OBG Management

In a peer-to-peer audiocast, Ms. DiVenere probed Dr. Smith for the problem areas that appear in the early to late stages of burnout. He spoke to the stressors that residents experience in the learning situation and that ObGyns must deal with in practice, as well as described strategies to deal with that stress.   

Have you read "ObGyn burnout: ACOG takes aim," by Lucia DiVenere, MA (September 2016)?

In a peer-to-peer audiocast, Ms. DiVenere probed Dr. Smith for the problem areas that appear in the early to late stages of burnout. He spoke to the stressors that residents experience in the learning situation and that ObGyns must deal with in practice, as well as described strategies to deal with that stress.   

Have you read "ObGyn burnout: ACOG takes aim," by Lucia DiVenere, MA (September 2016)?

In a peer-to-peer audiocast, Ms. DiVenere probed Dr. Smith for the problem areas that appear in the early to late stages of burnout. He spoke to the stressors that residents experience in the learning situation and that ObGyns must deal with in practice, as well as described strategies to deal with that stress.   

Have you read "ObGyn burnout: ACOG takes aim," by Lucia DiVenere, MA (September 2016)?

Was the pregnancy ectopic or intrauterine?A 40-year-old woman underwent ultrasonography (US) during an office visit with her ObGyn. Results indicated that there was no gestational sac in the uterus. Following repeat US at a radiology facility, the radiologist reported that he saw no evidence of pregnancy in the uterus but did see a complex structure outside the uterus. He recommended follow-up US to further investigate the possibility of an ectopic pregnancy. After reading the radiologist’s report, the ObGyn concluded that it was highly likely that the woman had an ectopic pregnancy. He sent her to a hospital’s emergency department (ED) for an injection of methotrexate to manage the ectopic pregnancy.

Two days later, the patient returned to the ED with abdominal pain and vaginal spotting. US results showed an intrauterine pregnancy. However, based on the high risk of fetal deformity or death caused by methotrexate, the patient agreed to undergo surgical removal of fetal remains.

PARENT'S CLAIM: The patient and her husband sued the radiologist, alleging that his misreading of the subsequent US fell below the standard of care. If he had not misread the US, the ObGyn would not have ordered termination of an ectopic pregnancy with a teratogenic medication. 

PHYSICIAN'S DEFENSE: The case was settled during trial.

VERDICT: An undisclosed Arizona settlement was reached with the radiologist.

Have you read this Editorial by Dr. Barbieri?
Stop using the hCG discriminatory zone of 1,500 to 2,000 mIU/mL to guide intervention during early pregnancy. (Editorial; January 2015)

Increasing pain after ovarian cystectomy: $1.5MA woman in her 40s underwent ovarian cystectomy performed by her gynecologist. After surgery, the patient reported increasingly intense abdominal pain to the gynecologist. After 10 days, laboratory testing showed an increase in the patient’s white blood cell count. During exploratory surgery, a perforation was found in her sigmoid colon, and a colostomy was performed.

PATIENT'S CLAIM: The gynecologist was negligent in injuring the colon and then not intraoperatively identifying and repairing the damage. Postoperatively, the gynecologist failed to address the injury in a timely manner.

PHYSICIAN'S DEFENSE: A colon injury is a known complication of the procedure. Such injuries are often not identified until days after the surgery.

VERDICT: A $1.52 million New York verdict was returned.

Bladder injury causes multiple operations A woman in her 30s underwent a hysterectomy performed by her ObGyn. During the procedure, the ObGyn perforated the patient’s bladder. The ObGyn attempted to repair the injury, but then called in a urologist to complete the procedure. The urologist had to reduce the size of the bladder in order to complete the repair. The patient underwent additional operations to treat a postsurgical infection and adhesions. During an operation to treat infection, a surgeon found that the ureter had been reimplanted.

PATIENT'S CLAIM: During the first repair procedure, the urologist was negligent in not inspecting adjacent organs for damage before closing. Infection developed because the repair was improperly performed.

PHYSICIAN'S DEFENSE: The urologist denied negligence. Infection is a known complication of an intraoperative bladder injury.

VERDICT: A Michigan defense verdict was reached.

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 rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Was the pregnancy ectopic or intrauterine?A 40-year-old woman underwent ultrasonography (US) during an office visit with her ObGyn. Results indicated that there was no gestational sac in the uterus. Following repeat US at a radiology facility, the radiologist reported that he saw no evidence of pregnancy in the uterus but did see a complex structure outside the uterus. He recommended follow-up US to further investigate the possibility of an ectopic pregnancy. After reading the radiologist’s report, the ObGyn concluded that it was highly likely that the woman had an ectopic pregnancy. He sent her to a hospital’s emergency department (ED) for an injection of methotrexate to manage the ectopic pregnancy.

Two days later, the patient returned to the ED with abdominal pain and vaginal spotting. US results showed an intrauterine pregnancy. However, based on the high risk of fetal deformity or death caused by methotrexate, the patient agreed to undergo surgical removal of fetal remains.

PARENT'S CLAIM: The patient and her husband sued the radiologist, alleging that his misreading of the subsequent US fell below the standard of care. If he had not misread the US, the ObGyn would not have ordered termination of an ectopic pregnancy with a teratogenic medication. 

PHYSICIAN'S DEFENSE: The case was settled during trial.

VERDICT: An undisclosed Arizona settlement was reached with the radiologist.

Have you read this Editorial by Dr. Barbieri?
Stop using the hCG discriminatory zone of 1,500 to 2,000 mIU/mL to guide intervention during early pregnancy. (Editorial; January 2015)

Increasing pain after ovarian cystectomy: $1.5MA woman in her 40s underwent ovarian cystectomy performed by her gynecologist. After surgery, the patient reported increasingly intense abdominal pain to the gynecologist. After 10 days, laboratory testing showed an increase in the patient’s white blood cell count. During exploratory surgery, a perforation was found in her sigmoid colon, and a colostomy was performed.

PATIENT'S CLAIM: The gynecologist was negligent in injuring the colon and then not intraoperatively identifying and repairing the damage. Postoperatively, the gynecologist failed to address the injury in a timely manner.

