk profile or a low likelihood of achieving cytoreduction to 1 cm or less of residual tumor should receive NACT. Prior to the initiation of NACT, histologic confirmation of ovarian cancer should be obtained.¹³ 

Outcomes for neoadjuvant chemotherapy versus primary cytoreduction

Four phase 3 randomized controlled trials (EORTC 55971, CHORUS, JCOG0602, and SCORPION) suggest that NACT is noninferior to PCS with regard to progression-free survival and overall survival. NACT is associated with less perioperative and postoperative morbidity and mortality and is associated with shorter hospital stays.

To date, complete data are available only from the EORTC and CHORUS trials, which both demonstrated similar progression-free survival and overall survival for NACT and PCS. Critics have noted, however, that both trials have shorter median overall survival for the PCS groups than were previously reported in other phase 3 studies in the United States, suggesting the possibility of different patient populations or less aggressive "surgical effort." Thus, PCS remains the preferred management strategy for women with advanced-stage ovarian cancer in whom there is a high likelihood of optimal cytoreduction.¹³

Recommendation: Use of neoadjuvant chemotherapy

Patients who are appropriate candidates for NACT should be treated with a platinum and taxane doublet and should receive interval cytoreduction following 3 to 4 cycles of therapy if a favorable response is noted. Patients whose disease progresses despite NACT have a poor prognosis, and there is little role for surgical treatment with the exception of palliative purposes.¹³  

Read about a new PARP inhibitor for maintenance therapy

Niraparib is promising as maintenance therapy in ovarian cancer 

Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.

Approximately 85% of women with ovarian cancer will develop recurrent disease. Women with ovarian cancer are commonly treated with a range of antineoplastic agents over the course of their lifetime. As such, there is a great need for additional active therapeutic agents in this setting. Recently, substantial effort has been directed toward "precision" or "personalized medicine" in oncology.

Precision medicine, targeted therapies in oncology

Precision medicine refers to the customization of medical therapy based on the genetic characterization of the individual patient or the molecular profile of the patient's tumor. As a result of large-scale molecular profiling from projects such as the International Cancer Genome Consortium and The Cancer Genome Atlas, an abundance of molecular data has been generated through the characterization of multiple tumor types. This has led to the discovery of key cancer drivers, alterations, and specific molecular profiles that have distinct prognostic and treatment implications. These data, in combination with the commercial availability of molecular profiling tests, has made precision medicine a reality for women with ovarian cancer.

This wealth of new information has led to development of targeted therapeutics that block the growth and spread of cancer by acting on specific molecules or molecular pathways. Targeted therapies approved for cancer treatment include hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, and immunotherapies.¹⁴ 

How PARP inhibitors work

PARP inhibitors are a class of agents that are emerging as important therapies for ovarian cancer. These agents block the nuclear protein PARP, which functions to detect and repair single-strand DNA breaks with the resulting accumulation of double-stranded DNA breaks.¹⁵ In the setting of DNA damage, the homologous recombination repair pathway is activated for repair. However, homologous recombination deficiencies (HRD) can arise as a result of BRCA1 or BRCA2 mutations or BRCA-independent pathways, which effectively disable this DNA repair pathway. As a result, when PARP inhibitors are used in patients with HRD, the cell cannot repair double-stranded DNA breaks and this leads to "synthetic lethality."¹⁶

Understanding this molecular mechanism of PARP inhibitors as well as the frequent abnormalities in the BRCA genes and HRD pathways in ovarian cancer has provided an important potential therapeutic target in ovarian cancer. A number of PARP inhibitors are now commercially available and are undergoing testing in ovarian cancer.

Related article:
Is a minimally invasive approach to hysterectomy for Gyn cancer utilized equally in all racial and income groups?

Niraparib for ovarian cancer

In a randomized, double-blind, phase 3 trial by Mizra and colleagues, 553 women with platinum-sensitive recurrent ovarian cancer who responded to therapy were divided according to the presence or absence of a germline BRCA (gBRCA) mutation and randomly assigned to niraparib 300 mg or placebo once daily. Women in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group. This was most pronounced in women in the gBRCA cohort (21.0 vs 5.5 months). Importantly, niraparib was associated with improved progression-free survival in HRD-positive patients without gBRCA mutations (12.9 vs 3.8 months) as well as in the HRD-negative subgroup (6.9 vs 3.8 months).¹⁷

