Applied Evidence

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.¹ In part 1, published in the May 2006 JFP, using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal.

Management choices

Once the diagnosis of ectopic pregnancy has been made, options include surgical, medical, or expectant management (FIGURE). The goal of treatment is to minimize disease-and treatment-related morbidity while maximizing reproductive potential.

Administer Rhogam to all Rh-negative women.

Clinical prediction tools have been developed to aid management decision making. Fernandez et al developed a score based on gestational age, β-hCG level, progesterone level, abdominal pain, hemoperitoneum volume, and hematosalpinx diameter.² A score <12 predicts a >80% success with expectant or nonsurgical management (TABLE 1). Similarly, to predict response to a single-dose of methotrexate, Elito et al³ developed a score based on β-hCG level, ultrasound findings, have size of the mass (cm), and color Doppler image aspects (TABLE 1). In a small study of for 40 patients, those with scores >5 had a the 97% success rate.³

FIGURE
Deciding which management option is best for your patient with ectopic pregnancy

TABLE 1
Predictive score for successful treatment of ectopic pregnancy

Surgical management

Surgery is preferred for ruptured ectopic pregnancy. Surgery is also indicated for patients with evidence of hemodynamic instability, anemia, pain for longer than 24 hours, β-hCG levels greater than 5000 mIU/mL, or with a gestational sac that measures more than 3.5 to 4 cm on ultrasound.^1,4,5

Laparoscopic techniques minimize the trauma and morbidity of salpingectomy or salpingostomy. Compared with older procedures, they lessen blood loss, decrease the need for analgesia, and allow a shorter hospital stay and an earlier return to work.⁶

Salpingostomy removes the ectopic pregnancy while preserving the Fallopian tube. Weekly quantitative β-hCG testing is required to rule out persistent ectopic pregnancy, which occurs in 5% to 8% of patients following salpingostomy.⁷ The likelihood of persistent ectopic pregnancy following salpingostomy increases with an ectopic pregnancy <2 cm in diameter, salpingostomy performed <6 weeks from the last menstrual period, a β-hCG level >3000 mIU/mL, or progesterone level over 35 nmol/L combined with a daily change in β-hCG over 100 mIU/mL.^8,9

Expectant management possible when β-hCG levels <1000 mIU/mL

Expectant management may be offered to asymptomatic women with small adnexal masses, lower β-hCG levels, and evidence of spontaneous resolution (eg, falling β-hCG levels) who are willing to accept the risk of tubal rupture.¹⁰ Rising β-hCG levels, pain, hemodynamic instability, or hemoperitoneum on ultrasound dictate switching to active management.¹¹

Eighty percent of women with initial β-hCG levels <1000 mIU/mL experience spontaneous resolution (TABLE 2).^1,4,5,11-17 In one study, women with initial β-hCG levels <1000 mIU/mL, adnexal masses <4 cm, no fetal heartbeat, and <100 mL of fluid in the pouch of Douglas were managed by serial ultrasound and β-hCG levels obtained twice-weekly for 2 weeks; the result was an 88% chance of spontaneous resolution.¹⁸ Women (n=9) with initial β-hCG levels ≤1000 mIU/mL with subsequent rising titers experienced no spontaneous resolution.

TABLE 2
Treatment options for ectopic pregnancy

Medical management an option for about 25% of patients

Methotrexate depletes tetrahydrofolate cofactors required for DNA and RNA synthesis and cell replication, and thereby inhibits the rapidly growing trophoblasts in patients with ectopic pregnancy.

Methotrexate may be used for primary treatment of ectopic pregnancy, for persistent ectopic pregnancy following tubal sparing surgery, as prophylaxis to reduce persistent ectopic pregnancy following salpingostomy, and in cornual and cervical pregnancies.^11,13,19

Who qualifies. Patients eligible for methotrexate administration are those without hemodynamic instability or evidence of tubal rupture (clinical or ultrasound), desiring future fertility, having a gestational sac <3.5 cm, a β-hCG level less than 5000 mIU/mL, no fetal cardiac motion on ultrasound, and the ability and willingness to comply with post-treatment monitoring.^10,14

Systemic methotrexate successfully resolves ectopic pregnancy in 90% of patients. Subsequent tubal patency rates approximate 80% and pregnancy rates 60% with recurrent ectopic pregnancy rates 8%.^10,13,15,16 The cost of treatment for systemic methotrexate was $5721 per patient compared with $4066 for salpingostomy.²⁰ Hematologic, liver, and renal functions should be assessed before treatment.