PHYSICIAN'S DEFENSE: A colon injury is a known complication of the procedure. Such injuries are often not identified until days after the surgery.

VERDICT: A $1.52 million New York verdict was returned.

Bladder injury causes multiple operations A woman in her 30s underwent a hysterectomy performed by her ObGyn. During the procedure, the ObGyn perforated the patient’s bladder. The ObGyn attempted to repair the injury, but then called in a urologist to complete the procedure. The urologist had to reduce the size of the bladder in order to complete the repair. The patient underwent additional operations to treat a postsurgical infection and adhesions. During an operation to treat infection, a surgeon found that the ureter had been reimplanted.

PATIENT'S CLAIM: During the first repair procedure, the urologist was negligent in not inspecting adjacent organs for damage before closing. Infection developed because the repair was improperly performed.

PHYSICIAN'S DEFENSE: The urologist denied negligence. Infection is a known complication of an intraoperative bladder injury.

VERDICT: A Michigan defense verdict was reached.

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 rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Was the pregnancy ectopic or intrauterine?A 40-year-old woman underwent ultrasonography (US) during an office visit with her ObGyn. Results indicated that there was no gestational sac in the uterus. Following repeat US at a radiology facility, the radiologist reported that he saw no evidence of pregnancy in the uterus but did see a complex structure outside the uterus. He recommended follow-up US to further investigate the possibility of an ectopic pregnancy. After reading the radiologist’s report, the ObGyn concluded that it was highly likely that the woman had an ectopic pregnancy. He sent her to a hospital’s emergency department (ED) for an injection of methotrexate to manage the ectopic pregnancy.

Two days later, the patient returned to the ED with abdominal pain and vaginal spotting. US results showed an intrauterine pregnancy. However, based on the high risk of fetal deformity or death caused by methotrexate, the patient agreed to undergo surgical removal of fetal remains.

PARENT'S CLAIM: The patient and her husband sued the radiologist, alleging that his misreading of the subsequent US fell below the standard of care. If he had not misread the US, the ObGyn would not have ordered termination of an ectopic pregnancy with a teratogenic medication. 

PHYSICIAN'S DEFENSE: The case was settled during trial.

VERDICT: An undisclosed Arizona settlement was reached with the radiologist.

Have you read this Editorial by Dr. Barbieri?
Stop using the hCG discriminatory zone of 1,500 to 2,000 mIU/mL to guide intervention during early pregnancy. (Editorial; January 2015)

Increasing pain after ovarian cystectomy: $1.5MA woman in her 40s underwent ovarian cystectomy performed by her gynecologist. After surgery, the patient reported increasingly intense abdominal pain to the gynecologist. After 10 days, laboratory testing showed an increase in the patient’s white blood cell count. During exploratory surgery, a perforation was found in her sigmoid colon, and a colostomy was performed.

PATIENT'S CLAIM: The gynecologist was negligent in injuring the colon and then not intraoperatively identifying and repairing the damage. Postoperatively, the gynecologist failed to address the injury in a timely manner.

PHYSICIAN'S DEFENSE: A colon injury is a known complication of the procedure. Such injuries are often not identified until days after the surgery.

VERDICT: A $1.52 million New York verdict was returned.

Bladder injury causes multiple operations A woman in her 30s underwent a hysterectomy performed by her ObGyn. During the procedure, the ObGyn perforated the patient’s bladder. The ObGyn attempted to repair the injury, but then called in a urologist to complete the procedure. The urologist had to reduce the size of the bladder in order to complete the repair. The patient underwent additional operations to treat a postsurgical infection and adhesions. During an operation to treat infection, a surgeon found that the ureter had been reimplanted.

PATIENT'S CLAIM: During the first repair procedure, the urologist was negligent in not inspecting adjacent organs for damage before closing. Infection developed because the repair was improperly performed.

PHYSICIAN'S DEFENSE: The urologist denied negligence. Infection is a known complication of an intraoperative bladder injury.

VERDICT: A Michigan defense verdict was reached.

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 rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Although RRSO is routinely recommended to decrease the risk of ovarian as well as breast cancer in women who harbor BRCA mutations, whether or not surgery should include hysterectomy has not been clear. Shu and colleagues prospectively evaluated the risk of uterine cancer in BRCA1 and BRCA2 mutation carriers who underwent RRSO without hysterectomy at 1 of 9 centers in the United States or the United Kingdom, comparing it with rates expected from national surveillance data.

Details of the study

Among 1,083 women (median age, 45.6 years at the time of RRSO; median follow-up, 5.1 years), 8 incident uterine cancers were observed (4.3 were expected; observed to expected [O:E] ratio, 1.9; P = .09). In an analysis stratified by tumor subtype, no elevated risk for endometrioid endometrial cancer or sarcoma was noted. Five serous and/or serous-like endometrial cancers were observed after RRSO. Four were found in BRCA1 carriers and 1 in a BRCA2 carrier, with the O:E ratio of 22.2 (P<.001) for BRCA1 and 6.4 (P = .15) for BRCA2 carriers.

Details of the accompanying editorial

Commenting on the study, Leath and colleagues noted that while the number of cases was small, the study demonstrated a link between the presence of BRCA mutations (particularly BRCA1 mutations) and a "small but not null risk of endometrial cancer." Many of these uterine cancers have a serous histology, a concern due to the likelihood of worse outcomes compared with the more common endometrioid variant.
 
The authors suggest that clinicians make patients with BRCA mutations undergoing RRSO aware of the potential risks and benefits of concomitant hysterectomy and work to make an individualized decision based on the limitations of available data. They state, "Perhaps it is time to consider that the line for risk-reducing gynecologic surgery in patients with BRCA mutations not stop at the ovaries and fallopian tubes. Thus, concomitant hysterectomy with RRSO, when performed with a minimally invasive surgical approach, particularly for women with a BRCA1 mutation, should be able to be performed with minimum morbidity and allow for use of estrogen-only hormone therapy after surgery, if needed."