Overall, niraparib was well tolerated. About 15% of women discontinued the drug due to toxicity. Significant (grade 3 or 4) adverse events were seen in three-quarters of women treated with niraparib, and they most commonly consisted of hematologic toxicities. Patient-reported outcomes were similar for both groups, indicating no significant effect from niraparib on quality of life.¹⁷   

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The recognition that human papillomavirus (HPV) oncogenic viruses cause cervical carcinoma remains one of the most game-changing medical discoveries of the last century. Improvements in screening options for detecting cervical cancer precursors followed. We now have the ability to detect high-risk HPV subtypes in routine specimens. Finally, a highly effective vaccine was developed that targets HPV types 16 and 18, which are responsible for causing approximately 70% of all cases of cervical carcinoma.

In one of the original vaccines HPV types 6 and 11, responsible for 90% of all genital warts, were also targeted. In 2014, a 9-valent vaccine incorporating an additional 5 HPV strains (31, 33, 45, 52, and 58) was approved and is set to replace all previous vaccine versions. Together, these 7 oncogenic HPV types are responsible for approximately 90% of HPV-related cancers, including cervical, anal, oropharyngeal, vaginal, and vulvar cancer.

By vaccinating boys and girls between ages 9 and 21 (for males) and 9 and 26 (for females), we could effectively eliminate 90% of genital warts and 90% of all HPV-related cancers. So why have we not capitalized on this extraordinary discovery? In 2016, why were only 40% of teenage girls and less than 25% of teenage boys vaccinated against HPV when we are immunizing 80% to 90% of these populations with tetanus, diphtheria, and acellular pertusis (Tdap) and meningococcal vaccines?

Related article:
2016 Update on cervical disease

Barriers to HPV vaccination

When the first HPV vaccine was approved in 2006, cost was a significant factor. Many health insurance plans did not cover this “discretionary” vaccine, which was viewed as a prevention for sexually transmitted infections rather than as a valuable intervention for the prevention of cervical and other cancers. At well over $125 per dose with 3 doses required for a full series, ObGyns were reluctant to stock and provide these expensive vaccines without assurance of reimbursement. The logistics of recalling patients for their subsequent vaccine doses were challenging for offices that were not accustomed to seeing patients for preventive care activities more than once a year. In addition, the office infrastructure required to maintain the vaccine stock and manage the necessary paperwork could be daunting. Finally, the requirement that patients be observed for 15 to 30 minutes in the office after vaccine administration created efficiency and rooming problems in busy, active practices.

Over time, almost all payers covered the HPV vaccines, but the logistical issues in ObGyn practices remain. Pediatric practices, on the other hand, are ideally suited for vaccine administration. Unfortunately, our colleagues delivering preventive care to young teens have persisted in considering the HPV vaccine as an optional adjunct to routine vaccination despite the advice of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), which for many years has recommended the HPV vaccine for girls. In 2011, the ACIP extended the HPV vaccine recommendation to include boys beginning at ages 11 to 12.

New 2-dose HPV vaccine schedule for children <15 years

In October 2016, 10 years after the first HPV vaccine approval, the ACIP and the CDC approved a reduced, 2-dose schedule for those younger than 15.¹ The first dose can be administered simultaneously with other recommended vaccines for 11- to 12-year-olds (the meningococcal and Tdap vaccines) and the second dose, 6 or 12 months later.² The 12-month interval would allow administration, once again, of all required vaccines at the annual visit.

Pivotal immunogenicity study

The new recommendation is based on robust multinational data (52 sites in 15 countries, N = 1,518) from an open-label trial.³ Immunogenicity of 2 doses of the 9-valent HPV vaccine in girls and boys ages 9 to 14 was compared with that of a standard 3-dose regimen in adolescents and young women ages 16 to 26. Five cohorts were studied: boys 9 to 14 given 2 doses at 6-month intervals; girls 9 to 14 given 2 doses at 6-month intervals; boys and girls 9 to 14 given 2 doses at a 12-month interval; girls 9 to 14 given the standard 3-dose regimen; and girls and young women 16 to 26 receiving 3 doses over 6 months.

The authors assessed the antibody responses against each HPV subtype 1 month after the final vaccine dose. Data from 1,377 participants (90.7% of the original cohort) were analyzed. Prespecified antibody titers were set conservatively to ensure adequate immunogenicity. Noninferiority criteria had to be met for all 9 HPV types.