Following methotrexate administration, some patients experience a transient increase in abdominal pain, vaginal bleeding, and rising β-hCG. Exclude a ruptured ectopic pregnancy in patients with worsening pain. Pelvic examinations, sexual intercourse, and TVUS should be avoided or minimized during treatment.¹⁰

Two regimens are used for the systemic administration of methotrexate (TABLE 2).

The single-dose regimen uses an intramuscular (IM) injection dose of 50 mg/m² of methotrexate without leucovorin. It has an overall success rate of 87%. β-hCG levels are measured on days 4 and 7, and the medication is repeated if no drop is noticed.¹³ β-hCG levels are then repeated weekly until undetectable (usually 4 weeks). Serum progesterone levels drop significantly faster than β-hCG following methotrexate administration, and levels <1.5 ng/mL predict ectopic pregnancy resolution more accurately than β-hCG levels.²¹ Repeat dosing is needed in up to 14% of women.

In the multidose regimen, IM injections of 1 mg/kg of methotrexate are given followed by leucovorin (0.1 mg/kg) after 24 hours. β-hCG levels are checked every other day until there is a 15% or more drop on 2 consecutive days, or 4 doses of methotrexate are administered.¹ β-hCG levels are then repeated weekly until undetectable. About half of the women receiving the multidose regimen require 4 or more doses (6.8% require >4 doses). On the other hand, 10% of women treated with this regimen require only 1 dose. Multidose methotrexate has also been used as first-line therapy in cervical, interstitial, ovarian, and abdominal gestation, but with substantially lower success.¹⁹

Single-dose vs multidose regimens. Although there are no direct comparison trials, a meta-analysis combining the results of 26 studies with 1067 women treated with a single-dose regimen and 267 women treated with a multidose regimen found that the multidose regimen was slightly more effective.¹⁶ The success rate for women with multidose treatment was 92.7% (95% confidence interval [CI], 89–96) vs a single-dose treatment success rate of 88.1% (95% CI, 86–90).

Women treated with single-dose regimens had fewer side effects (31.3% vs 41.2%). However, in both regimens, women who experienced adverse side effects were less likely to have failed treatment (single dose, odds ratio [OR]=0.27; multidose, OR=0.72). Another systematic review including 19 studies with 393 women treated with single-dose methotrexate and 338 women treated with multidose methotrexate had similar outcome findings; the multidose regimen was slightly more effective (93% vs 87%).¹³

A recent retrospective study comparing the multidose and single-dose regimens in 643 patients with ectopic pregnancy (single dose, n=555; multidose, n=97) from a single database also showed slightly better success with the multidose regimen (95% vs 90%, P=.18).²² Therefore, the multidose regimen may be preferred but a randomized controlled trial comparing the 2 regimens is needed.

In clinically stable women, the serum β-hCG level at presentation is probably the most important single factor determining failure of single-dose methotrexate; patients with low β-hCG levels (1000–2000 mIU/mL) have a high (~98%) response rate.²³

Add mifepristone? Mifepristone 600 mg orally added to methotrexate increases successful resolution of unruptured ectopic pregnancy, decreases resolution time, and reduces the need for a second injection or laparotomy, without worsening side effects.²⁴ A recent randomized controlled trial, however, showed that this combination had little advantage over methotrexate alone, and concluded that adding mifepristone be limited to patients with serum progesterone ≥10 ng/mL.²⁵

Direct injection. When fetal cardiac activity is present, injection of 20% potassium chloride (KCl) 0.5 mL into the gestational sac under ultrasound guidance results in asystole and a slow resolution of ectopic pregnancy. Because KCl does not affect the trophoblast, trophoblastic tissue may continue to proliferate leading to tubal rupture.²⁶ Hyperosmolar glucose 1 to 3 mL injected laparoscopically or under ultrasound guidance into the gestational sac maintains tubal patency, has few side effects, but its initial high success rates in resolving ectopic pregnancy (94% to 100%) has not been duplicated.^11,13 Another option is prostaglandin F-2 alpha, which when injected into the Fallopian tube causes contractions and vasoconstriction, resulting in a resolution of ectopic pregnancy in 92% of patients.¹³ However, serious side effects have been reported, including severe abdominal discomfort, vomiting, and pulmonary edema.

CORRESPONDENCE
K. Ramakrishnan, MD, Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: [email protected]

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.¹ In part 1, published in the May 2006 JFP, using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal.

Management choices

Once the diagnosis of ectopic pregnancy has been made, options include surgical, medical, or expectant management (FIGURE). The goal of treatment is to minimize disease-and treatment-related morbidity while maximizing reproductive potential.