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Although RRSO is routinely recommended to decrease the risk of ovarian as well as breast cancer in women who harbor BRCA mutations, whether or not surgery should include hysterectomy has not been clear. Shu and colleagues prospectively evaluated the risk of uterine cancer in BRCA1 and BRCA2 mutation carriers who underwent RRSO without hysterectomy at 1 of 9 centers in the United States or the United Kingdom, comparing it with rates expected from national surveillance data.

Details of the study

Among 1,083 women (median age, 45.6 years at the time of RRSO; median follow-up, 5.1 years), 8 incident uterine cancers were observed (4.3 were expected; observed to expected [O:E] ratio, 1.9; P = .09). In an analysis stratified by tumor subtype, no elevated risk for endometrioid endometrial cancer or sarcoma was noted. Five serous and/or serous-like endometrial cancers were observed after RRSO. Four were found in BRCA1 carriers and 1 in a BRCA2 carrier, with the O:E ratio of 22.2 (P<.001) for BRCA1 and 6.4 (P = .15) for BRCA2 carriers.

Details of the accompanying editorial

Commenting on the study, Leath and colleagues noted that while the number of cases was small, the study demonstrated a link between the presence of BRCA mutations (particularly BRCA1 mutations) and a "small but not null risk of endometrial cancer." Many of these uterine cancers have a serous histology, a concern due to the likelihood of worse outcomes compared with the more common endometrioid variant.
 
The authors suggest that clinicians make patients with BRCA mutations undergoing RRSO aware of the potential risks and benefits of concomitant hysterectomy and work to make an individualized decision based on the limitations of available data. They state, "Perhaps it is time to consider that the line for risk-reducing gynecologic surgery in patients with BRCA mutations not stop at the ovaries and fallopian tubes. Thus, concomitant hysterectomy with RRSO, when performed with a minimally invasive surgical approach, particularly for women with a BRCA1 mutation, should be able to be performed with minimum morbidity and allow for use of estrogen-only hormone therapy after surgery, if needed."

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Although RRSO is routinely recommended to decrease the risk of ovarian as well as breast cancer in women who harbor BRCA mutations, whether or not surgery should include hysterectomy has not been clear. Shu and colleagues prospectively evaluated the risk of uterine cancer in BRCA1 and BRCA2 mutation carriers who underwent RRSO without hysterectomy at 1 of 9 centers in the United States or the United Kingdom, comparing it with rates expected from national surveillance data.

Details of the study

Among 1,083 women (median age, 45.6 years at the time of RRSO; median follow-up, 5.1 years), 8 incident uterine cancers were observed (4.3 were expected; observed to expected [O:E] ratio, 1.9; P = .09). In an analysis stratified by tumor subtype, no elevated risk for endometrioid endometrial cancer or sarcoma was noted. Five serous and/or serous-like endometrial cancers were observed after RRSO. Four were found in BRCA1 carriers and 1 in a BRCA2 carrier, with the O:E ratio of 22.2 (P<.001) for BRCA1 and 6.4 (P = .15) for BRCA2 carriers.

Details of the accompanying editorial

Commenting on the study, Leath and colleagues noted that while the number of cases was small, the study demonstrated a link between the presence of BRCA mutations (particularly BRCA1 mutations) and a "small but not null risk of endometrial cancer." Many of these uterine cancers have a serous histology, a concern due to the likelihood of worse outcomes compared with the more common endometrioid variant.
 
The authors suggest that clinicians make patients with BRCA mutations undergoing RRSO aware of the potential risks and benefits of concomitant hysterectomy and work to make an individualized decision based on the limitations of available data. They state, "Perhaps it is time to consider that the line for risk-reducing gynecologic surgery in patients with BRCA mutations not stop at the ovaries and fallopian tubes. Thus, concomitant hysterectomy with RRSO, when performed with a minimally invasive surgical approach, particularly for women with a BRCA1 mutation, should be able to be performed with minimum morbidity and allow for use of estrogen-only hormone therapy after surgery, if needed."

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

We recently reviewed the most current information on the epidemiology, clinical manifestations, and diagnosis of maternal and congenital Zika virus (ZV) infection.¹ We also offered tentative recommendations for reducing the risk of infection and for managing the treatment of women exposed to the virus.

In this update, we present new information on the broadened spectrum of anomalies now known to be causally related to congenital ZV infection and on the increasing number of serious neurologic complications directly related to ZV infection in adults. We also update recommendations for diagnosing maternal, fetal, and neonatal infection and present guidelines for preventing sexual transmission of ZV infection.

CASE Woman from Brazil gives birth to stillborn baby with microcephaly

A 23-year-old woman (G2P1) recently emigrated from Pernambuco in Brazil to the United States and now presents to the hospital in advanced labor. Based on results of first-trimester ultrasonography performed in Brazil, it is determined that she is at 39 weeks’ gestation. The patient has not had any prenatal care since early in the second trimester because of low income and lack of medical insurance. She reports no serious illness before or during the pregnancy.

In the labor and delivery suite, she rapidly delivers a stillborn female infant—5 pounds 3 ounces, growth restricted, with multiple congenital anomalies. Postmortem examination reveals microcephaly, ventriculomegaly, extensive brain atrophy, intracranial calcifications, cerebellar agenesis, cataracts, ocular calcifications, redundant scalp tissue, and multiple joint contractures.

What is the most likely cause of these multiple anomalies?

The patient’s findings are most consistent with a diagnosis of severe intrauterine infection. Possible pathogenic organisms include rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, toxoplasmosis, and ZV.² Given the patient’s recent move from Pernambuco in northeastern Brazil, the epicenter of the ZV epidemic in the Americas, the most likely diagnosis is congenital ZV infection.