Trial results. The immune responses for the 9- to 14-year-olds were consistently higher than those for the 16- to 26-year-old age group regardless of the regimen—not a surprising finding since the initial trials for HPV vaccine demonstrated a greater response among younger vaccine recipients. In this trial, higher antibody responses were found for the 12-month dosing interval than for the 6-month interval, although both regimens produced an adequate response.

Immunogenicity remained at 6 months. Antibody levels were retested 6 months after the last dose of HPV vaccine in a post hoc analysis. In all groups the antibody titers declined; however, there was no difference between the 2- and 3-dose cohorts. All levels remained above a threshold required for immunogenicity.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Simplified dosing may help increase vaccination rates

What does this new dosing regimen mean for practice? It will be simpler to incorporate HPV vaccination routinely into the standard vaccine regimen for preadolescent boys and girls. In addition, counseling for HPV vaccine administration can be combined with counseling for the meningococcal vaccine and routine Tdap booster.

Notably, primary care physicians have reported perceiving HPV vaccine discussions with parents as burdensome, and they tend to discuss it last after conversations about Tdap and meningococcal vaccines.⁴ Brewer and colleagues⁵ documented a 5% increase in first HPV vaccine doses among patients in practices in which the providers were taught to “announce” the need for HPV vaccine along with other routine vaccines. There was no increase in HPV vaccine uptake among practices in which providers were taught to “discuss” HPV with parents and to address their concerns, or in control practices. Therefore, less conversation about HPV and the HPV vaccine, as distinct from any other recommended vaccines, is better.

With the new 2-dose regimen, it should be easier to convey that the HPV vaccine is another necessary, routine intervention for children’s health. We should be able to achieve 90% vaccination rates for HPV—similar to rates for Tdap.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The recognition that human papillomavirus (HPV) oncogenic viruses cause cervical carcinoma remains one of the most game-changing medical discoveries of the last century. Improvements in screening options for detecting cervical cancer precursors followed. We now have the ability to detect high-risk HPV subtypes in routine specimens. Finally, a highly effective vaccine was developed that targets HPV types 16 and 18, which are responsible for causing approximately 70% of all cases of cervical carcinoma.

In one of the original vaccines HPV types 6 and 11, responsible for 90% of all genital warts, were also targeted. In 2014, a 9-valent vaccine incorporating an additional 5 HPV strains (31, 33, 45, 52, and 58) was approved and is set to replace all previous vaccine versions. Together, these 7 oncogenic HPV types are responsible for approximately 90% of HPV-related cancers, including cervical, anal, oropharyngeal, vaginal, and vulvar cancer.

By vaccinating boys and girls between ages 9 and 21 (for males) and 9 and 26 (for females), we could effectively eliminate 90% of genital warts and 90% of all HPV-related cancers. So why have we not capitalized on this extraordinary discovery? In 2016, why were only 40% of teenage girls and less than 25% of teenage boys vaccinated against HPV when we are immunizing 80% to 90% of these populations with tetanus, diphtheria, and acellular pertusis (Tdap) and meningococcal vaccines?

Related article:
2016 Update on cervical disease

Barriers to HPV vaccination

When the first HPV vaccine was approved in 2006, cost was a significant factor. Many health insurance plans did not cover this “discretionary” vaccine, which was viewed as a prevention for sexually transmitted infections rather than as a valuable intervention for the prevention of cervical and other cancers. At well over $125 per dose with 3 doses required for a full series, ObGyns were reluctant to stock and provide these expensive vaccines without assurance of reimbursement. The logistics of recalling patients for their subsequent vaccine doses were challenging for offices that were not accustomed to seeing patients for preventive care activities more than once a year. In addition, the office infrastructure required to maintain the vaccine stock and manage the necessary paperwork could be daunting. Finally, the requirement that patients be observed for 15 to 30 minutes in the office after vaccine administration created efficiency and rooming problems in busy, active practices.

Over time, almost all payers covered the HPV vaccines, but the logistical issues in ObGyn practices remain. Pediatric practices, on the other hand, are ideally suited for vaccine administration. Unfortunately, our colleagues delivering preventive care to young teens have persisted in considering the HPV vaccine as an optional adjunct to routine vaccination despite the advice of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), which for many years has recommended the HPV vaccine for girls. In 2011, the ACIP extended the HPV vaccine recommendation to include boys beginning at ages 11 to 12.