Administer Rhogam to all Rh-negative women.

Clinical prediction tools have been developed to aid management decision making. Fernandez et al developed a score based on gestational age, β-hCG level, progesterone level, abdominal pain, hemoperitoneum volume, and hematosalpinx diameter.² A score <12 predicts a >80% success with expectant or nonsurgical management (TABLE 1). Similarly, to predict response to a single-dose of methotrexate, Elito et al³ developed a score based on β-hCG level, ultrasound findings, have size of the mass (cm), and color Doppler image aspects (TABLE 1). In a small study of for 40 patients, those with scores >5 had a the 97% success rate.³

FIGURE
Deciding which management option is best for your patient with ectopic pregnancy

TABLE 1
Predictive score for successful treatment of ectopic pregnancy

Surgical management

Surgery is preferred for ruptured ectopic pregnancy. Surgery is also indicated for patients with evidence of hemodynamic instability, anemia, pain for longer than 24 hours, β-hCG levels greater than 5000 mIU/mL, or with a gestational sac that measures more than 3.5 to 4 cm on ultrasound.^1,4,5

Laparoscopic techniques minimize the trauma and morbidity of salpingectomy or salpingostomy. Compared with older procedures, they lessen blood loss, decrease the need for analgesia, and allow a shorter hospital stay and an earlier return to work.⁶

Salpingostomy removes the ectopic pregnancy while preserving the Fallopian tube. Weekly quantitative β-hCG testing is required to rule out persistent ectopic pregnancy, which occurs in 5% to 8% of patients following salpingostomy.⁷ The likelihood of persistent ectopic pregnancy following salpingostomy increases with an ectopic pregnancy <2 cm in diameter, salpingostomy performed <6 weeks from the last menstrual period, a β-hCG level >3000 mIU/mL, or progesterone level over 35 nmol/L combined with a daily change in β-hCG over 100 mIU/mL.^8,9

Expectant management possible when β-hCG levels <1000 mIU/mL

Expectant management may be offered to asymptomatic women with small adnexal masses, lower β-hCG levels, and evidence of spontaneous resolution (eg, falling β-hCG levels) who are willing to accept the risk of tubal rupture.¹⁰ Rising β-hCG levels, pain, hemodynamic instability, or hemoperitoneum on ultrasound dictate switching to active management.¹¹

Eighty percent of women with initial β-hCG levels <1000 mIU/mL experience spontaneous resolution (TABLE 2).^1,4,5,11-17 In one study, women with initial β-hCG levels <1000 mIU/mL, adnexal masses <4 cm, no fetal heartbeat, and <100 mL of fluid in the pouch of Douglas were managed by serial ultrasound and β-hCG levels obtained twice-weekly for 2 weeks; the result was an 88% chance of spontaneous resolution.¹⁸ Women (n=9) with initial β-hCG levels ≤1000 mIU/mL with subsequent rising titers experienced no spontaneous resolution.

TABLE 2
Treatment options for ectopic pregnancy

Medical management an option for about 25% of patients

Methotrexate depletes tetrahydrofolate cofactors required for DNA and RNA synthesis and cell replication, and thereby inhibits the rapidly growing trophoblasts in patients with ectopic pregnancy.

Methotrexate may be used for primary treatment of ectopic pregnancy, for persistent ectopic pregnancy following tubal sparing surgery, as prophylaxis to reduce persistent ectopic pregnancy following salpingostomy, and in cornual and cervical pregnancies.^11,13,19

Who qualifies. Patients eligible for methotrexate administration are those without hemodynamic instability or evidence of tubal rupture (clinical or ultrasound), desiring future fertility, having a gestational sac <3.5 cm, a β-hCG level less than 5000 mIU/mL, no fetal cardiac motion on ultrasound, and the ability and willingness to comply with post-treatment monitoring.^10,14

Systemic methotrexate successfully resolves ectopic pregnancy in 90% of patients. Subsequent tubal patency rates approximate 80% and pregnancy rates 60% with recurrent ectopic pregnancy rates 8%.^10,13,15,16 The cost of treatment for systemic methotrexate was $5721 per patient compared with $4066 for salpingostomy.²⁰ Hematologic, liver, and renal functions should be assessed before treatment.

Following methotrexate administration, some patients experience a transient increase in abdominal pain, vaginal bleeding, and rising β-hCG. Exclude a ruptured ectopic pregnancy in patients with worsening pain. Pelvic examinations, sexual intercourse, and TVUS should be avoided or minimized during treatment.¹⁰

Two regimens are used for the systemic administration of methotrexate (TABLE 2).