The initial reports of congenital anomalies associated with ZV infection focused on microcephaly, usually defined as head circumference less than 3 standard deviations below the mean, or less than the third or fifth percentile for gestational age. Subsequent reports have linked many other serious central nervous system (CNS) anomalies to the virus. In a retrospective case series, de Fatima Vasco Aragao and colleagues³ described neuroimaging findings in 23 infants with presumed congenital ZV infection. Of the 22 with computed tomography scans, all had calcifications at the junction of cortical and subcortical white matter, 21 (95%) had disordered cortical development, 20 (91%) had a significant decrease in brain volume, 19 (86%) had ventriculomegaly, and half had distinct hypoplasia of either cerebellum or brainstem. In addition, of the 8 infants with magnetic resonance imaging (MRI) studies, 7 (88%) had an enlarged cisterna magna, 7 (88%) had delayed myelination, 6 (75%) had a simplified gyral pattern, and 3 (38%) had hypoplasia of corpus callosum.

De Paula Freitas and colleagues⁴ recently found congenital ZV infection associated with severe ocular abnormalities. Comprehensive ophthalmologic examination of 29 infants with microcephaly, presumed caused by congenital ZV infection, revealed 10 (35%) had abnormalities, which included focal pigment mottling, chorioretinal atrophy, hypoplasia and cupping of optic disk, loss of foveal reflex, macular atrophy, lens subluxation, and coloboma of iris.

Other conditions linked to congenital ZV infection include intrauterine growth restriction, redundant scalp tissue, contractures of multiple joints, and clubfoot.²

Bottom line. Although the ocular abnormalities are undetectable by prenatal ultrasound, many of the CNS and skeletal anomalies can be identified antenatally. Therefore, serial ultrasound examinations should be performed on adults who have a clinical illness consistent with ZV infection or who have traveled to an endemic area or have a sexual partner who has been in an endemic area. Patients should be assessed for possible microcephaly, ventriculomegaly, agenesis of corpus callosum, hypoplasia of cerebellum, and skeletal deformities.

Did ZV cause these anomalies?

How certain can we be that the anomalies present in the case patient’s baby were caused by ZV? In the past, and for many years, scientists relied on Koch’s 4 postulates (TABLE 1) to answer this question and establish a causal relationship between a microorganism and a specific clinical disease.⁵ Koch’s postulates have not been satisfied for the relationship between maternal ZV infection and congenital anomalies. Today’s more relevant standards for determining causality of a teratogen were published in 1994 by Shepard.⁶ In 2016, Rasmussen and colleagues⁷ found that the critical components of these criteria are fulfilled and concluded that there is little doubt ZV is a proven and extremely dangerous teratogen. See “Zika virus has been shown to be a direct cause of microcephaly”.

Rasmussen and colleagues⁷ also used Hill’s criteria to assess the evidence for causation. Hill’s systematic assessment is based on 9 factors (TABLE 2)⁸, and Rasmussen and colleagues⁷ concluded that the necessary 7 of these 9 criteria have been met (the experimental animal model criterion was not satisfied, and the biological gradient criterion was not applicable). Given their assessment of Shepard’s criteria,⁶ the authors argued that the link between maternal ZV infection and severe congenital anomalies has risen from association to well-defined causation.

How should ZV infection be confirmed in adults and newborns?

After our first review was published in March 2016,¹ the testing algorithm recommended by the US Centers for Disease Control and Prevention (CDC) was revised.⁹ Now, according to the CDC, if a patient has had symptoms of ZV infection for less than 5 days, serum and urine should be obtained for reverse transcriptase–polymerase chain reaction (RT-PCR) testing. If symptoms have been present for 5 to 14 days, urine should be tested by RT-PCR because urine samples appear to remain positive for virus longer than serum samples do. If RT-PCR is performed within the appropriate period and the result is negative, ZV infection is excluded; if the result is positive, acute ZV infection is confirmed, and additional testing is not indicated. RT-PCR can be performed by 2 commercial laboratories (Quest Diagnostics and LabCorp), state health departments, and the CDC.

If serum or urine is collected more than 5 days after symptom onset and the RT-PCR result is negative, the patient should have an immunoglobulin M (IgM) assay for ZV. If the assay result is negative, infection is excluded; if the result is positive or equivocal, additional testing is needed to ensure that the presence of the antibody does not reflect a cross-reaction to dengue or chikungunya virus. The confirmatory plaque reduction neutralization test (PRNT) is performed only by the CDC. To be considered positive, the PRNT result must be at least 4-fold higher than the dengue virus neutralizing antibody titer.

In patients with suspected Guillain-Barré syndrome (GBS), RT-PCR can be performed on cerebrospinal fluid. For suspected fetal or neonatal infection, RT-PCR can be performed on amniotic fluid, umbilical cord blood, and fetal and placental tissue.

CASE 2 Nonpregnant woman with possible Zika virus exposure presents to ED with neurologic symptoms

A 31-year-old nulligravid woman presents to the emergency department (ED) for evaluation of numbness, tingling, and weakness in the lower extremities and difficulty walking. She reports having had a low-grade fever and a fine disseminated macular rash 1 week earlier. She denies recent travel and exposure to friends or relatives with illness, but she says her husband travels extensively and was living and working in Puerto Rico. The patient has no other neurologic symptoms.

Serum and cerebrospinal fluid chemistries and MRI findings are normal. However, the ZV IgM assay is positive, and nerve conduction study results are consistent with GBS. The patient is admitted to the hospital, treated with intravenous immunoglobulin and given supportive care. Over 10 days, her neurologic condition gradually improves.

What is the link between ZV infection and serious neurologic complications in adults?

ZV infection has been associated with serious neurologic complications in adults. Investigators in several countries have reported dramatic increases in GBS cases during the ZV outbreak.¹⁰

GBS is an acute, immune-mediated, demyelinating peripheral neuropathy that can vary in presentation but most commonly manifests as a rapidly ascending paralysis. The disorder often is preceded by an immunization or live viral infection. In some patients, paralysis severely weakens the respiratory muscles and even the cranial nerves, and affected individuals may require intubation, ventilator support, and parenteral or enteral alimentation.