New 2-dose HPV vaccine schedule for children <15 years

In October 2016, 10 years after the first HPV vaccine approval, the ACIP and the CDC approved a reduced, 2-dose schedule for those younger than 15.¹ The first dose can be administered simultaneously with other recommended vaccines for 11- to 12-year-olds (the meningococcal and Tdap vaccines) and the second dose, 6 or 12 months later.² The 12-month interval would allow administration, once again, of all required vaccines at the annual visit.

Pivotal immunogenicity study

The new recommendation is based on robust multinational data (52 sites in 15 countries, N = 1,518) from an open-label trial.³ Immunogenicity of 2 doses of the 9-valent HPV vaccine in girls and boys ages 9 to 14 was compared with that of a standard 3-dose regimen in adolescents and young women ages 16 to 26. Five cohorts were studied: boys 9 to 14 given 2 doses at 6-month intervals; girls 9 to 14 given 2 doses at 6-month intervals; boys and girls 9 to 14 given 2 doses at a 12-month interval; girls 9 to 14 given the standard 3-dose regimen; and girls and young women 16 to 26 receiving 3 doses over 6 months.

The authors assessed the antibody responses against each HPV subtype 1 month after the final vaccine dose. Data from 1,377 participants (90.7% of the original cohort) were analyzed. Prespecified antibody titers were set conservatively to ensure adequate immunogenicity. Noninferiority criteria had to be met for all 9 HPV types.

Trial results. The immune responses for the 9- to 14-year-olds were consistently higher than those for the 16- to 26-year-old age group regardless of the regimen—not a surprising finding since the initial trials for HPV vaccine demonstrated a greater response among younger vaccine recipients. In this trial, higher antibody responses were found for the 12-month dosing interval than for the 6-month interval, although both regimens produced an adequate response.

Immunogenicity remained at 6 months. Antibody levels were retested 6 months after the last dose of HPV vaccine in a post hoc analysis. In all groups the antibody titers declined; however, there was no difference between the 2- and 3-dose cohorts. All levels remained above a threshold required for immunogenicity.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Simplified dosing may help increase vaccination rates

What does this new dosing regimen mean for practice? It will be simpler to incorporate HPV vaccination routinely into the standard vaccine regimen for preadolescent boys and girls. In addition, counseling for HPV vaccine administration can be combined with counseling for the meningococcal vaccine and routine Tdap booster.

Notably, primary care physicians have reported perceiving HPV vaccine discussions with parents as burdensome, and they tend to discuss it last after conversations about Tdap and meningococcal vaccines.⁴ Brewer and colleagues⁵ documented a 5% increase in first HPV vaccine doses among patients in practices in which the providers were taught to “announce” the need for HPV vaccine along with other routine vaccines. There was no increase in HPV vaccine uptake among practices in which providers were taught to “discuss” HPV with parents and to address their concerns, or in control practices. Therefore, less conversation about HPV and the HPV vaccine, as distinct from any other recommended vaccines, is better.

With the new 2-dose regimen, it should be easier to convey that the HPV vaccine is another necessary, routine intervention for children’s health. We should be able to achieve 90% vaccination rates for HPV—similar to rates for Tdap.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The recognition that human papillomavirus (HPV) oncogenic viruses cause cervical carcinoma remains one of the most game-changing medical discoveries of the last century. Improvements in screening options for detecting cervical cancer precursors followed. We now have the ability to detect high-risk HPV subtypes in routine specimens. Finally, a highly effective vaccine was developed that targets HPV types 16 and 18, which are responsible for causing approximately 70% of all cases of cervical carcinoma.

In one of the original vaccines HPV types 6 and 11, responsible for 90% of all genital warts, were also targeted. In 2014, a 9-valent vaccine incorporating an additional 5 HPV strains (31, 33, 45, 52, and 58) was approved and is set to replace all previous vaccine versions. Together, these 7 oncogenic HPV types are responsible for approximately 90% of HPV-related cancers, including cervical, anal, oropharyngeal, vaginal, and vulvar cancer.

By vaccinating boys and girls between ages 9 and 21 (for males) and 9 and 26 (for females), we could effectively eliminate 90% of genital warts and 90% of all HPV-related cancers. So why have we not capitalized on this extraordinary discovery? In 2016, why were only 40% of teenage girls and less than 25% of teenage boys vaccinated against HPV when we are immunizing 80% to 90% of these populations with tetanus, diphtheria, and acellular pertusis (Tdap) and meningococcal vaccines?

Related article:
2016 Update on cervical disease

Barriers to HPV vaccination

When the first HPV vaccine was approved in 2006, cost was a significant factor. Many health insurance plans did not cover this “discretionary” vaccine, which was viewed as a prevention for sexually transmitted infections rather than as a valuable intervention for the prevention of cervical and other cancers. At well over $125 per dose with 3 doses required for a full series, ObGyns were reluctant to stock and provide these expensive vaccines without assurance of reimbursement. The logistics of recalling patients for their subsequent vaccine doses were challenging for offices that were not accustomed to seeing patients for preventive care activities more than once a year. In addition, the office infrastructure required to maintain the vaccine stock and manage the necessary paperwork could be daunting. Finally, the requirement that patients be observed for 15 to 30 minutes in the office after vaccine administration created efficiency and rooming problems in busy, active practices.

Over time, almost all payers covered the HPV vaccines, but the logistical issues in ObGyn practices remain. Pediatric practices, on the other hand, are ideally suited for vaccine administration. Unfortunately, our colleagues delivering preventive care to young teens have persisted in considering the HPV vaccine as an optional adjunct to routine vaccination despite the advice of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), which for many years has recommended the HPV vaccine for girls. In 2011, the ACIP extended the HPV vaccine recommendation to include boys beginning at ages 11 to 12.

New 2-dose HPV vaccine schedule for children <15 years

In October 2016, 10 years after the first HPV vaccine approval, the ACIP and the CDC approved a reduced, 2-dose schedule for those younger than 15.¹ The first dose can be administered simultaneously with other recommended vaccines for 11- to 12-year-olds (the meningococcal and Tdap vaccines) and the second dose, 6 or 12 months later.² The 12-month interval would allow administration, once again, of all required vaccines at the annual visit.

Pivotal immunogenicity study

The new recommendation is based on robust multinational data (52 sites in 15 countries, N = 1,518) from an open-label trial.³ Immunogenicity of 2 doses of the 9-valent HPV vaccine in girls and boys ages 9 to 14 was compared with that of a standard 3-dose regimen in adolescents and young women ages 16 to 26. Five cohorts were studied: boys 9 to 14 given 2 doses at 6-month intervals; girls 9 to 14 given 2 doses at 6-month intervals; boys and girls 9 to 14 given 2 doses at a 12-month interval; girls 9 to 14 given the standard 3-dose regimen; and girls and young women 16 to 26 receiving 3 doses over 6 months.

The authors assessed the antibody responses against each HPV subtype 1 month after the final vaccine dose. Data from 1,377 participants (90.7% of the original cohort) were analyzed. Prespecified antibody titers were set conservatively to ensure adequate immunogenicity. Noninferiority criteria had to be met for all 9 HPV types.

Trial results. The immune responses for the 9- to 14-year-olds were consistently higher than those for the 16- to 26-year-old age group regardless of the regimen—not a surprising finding since the initial trials for HPV vaccine demonstrated a greater response among younger vaccine recipients. In this trial, higher antibody responses were found for the 12-month dosing interval than for the 6-month interval, although both regimens produced an adequate response.

Immunogenicity remained at 6 months. Antibody levels were retested 6 months after the last dose of HPV vaccine in a post hoc analysis. In all groups the antibody titers declined; however, there was no difference between the 2- and 3-dose cohorts. All levels remained above a threshold required for immunogenicity.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Simplified dosing may help increase vaccination rates

What does this new dosing regimen mean for practice? It will be simpler to incorporate HPV vaccination routinely into the standard vaccine regimen for preadolescent boys and girls. In addition, counseling for HPV vaccine administration can be combined with counseling for the meningococcal vaccine and routine Tdap booster.

Notably, primary care physicians have reported perceiving HPV vaccine discussions with parents as burdensome, and they tend to discuss it last after conversations about Tdap and meningococcal vaccines.⁴ Brewer and colleagues⁵ documented a 5% increase in first HPV vaccine doses among patients in practices in which the providers were taught to “announce” the need for HPV vaccine along with other routine vaccines. There was no increase in HPV vaccine uptake among practices in which providers were taught to “discuss” HPV with parents and to address their concerns, or in control practices. Therefore, less conversation about HPV and the HPV vaccine, as distinct from any other recommended vaccines, is better.