In a case-control study conducted duringthe 2013–2014 outbreak in French Polynesia, the association between ZV infection and GBS was evaluated in 3 groups of patients: 42 patients with GBS, 98 control patients, and 70 patients with ZV infection but no neurologic complications.¹¹ Symptoms of ZV infection were present in about 88% of the patients with GBS, and the median interval from viral infection to onset of neurologic symptoms was 6 days. The ZV IgM assay was positive in 93% of GBS cases. Nerve conduction study results were consistent with the acute motor axonal neuropathy of GBS. All patients were treated with intravenous immunoglobulin; 38% of patients had to be admitted to the intensive care unit, and 29% needed respiratory support. There were no fatalities. The overall incidence of GBS was 2.4 cases per 10,000 ZV infections.

Other neurologic complications that have been associated with ZV infection are meningoencephalitis,¹² brain ischemia,¹³ and myelitis.¹⁴

Bottom line. ZV infection may cause serious neurologic complications in adults. The most devastating complication is GBS, which can result in respiratory muscle paralysis and cranial nerve palsies.

How can patients prevent sexual transmission of ZV infection?

The ZV can be transmitted by sexual contact, including vaginal, anal, and oral sex.¹⁵ It is known to persist longer in semen than in blood or urine, though the exact duration remains unknown. Atkinson and colleagues¹⁶ reported RT-PCR detection of ZV RNA in semen about 62 days after onset of febrile illness—long after the virus became undetectable in blood.¹⁵

Mansuy and colleagues¹⁷ found that the viral load in semen was more than 100,000 times that in blood and urine more than 2 weeks after symptom onset.¹⁶ The ZV has been detected in saliva, urine, and breast milk. Although it has not been identified in vaginal secretions in humans, it has been detected in the vaginal secretions of nonhuman primates up to 7 days after subcutaneous inoculation of virus.¹⁸ In addition, the first case of female-to-male sexual transmission of ZV infection was just reported.¹⁹ In this report, transmission seems to have occurred on day 3 of the woman’s symptomatic illness, when she had unprotected vaginal intercourse with her partner. The partner became symptomatic 7 days after sexual exposure. To date, there is no evidence that infection is spread through kissing or breastfeeding.

The most recent recommendations from the CDC are that a man with symptomatic ZV infection wait at least 6 months before having unprotected sexual contact. In addition, a man who is asymptomatic after ZV exposure should wait at least 8 weeks before having unprotected sexual contact.¹⁷

A woman planning a pregnancy should know there is no evidence that prior ZV infection increases the risk of birth defects. However, a woman with a proven ZV infection should wait at least 8 weeks after symptom onset before trying to conceive. Even an asymptomatic woman with possible exposure should wait at least 8 weeks after the last exposure before attempting conception. In addition, given the risks associated with maternal and fetal infection, a man who has been exposed to the virus and who has a pregnant partner should abstain from unprotected sexual contact for the duration of the pregnancy.²⁰

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

We recently reviewed the most current information on the epidemiology, clinical manifestations, and diagnosis of maternal and congenital Zika virus (ZV) infection.¹ We also offered tentative recommendations for reducing the risk of infection and for managing the treatment of women exposed to the virus.

In this update, we present new information on the broadened spectrum of anomalies now known to be causally related to congenital ZV infection and on the increasing number of serious neurologic complications directly related to ZV infection in adults. We also update recommendations for diagnosing maternal, fetal, and neonatal infection and present guidelines for preventing sexual transmission of ZV infection.

CASE Woman from Brazil gives birth to stillborn baby with microcephaly

A 23-year-old woman (G2P1) recently emigrated from Pernambuco in Brazil to the United States and now presents to the hospital in advanced labor. Based on results of first-trimester ultrasonography performed in Brazil, it is determined that she is at 39 weeks’ gestation. The patient has not had any prenatal care since early in the second trimester because of low income and lack of medical insurance. She reports no serious illness before or during the pregnancy.

In the labor and delivery suite, she rapidly delivers a stillborn female infant—5 pounds 3 ounces, growth restricted, with multiple congenital anomalies. Postmortem examination reveals microcephaly, ventriculomegaly, extensive brain atrophy, intracranial calcifications, cerebellar agenesis, cataracts, ocular calcifications, redundant scalp tissue, and multiple joint contractures.

What is the most likely cause of these multiple anomalies?

The patient’s findings are most consistent with a diagnosis of severe intrauterine infection. Possible pathogenic organisms include rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, toxoplasmosis, and ZV.² Given the patient’s recent move from Pernambuco in northeastern Brazil, the epicenter of the ZV epidemic in the Americas, the most likely diagnosis is congenital ZV infection.

The initial reports of congenital anomalies associated with ZV infection focused on microcephaly, usually defined as head circumference less than 3 standard deviations below the mean, or less than the third or fifth percentile for gestational age. Subsequent reports have linked many other serious central nervous system (CNS) anomalies to the virus. In a retrospective case series, de Fatima Vasco Aragao and colleagues³ described neuroimaging findings in 23 infants with presumed congenital ZV infection. Of the 22 with computed tomography scans, all had calcifications at the junction of cortical and subcortical white matter, 21 (95%) had disordered cortical development, 20 (91%) had a significant decrease in brain volume, 19 (86%) had ventriculomegaly, and half had distinct hypoplasia of either cerebellum or brainstem. In addition, of the 8 infants with magnetic resonance imaging (MRI) studies, 7 (88%) had an enlarged cisterna magna, 7 (88%) had delayed myelination, 6 (75%) had a simplified gyral pattern, and 3 (38%) had hypoplasia of corpus callosum.

De Paula Freitas and colleagues⁴ recently found congenital ZV infection associated with severe ocular abnormalities. Comprehensive ophthalmologic examination of 29 infants with microcephaly, presumed caused by congenital ZV infection, revealed 10 (35%) had abnormalities, which included focal pigment mottling, chorioretinal atrophy, hypoplasia and cupping of optic disk, loss of foveal reflex, macular atrophy, lens subluxation, and coloboma of iris.

Other conditions linked to congenital ZV infection include intrauterine growth restriction, redundant scalp tissue, contractures of multiple joints, and clubfoot.²

Bottom line. Although the ocular abnormalities are undetectable by prenatal ultrasound, many of the CNS and skeletal anomalies can be identified antenatally. Therefore, serial ultrasound examinations should be performed on adults who have a clinical illness consistent with ZV infection or who have traveled to an endemic area or have a sexual partner who has been in an endemic area. Patients should be assessed for possible microcephaly, ventriculomegaly, agenesis of corpus callosum, hypoplasia of cerebellum, and skeletal deformities.