With the new 2-dose regimen, it should be easier to convey that the HPV vaccine is another necessary, routine intervention for children’s health. We should be able to achieve 90% vaccination rates for HPV—similar to rates for Tdap.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The purpose of screening mammography is to detect tumors when they are small and nonpalpable in order to prevent more advanced breast tumors in women. Overdiagnosis, which leads to unnecessary treatment, refers to screen-detected tumors that will not lead to symptoms. Overdiagnosis cannot be measured directly and, therefore, understanding this concept is problematic for both women and clinicians.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Observations from other types of cancer screening put overdiagnosis in perspective

To help us grasp the overall issue of overdiagnosis, we can consider screening mammography alongside cervical cancer screening and colon cancer screening. For instance, screening with cervical cytology has reduced the incidence of and mortality from invasive cervical cancer.¹ Likewise, colonoscopy repeatedly has been found to reduce colon cancer mortality.^2,3 Decades of media messaging have emphasized the benefits of screening mammograms.⁴ However, and in contrast with cervical cytology and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic (advanced) disease.⁵ Likewise, as the Danish authors of a recent study published in Annals of Internal Medicine point out, screening mammography has not achieved the promised reduction in breast cancer mortality.

New data from Denmark highlight overdiagnosis concerns

Jørgensen and colleagues conducted a cohort study to estimate the incidence of screen-detected tumors that would not become clinically relevant (overdiagnosis) among women aged 35 to 84 years between 1980 and 2010 in Denmark.⁶ This country offers a particularly well-suited backdrop for a study of overdiagnosis because biennial screening mammography was introduced by region beginning in the early 1990s. By 2007, one-fifth of the country’s female population aged 50 to 69 years were invited to participate. In the following years, screening became universal for Danish women in this age group.

For the study, researchers identified the size of all invasive breast cancer tumors diagnosed over the study period and then compared the incidence rates of advanced tumors (more than 20-mm in size at detection) with nonadvanced tumors in screened and unscreened Danish regions. The investigators took into account regional differences not related to screening by assessing the trends in diagnosis of advanced and nonadvanced tumors in screened and unscreened regions among women older and younger than those screened. This gave them a better estimate of the incidence of overdiagnosis.⁶

Jørgensen and colleagues found that breast cancer screening resulted in an increase in the incidence of nonadvanced tumors, but that it did not reduce the incidence of advanced tumors. They estimated that 39% of the invasive tumors found among women aged 50 to 69 were overdiagnosed.⁶

These Danish study results, that more than one-third of screen-detected tumors represent overdiagnosis, are similar to those found for studies conducted in the United States and other countries.^7,8 The lengthy follow-up after initiation of screening and the assessment of trends in unscreened women represent strengths of the study by Jørgensen and colleagues, and speak to concerns voiced by those skeptical of reported overdiagnosis incidence rates.⁹

Although breast cancer mortality is declining, the lion’s share of this decline has resulted from improvements in systemic therapy rather than from screening mammography. Widespread screening mammography has resulted in a scenario in which women are more likely to have a breast cancer that was overdiagnosed than in having earlier detection of a tumor destined to grow larger.⁵ In the future, by targeting higher-risk women, screening may result in a better benefit:risk ratio. However, and as pointed out by Otis Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, we must acknowledge that overdiagnosis is common, the benefits of screening have been overstated, and some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.¹⁰

Related article:
No surprises from the USPSTF with new guidance on screening mammography

My breast cancer screening approach

As Brawley indicates, we should not abandon screening.¹⁰ I continue to recommend screening based on US Preventive Services Taskforce guidance, beginning biennial screens at age 50.¹¹ I also recognize that some women prefer earlier and more frequent screens, while others may prefer less frequent or even no screening.

The purpose of screening mammography is to detect tumors when they are small and nonpalpable in order to prevent more advanced breast tumors in women. Overdiagnosis, which leads to unnecessary treatment, refers to screen-detected tumors that will not lead to symptoms. Overdiagnosis cannot be measured directly and, therefore, understanding this concept is problematic for both women and clinicians.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Observations from other types of cancer screening put overdiagnosis in perspective

To help us grasp the overall issue of overdiagnosis, we can consider screening mammography alongside cervical cancer screening and colon cancer screening. For instance, screening with cervical cytology has reduced the incidence of and mortality from invasive cervical cancer.¹ Likewise, colonoscopy repeatedly has been found to reduce colon cancer mortality.^2,3 Decades of media messaging have emphasized the benefits of screening mammograms.⁴ However, and in contrast with cervical cytology and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic (advanced) disease.⁵ Likewise, as the Danish authors of a recent study published in Annals of Internal Medicine point out, screening mammography has not achieved the promised reduction in breast cancer mortality.