Did ZV cause these anomalies?

How certain can we be that the anomalies present in the case patient’s baby were caused by ZV? In the past, and for many years, scientists relied on Koch’s 4 postulates (TABLE 1) to answer this question and establish a causal relationship between a microorganism and a specific clinical disease.⁵ Koch’s postulates have not been satisfied for the relationship between maternal ZV infection and congenital anomalies. Today’s more relevant standards for determining causality of a teratogen were published in 1994 by Shepard.⁶ In 2016, Rasmussen and colleagues⁷ found that the critical components of these criteria are fulfilled and concluded that there is little doubt ZV is a proven and extremely dangerous teratogen. See “Zika virus has been shown to be a direct cause of microcephaly”.

Rasmussen and colleagues⁷ also used Hill’s criteria to assess the evidence for causation. Hill’s systematic assessment is based on 9 factors (TABLE 2)⁸, and Rasmussen and colleagues⁷ concluded that the necessary 7 of these 9 criteria have been met (the experimental animal model criterion was not satisfied, and the biological gradient criterion was not applicable). Given their assessment of Shepard’s criteria,⁶ the authors argued that the link between maternal ZV infection and severe congenital anomalies has risen from association to well-defined causation.

How should ZV infection be confirmed in adults and newborns?

After our first review was published in March 2016,¹ the testing algorithm recommended by the US Centers for Disease Control and Prevention (CDC) was revised.⁹ Now, according to the CDC, if a patient has had symptoms of ZV infection for less than 5 days, serum and urine should be obtained for reverse transcriptase–polymerase chain reaction (RT-PCR) testing. If symptoms have been present for 5 to 14 days, urine should be tested by RT-PCR because urine samples appear to remain positive for virus longer than serum samples do. If RT-PCR is performed within the appropriate period and the result is negative, ZV infection is excluded; if the result is positive, acute ZV infection is confirmed, and additional testing is not indicated. RT-PCR can be performed by 2 commercial laboratories (Quest Diagnostics and LabCorp), state health departments, and the CDC.

If serum or urine is collected more than 5 days after symptom onset and the RT-PCR result is negative, the patient should have an immunoglobulin M (IgM) assay for ZV. If the assay result is negative, infection is excluded; if the result is positive or equivocal, additional testing is needed to ensure that the presence of the antibody does not reflect a cross-reaction to dengue or chikungunya virus. The confirmatory plaque reduction neutralization test (PRNT) is performed only by the CDC. To be considered positive, the PRNT result must be at least 4-fold higher than the dengue virus neutralizing antibody titer.

In patients with suspected Guillain-Barré syndrome (GBS), RT-PCR can be performed on cerebrospinal fluid. For suspected fetal or neonatal infection, RT-PCR can be performed on amniotic fluid, umbilical cord blood, and fetal and placental tissue.

CASE 2 Nonpregnant woman with possible Zika virus exposure presents to ED with neurologic symptoms

A 31-year-old nulligravid woman presents to the emergency department (ED) for evaluation of numbness, tingling, and weakness in the lower extremities and difficulty walking. She reports having had a low-grade fever and a fine disseminated macular rash 1 week earlier. She denies recent travel and exposure to friends or relatives with illness, but she says her husband travels extensively and was living and working in Puerto Rico. The patient has no other neurologic symptoms.

Serum and cerebrospinal fluid chemistries and MRI findings are normal. However, the ZV IgM assay is positive, and nerve conduction study results are consistent with GBS. The patient is admitted to the hospital, treated with intravenous immunoglobulin and given supportive care. Over 10 days, her neurologic condition gradually improves.

What is the link between ZV infection and serious neurologic complications in adults?

ZV infection has been associated with serious neurologic complications in adults. Investigators in several countries have reported dramatic increases in GBS cases during the ZV outbreak.¹⁰

GBS is an acute, immune-mediated, demyelinating peripheral neuropathy that can vary in presentation but most commonly manifests as a rapidly ascending paralysis. The disorder often is preceded by an immunization or live viral infection. In some patients, paralysis severely weakens the respiratory muscles and even the cranial nerves, and affected individuals may require intubation, ventilator support, and parenteral or enteral alimentation.

In a case-control study conducted duringthe 2013–2014 outbreak in French Polynesia, the association between ZV infection and GBS was evaluated in 3 groups of patients: 42 patients with GBS, 98 control patients, and 70 patients with ZV infection but no neurologic complications.¹¹ Symptoms of ZV infection were present in about 88% of the patients with GBS, and the median interval from viral infection to onset of neurologic symptoms was 6 days. The ZV IgM assay was positive in 93% of GBS cases. Nerve conduction study results were consistent with the acute motor axonal neuropathy of GBS. All patients were treated with intravenous immunoglobulin; 38% of patients had to be admitted to the intensive care unit, and 29% needed respiratory support. There were no fatalities. The overall incidence of GBS was 2.4 cases per 10,000 ZV infections.

Other neurologic complications that have been associated with ZV infection are meningoencephalitis,¹² brain ischemia,¹³ and myelitis.¹⁴

Bottom line. ZV infection may cause serious neurologic complications in adults. The most devastating complication is GBS, which can result in respiratory muscle paralysis and cranial nerve palsies.

How can patients prevent sexual transmission of ZV infection?

The ZV can be transmitted by sexual contact, including vaginal, anal, and oral sex.¹⁵ It is known to persist longer in semen than in blood or urine, though the exact duration remains unknown. Atkinson and colleagues¹⁶ reported RT-PCR detection of ZV RNA in semen about 62 days after onset of febrile illness—long after the virus became undetectable in blood.¹⁵

Mansuy and colleagues¹⁷ found that the viral load in semen was more than 100,000 times that in blood and urine more than 2 weeks after symptom onset.¹⁶ The ZV has been detected in saliva, urine, and breast milk. Although it has not been identified in vaginal secretions in humans, it has been detected in the vaginal secretions of nonhuman primates up to 7 days after subcutaneous inoculation of virus.¹⁸ In addition, the first case of female-to-male sexual transmission of ZV infection was just reported.¹⁹ In this report, transmission seems to have occurred on day 3 of the woman’s symptomatic illness, when she had unprotected vaginal intercourse with her partner. The partner became symptomatic 7 days after sexual exposure. To date, there is no evidence that infection is spread through kissing or breastfeeding.

The most recent recommendations from the CDC are that a man with symptomatic ZV infection wait at least 6 months before having unprotected sexual contact. In addition, a man who is asymptomatic after ZV exposure should wait at least 8 weeks before having unprotected sexual contact.¹⁷

A woman planning a pregnancy should know there is no evidence that prior ZV infection increases the risk of birth defects. However, a woman with a proven ZV infection should wait at least 8 weeks after symptom onset before trying to conceive. Even an asymptomatic woman with possible exposure should wait at least 8 weeks after the last exposure before attempting conception. In addition, given the risks associated with maternal and fetal infection, a man who has been exposed to the virus and who has a pregnant partner should abstain from unprotected sexual contact for the duration of the pregnancy.²⁰

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

We recently reviewed the most current information on the epidemiology, clinical manifestations, and diagnosis of maternal and congenital Zika virus (ZV) infection.¹ We also offered tentative recommendations for reducing the risk of infection and for managing the treatment of women exposed to the virus.

In this update, we present new information on the broadened spectrum of anomalies now known to be causally related to congenital ZV infection and on the increasing number of serious neurologic complications directly related to ZV infection in adults. We also update recommendations for diagnosing maternal, fetal, and neonatal infection and present guidelines for preventing sexual transmission of ZV infection.

CASE Woman from Brazil gives birth to stillborn baby with microcephaly

A 23-year-old woman (G2P1) recently emigrated from Pernambuco in Brazil to the United States and now presents to the hospital in advanced labor. Based on results of first-trimester ultrasonography performed in Brazil, it is determined that she is at 39 weeks’ gestation. The patient has not had any prenatal care since early in the second trimester because of low income and lack of medical insurance. She reports no serious illness before or during the pregnancy.

In the labor and delivery suite, she rapidly delivers a stillborn female infant—5 pounds 3 ounces, growth restricted, with multiple congenital anomalies. Postmortem examination reveals microcephaly, ventriculomegaly, extensive brain atrophy, intracranial calcifications, cerebellar agenesis, cataracts, ocular calcifications, redundant scalp tissue, and multiple joint contractures.

What is the most likely cause of these multiple anomalies?

The patient’s findings are most consistent with a diagnosis of severe intrauterine infection. Possible pathogenic organisms include rubella virus, cytomegalovirus, lymphocytic choriomeningitis virus, toxoplasmosis, and ZV.² Given the patient’s recent move from Pernambuco in northeastern Brazil, the epicenter of the ZV epidemic in the Americas, the most likely diagnosis is congenital ZV infection.

The initial reports of congenital anomalies associated with ZV infection focused on microcephaly, usually defined as head circumference less than 3 standard deviations below the mean, or less than the third or fifth percentile for gestational age. Subsequent reports have linked many other serious central nervous system (CNS) anomalies to the virus. In a retrospective case series, de Fatima Vasco Aragao and colleagues³ described neuroimaging findings in 23 infants with presumed congenital ZV infection. Of the 22 with computed tomography scans, all had calcifications at the junction of cortical and subcortical white matter, 21 (95%) had disordered cortical development, 20 (91%) had a significant decrease in brain volume, 19 (86%) had ventriculomegaly, and half had distinct hypoplasia of either cerebellum or brainstem. In addition, of the 8 infants with magnetic resonance imaging (MRI) studies, 7 (88%) had an enlarged cisterna magna, 7 (88%) had delayed myelination, 6 (75%) had a simplified gyral pattern, and 3 (38%) had hypoplasia of corpus callosum.

De Paula Freitas and colleagues⁴ recently found congenital ZV infection associated with severe ocular abnormalities. Comprehensive ophthalmologic examination of 29 infants with microcephaly, presumed caused by congenital ZV infection, revealed 10 (35%) had abnormalities, which included focal pigment mottling, chorioretinal atrophy, hypoplasia and cupping of optic disk, loss of foveal reflex, macular atrophy, lens subluxation, and coloboma of iris.

Other conditions linked to congenital ZV infection include intrauterine growth restriction, redundant scalp tissue, contractures of multiple joints, and clubfoot.²

Bottom line. Although the ocular abnormalities are undetectable by prenatal ultrasound, many of the CNS and skeletal anomalies can be identified antenatally. Therefore, serial ultrasound examinations should be performed on adults who have a clinical illness consistent with ZV infection or who have traveled to an endemic area or have a sexual partner who has been in an endemic area. Patients should be assessed for possible microcephaly, ventriculomegaly, agenesis of corpus callosum, hypoplasia of cerebellum, and skeletal deformities.

Did ZV cause these anomalies?

How certain can we be that the anomalies present in the case patient’s baby were caused by ZV? In the past, and for many years, scientists relied on Koch’s 4 postulates (TABLE 1) to answer this question and establish a causal relationship between a microorganism and a specific clinical disease.⁵ Koch’s postulates have not been satisfied for the relationship between maternal ZV infection and congenital anomalies. Today’s more relevant standards for determining causality of a teratogen were published in 1994 by Shepard.⁶ In 2016, Rasmussen and colleagues⁷ found that the critical components of these criteria are fulfilled and concluded that there is little doubt ZV is a proven and extremely dangerous teratogen. See “Zika virus has been shown to be a direct cause of microcephaly”.

Rasmussen and colleagues⁷ also used Hill’s criteria to assess the evidence for causation. Hill’s systematic assessment is based on 9 factors (TABLE 2)⁸, and Rasmussen and colleagues⁷ concluded that the necessary 7 of these 9 criteria have been met (the experimental animal model criterion was not satisfied, and the biological gradient criterion was not applicable). Given their assessment of Shepard’s criteria,⁶ the authors argued that the link between maternal ZV infection and severe congenital anomalies has risen from association to well-defined causation.