New data from Denmark highlight overdiagnosis concerns

Jørgensen and colleagues conducted a cohort study to estimate the incidence of screen-detected tumors that would not become clinically relevant (overdiagnosis) among women aged 35 to 84 years between 1980 and 2010 in Denmark.⁶ This country offers a particularly well-suited backdrop for a study of overdiagnosis because biennial screening mammography was introduced by region beginning in the early 1990s. By 2007, one-fifth of the country’s female population aged 50 to 69 years were invited to participate. In the following years, screening became universal for Danish women in this age group.

For the study, researchers identified the size of all invasive breast cancer tumors diagnosed over the study period and then compared the incidence rates of advanced tumors (more than 20-mm in size at detection) with nonadvanced tumors in screened and unscreened Danish regions. The investigators took into account regional differences not related to screening by assessing the trends in diagnosis of advanced and nonadvanced tumors in screened and unscreened regions among women older and younger than those screened. This gave them a better estimate of the incidence of overdiagnosis.⁶

Jørgensen and colleagues found that breast cancer screening resulted in an increase in the incidence of nonadvanced tumors, but that it did not reduce the incidence of advanced tumors. They estimated that 39% of the invasive tumors found among women aged 50 to 69 were overdiagnosed.⁶

These Danish study results, that more than one-third of screen-detected tumors represent overdiagnosis, are similar to those found for studies conducted in the United States and other countries.^7,8 The lengthy follow-up after initiation of screening and the assessment of trends in unscreened women represent strengths of the study by Jørgensen and colleagues, and speak to concerns voiced by those skeptical of reported overdiagnosis incidence rates.⁹

Although breast cancer mortality is declining, the lion’s share of this decline has resulted from improvements in systemic therapy rather than from screening mammography. Widespread screening mammography has resulted in a scenario in which women are more likely to have a breast cancer that was overdiagnosed than in having earlier detection of a tumor destined to grow larger.⁵ In the future, by targeting higher-risk women, screening may result in a better benefit:risk ratio. However, and as pointed out by Otis Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, we must acknowledge that overdiagnosis is common, the benefits of screening have been overstated, and some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.¹⁰

Related article:
No surprises from the USPSTF with new guidance on screening mammography

My breast cancer screening approach

As Brawley indicates, we should not abandon screening.¹⁰ I continue to recommend screening based on US Preventive Services Taskforce guidance, beginning biennial screens at age 50.¹¹ I also recognize that some women prefer earlier and more frequent screens, while others may prefer less frequent or even no screening.

The purpose of screening mammography is to detect tumors when they are small and nonpalpable in order to prevent more advanced breast tumors in women. Overdiagnosis, which leads to unnecessary treatment, refers to screen-detected tumors that will not lead to symptoms. Overdiagnosis cannot be measured directly and, therefore, understanding this concept is problematic for both women and clinicians.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Observations from other types of cancer screening put overdiagnosis in perspective

To help us grasp the overall issue of overdiagnosis, we can consider screening mammography alongside cervical cancer screening and colon cancer screening. For instance, screening with cervical cytology has reduced the incidence of and mortality from invasive cervical cancer.¹ Likewise, colonoscopy repeatedly has been found to reduce colon cancer mortality.^2,3 Decades of media messaging have emphasized the benefits of screening mammograms.⁴ However, and in contrast with cervical cytology and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic (advanced) disease.⁵ Likewise, as the Danish authors of a recent study published in Annals of Internal Medicine point out, screening mammography has not achieved the promised reduction in breast cancer mortality.

New data from Denmark highlight overdiagnosis concerns

Jørgensen and colleagues conducted a cohort study to estimate the incidence of screen-detected tumors that would not become clinically relevant (overdiagnosis) among women aged 35 to 84 years between 1980 and 2010 in Denmark.⁶ This country offers a particularly well-suited backdrop for a study of overdiagnosis because biennial screening mammography was introduced by region beginning in the early 1990s. By 2007, one-fifth of the country’s female population aged 50 to 69 years were invited to participate. In the following years, screening became universal for Danish women in this age group.