How should ZV infection be confirmed in adults and newborns?

After our first review was published in March 2016,¹ the testing algorithm recommended by the US Centers for Disease Control and Prevention (CDC) was revised.⁹ Now, according to the CDC, if a patient has had symptoms of ZV infection for less than 5 days, serum and urine should be obtained for reverse transcriptase–polymerase chain reaction (RT-PCR) testing. If symptoms have been present for 5 to 14 days, urine should be tested by RT-PCR because urine samples appear to remain positive for virus longer than serum samples do. If RT-PCR is performed within the appropriate period and the result is negative, ZV infection is excluded; if the result is positive, acute ZV infection is confirmed, and additional testing is not indicated. RT-PCR can be performed by 2 commercial laboratories (Quest Diagnostics and LabCorp), state health departments, and the CDC.

If serum or urine is collected more than 5 days after symptom onset and the RT-PCR result is negative, the patient should have an immunoglobulin M (IgM) assay for ZV. If the assay result is negative, infection is excluded; if the result is positive or equivocal, additional testing is needed to ensure that the presence of the antibody does not reflect a cross-reaction to dengue or chikungunya virus. The confirmatory plaque reduction neutralization test (PRNT) is performed only by the CDC. To be considered positive, the PRNT result must be at least 4-fold higher than the dengue virus neutralizing antibody titer.

In patients with suspected Guillain-Barré syndrome (GBS), RT-PCR can be performed on cerebrospinal fluid. For suspected fetal or neonatal infection, RT-PCR can be performed on amniotic fluid, umbilical cord blood, and fetal and placental tissue.

CASE 2 Nonpregnant woman with possible Zika virus exposure presents to ED with neurologic symptoms

A 31-year-old nulligravid woman presents to the emergency department (ED) for evaluation of numbness, tingling, and weakness in the lower extremities and difficulty walking. She reports having had a low-grade fever and a fine disseminated macular rash 1 week earlier. She denies recent travel and exposure to friends or relatives with illness, but she says her husband travels extensively and was living and working in Puerto Rico. The patient has no other neurologic symptoms.

Serum and cerebrospinal fluid chemistries and MRI findings are normal. However, the ZV IgM assay is positive, and nerve conduction study results are consistent with GBS. The patient is admitted to the hospital, treated with intravenous immunoglobulin and given supportive care. Over 10 days, her neurologic condition gradually improves.

What is the link between ZV infection and serious neurologic complications in adults?

ZV infection has been associated with serious neurologic complications in adults. Investigators in several countries have reported dramatic increases in GBS cases during the ZV outbreak.¹⁰

GBS is an acute, immune-mediated, demyelinating peripheral neuropathy that can vary in presentation but most commonly manifests as a rapidly ascending paralysis. The disorder often is preceded by an immunization or live viral infection. In some patients, paralysis severely weakens the respiratory muscles and even the cranial nerves, and affected individuals may require intubation, ventilator support, and parenteral or enteral alimentation.

In a case-control study conducted duringthe 2013–2014 outbreak in French Polynesia, the association between ZV infection and GBS was evaluated in 3 groups of patients: 42 patients with GBS, 98 control patients, and 70 patients with ZV infection but no neurologic complications.¹¹ Symptoms of ZV infection were present in about 88% of the patients with GBS, and the median interval from viral infection to onset of neurologic symptoms was 6 days. The ZV IgM assay was positive in 93% of GBS cases. Nerve conduction study results were consistent with the acute motor axonal neuropathy of GBS. All patients were treated with intravenous immunoglobulin; 38% of patients had to be admitted to the intensive care unit, and 29% needed respiratory support. There were no fatalities. The overall incidence of GBS was 2.4 cases per 10,000 ZV infections.

Other neurologic complications that have been associated with ZV infection are meningoencephalitis,¹² brain ischemia,¹³ and myelitis.¹⁴

Bottom line. ZV infection may cause serious neurologic complications in adults. The most devastating complication is GBS, which can result in respiratory muscle paralysis and cranial nerve palsies.

How can patients prevent sexual transmission of ZV infection?

The ZV can be transmitted by sexual contact, including vaginal, anal, and oral sex.¹⁵ It is known to persist longer in semen than in blood or urine, though the exact duration remains unknown. Atkinson and colleagues¹⁶ reported RT-PCR detection of ZV RNA in semen about 62 days after onset of febrile illness—long after the virus became undetectable in blood.¹⁵

Mansuy and colleagues¹⁷ found that the viral load in semen was more than 100,000 times that in blood and urine more than 2 weeks after symptom onset.¹⁶ The ZV has been detected in saliva, urine, and breast milk. Although it has not been identified in vaginal secretions in humans, it has been detected in the vaginal secretions of nonhuman primates up to 7 days after subcutaneous inoculation of virus.¹⁸ In addition, the first case of female-to-male sexual transmission of ZV infection was just reported.¹⁹ In this report, transmission seems to have occurred on day 3 of the woman’s symptomatic illness, when she had unprotected vaginal intercourse with her partner. The partner became symptomatic 7 days after sexual exposure. To date, there is no evidence that infection is spread through kissing or breastfeeding.

The most recent recommendations from the CDC are that a man with symptomatic ZV infection wait at least 6 months before having unprotected sexual contact. In addition, a man who is asymptomatic after ZV exposure should wait at least 8 weeks before having unprotected sexual contact.¹⁷

A woman planning a pregnancy should know there is no evidence that prior ZV infection increases the risk of birth defects. However, a woman with a proven ZV infection should wait at least 8 weeks after symptom onset before trying to conceive. Even an asymptomatic woman with possible exposure should wait at least 8 weeks after the last exposure before attempting conception. In addition, given the risks associated with maternal and fetal infection, a man who has been exposed to the virus and who has a pregnant partner should abstain from unprotected sexual contact for the duration of the pregnancy.²⁰

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.