For the study, researchers identified the size of all invasive breast cancer tumors diagnosed over the study period and then compared the incidence rates of advanced tumors (more than 20-mm in size at detection) with nonadvanced tumors in screened and unscreened Danish regions. The investigators took into account regional differences not related to screening by assessing the trends in diagnosis of advanced and nonadvanced tumors in screened and unscreened regions among women older and younger than those screened. This gave them a better estimate of the incidence of overdiagnosis.⁶

Jørgensen and colleagues found that breast cancer screening resulted in an increase in the incidence of nonadvanced tumors, but that it did not reduce the incidence of advanced tumors. They estimated that 39% of the invasive tumors found among women aged 50 to 69 were overdiagnosed.⁶

These Danish study results, that more than one-third of screen-detected tumors represent overdiagnosis, are similar to those found for studies conducted in the United States and other countries.^7,8 The lengthy follow-up after initiation of screening and the assessment of trends in unscreened women represent strengths of the study by Jørgensen and colleagues, and speak to concerns voiced by those skeptical of reported overdiagnosis incidence rates.⁹

Although breast cancer mortality is declining, the lion’s share of this decline has resulted from improvements in systemic therapy rather than from screening mammography. Widespread screening mammography has resulted in a scenario in which women are more likely to have a breast cancer that was overdiagnosed than in having earlier detection of a tumor destined to grow larger.⁵ In the future, by targeting higher-risk women, screening may result in a better benefit:risk ratio. However, and as pointed out by Otis Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, we must acknowledge that overdiagnosis is common, the benefits of screening have been overstated, and some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.¹⁰

Related article:
No surprises from the USPSTF with new guidance on screening mammography

My breast cancer screening approach

As Brawley indicates, we should not abandon screening.¹⁰ I continue to recommend screening based on US Preventive Services Taskforce guidance, beginning biennial screens at age 50.¹¹ I also recognize that some women prefer earlier and more frequent screens, while others may prefer less frequent or even no screening.

EXPERT COMMENTARY

Both the Centers for Disease Control and Prevention and the World Health Organization currently recommend that patients with trichomoniasis be treated with a single 2-g oral dose of metronidazole.¹ Following treatment, the reported rates of repeat infection or persistent infection range from 5% to 31%. Repeat infection rates may be even higher in HIV-infected patients.

Repeat infections presumably result from a failure to treat the patient’s sexual partner(s) or from the patient’s exposure to a new partner. Persistent infections, however, may be the result of inadequate primary therapy, even though inherent resistance of the organism to metronidazole is quite rare. To date, no single study has shown that single-dose therapy is inferior to multidose therapy, but most of these studies lack sufficient power to completely exclude the possibility of a type-2 statistical error.² To compare single-dose with multidose therapy for trichomoniasis in a more systematic manner, Howe and Kissinger conducted a meta-analysis, which was recently published in Sexually Transmitted Diseases.

Related article:
2016 Update on infectious disease

Details of the study

The investigators conducted a comprehensive literature search using Embase, Medline, and ClinicalTrials.gov; 6 articles were included in the final results, 4 of which were randomized controlled trials. Approximately 1,300 participants were included in the 6 trials. All of the patients in the single-dose treatment arms received a 2-g oral dose of metronidazole. In the multidose treatment arms for 2 studies the participants received metronidazole 250 mg orally 3 times daily for 7 days, and for 2 studies the dose was 200 mg 3 times daily for 7 days. The fifth study employed a 500-mg oral dose of metronidazole twice daily for 7 days. The final study used a 400-mg oral dose twice daily for 5 days. The key study end point was treatment failure.

Howe and Kissinger demonstrated that women who received the single 2-g dose were 1.87 times (95% CI, 1.23−2.82; P<.01) more likely to experience a treatment failure compared with women who received a multidose regimen. When the one study that focused only on HIV-infected women was excluded from analysis, the results were similar. The relative risk of treatment failure was 1.80 (95% CI, 1.07−3.02; P<.03).

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

Study limitations

The results of this meta-analysis are interesting and provocative. However, the analysis has several important limitations. Five of the 6 studies were published many years ago (1971, 1972, 1979, 1980, and 1982). The most recent study was published in 2010. The investigators used 4 different multidose regimens, with metronidazole doses ranging from 200 mg to 500 mg and duration of therapy ranging from 5 to 7 days. Four of the six investigations used saline microscopy as the definitive diagnostic test of treatment failure. Compared with culture or DNA testing, microscopy is not as accurate. Moreover, the timing of retesting varied in the studies, and some apparent treatment failures actually may have been due to reinfection. In addition, the studies did not consistently track the adequacy of treatment of the sexual partner.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.