The single-dose regimen uses an intramuscular (IM) injection dose of 50 mg/m² of methotrexate without leucovorin. It has an overall success rate of 87%. β-hCG levels are measured on days 4 and 7, and the medication is repeated if no drop is noticed.¹³ β-hCG levels are then repeated weekly until undetectable (usually 4 weeks). Serum progesterone levels drop significantly faster than β-hCG following methotrexate administration, and levels <1.5 ng/mL predict ectopic pregnancy resolution more accurately than β-hCG levels.²¹ Repeat dosing is needed in up to 14% of women.

In the multidose regimen, IM injections of 1 mg/kg of methotrexate are given followed by leucovorin (0.1 mg/kg) after 24 hours. β-hCG levels are checked every other day until there is a 15% or more drop on 2 consecutive days, or 4 doses of methotrexate are administered.¹ β-hCG levels are then repeated weekly until undetectable. About half of the women receiving the multidose regimen require 4 or more doses (6.8% require >4 doses). On the other hand, 10% of women treated with this regimen require only 1 dose. Multidose methotrexate has also been used as first-line therapy in cervical, interstitial, ovarian, and abdominal gestation, but with substantially lower success.¹⁹

Single-dose vs multidose regimens. Although there are no direct comparison trials, a meta-analysis combining the results of 26 studies with 1067 women treated with a single-dose regimen and 267 women treated with a multidose regimen found that the multidose regimen was slightly more effective.¹⁶ The success rate for women with multidose treatment was 92.7% (95% confidence interval [CI], 89–96) vs a single-dose treatment success rate of 88.1% (95% CI, 86–90).

Women treated with single-dose regimens had fewer side effects (31.3% vs 41.2%). However, in both regimens, women who experienced adverse side effects were less likely to have failed treatment (single dose, odds ratio [OR]=0.27; multidose, OR=0.72). Another systematic review including 19 studies with 393 women treated with single-dose methotrexate and 338 women treated with multidose methotrexate had similar outcome findings; the multidose regimen was slightly more effective (93% vs 87%).¹³

A recent retrospective study comparing the multidose and single-dose regimens in 643 patients with ectopic pregnancy (single dose, n=555; multidose, n=97) from a single database also showed slightly better success with the multidose regimen (95% vs 90%, P=.18).²² Therefore, the multidose regimen may be preferred but a randomized controlled trial comparing the 2 regimens is needed.

In clinically stable women, the serum β-hCG level at presentation is probably the most important single factor determining failure of single-dose methotrexate; patients with low β-hCG levels (1000–2000 mIU/mL) have a high (~98%) response rate.²³

Add mifepristone? Mifepristone 600 mg orally added to methotrexate increases successful resolution of unruptured ectopic pregnancy, decreases resolution time, and reduces the need for a second injection or laparotomy, without worsening side effects.²⁴ A recent randomized controlled trial, however, showed that this combination had little advantage over methotrexate alone, and concluded that adding mifepristone be limited to patients with serum progesterone ≥10 ng/mL.²⁵

Direct injection. When fetal cardiac activity is present, injection of 20% potassium chloride (KCl) 0.5 mL into the gestational sac under ultrasound guidance results in asystole and a slow resolution of ectopic pregnancy. Because KCl does not affect the trophoblast, trophoblastic tissue may continue to proliferate leading to tubal rupture.²⁶ Hyperosmolar glucose 1 to 3 mL injected laparoscopically or under ultrasound guidance into the gestational sac maintains tubal patency, has few side effects, but its initial high success rates in resolving ectopic pregnancy (94% to 100%) has not been duplicated.^11,13 Another option is prostaglandin F-2 alpha, which when injected into the Fallopian tube causes contractions and vasoconstriction, resulting in a resolution of ectopic pregnancy in 92% of patients.¹³ However, serious side effects have been reported, including severe abdominal discomfort, vomiting, and pulmonary edema.

CORRESPONDENCE
K. Ramakrishnan, MD, Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: [email protected]

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.¹ In part 1, published in the May 2006 JFP, using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal.

Management choices

Once the diagnosis of ectopic pregnancy has been made, options include surgical, medical, or expectant management (FIGURE). The goal of treatment is to minimize disease-and treatment-related morbidity while maximizing reproductive potential.

Administer Rhogam to all Rh-negative women.

Clinical prediction tools have been developed to aid management decision making. Fernandez et al developed a score based on gestational age, β-hCG level, progesterone level, abdominal pain, hemoperitoneum volume, and hematosalpinx diameter.² A score <12 predicts a >80% success with expectant or nonsurgical management (TABLE 1). Similarly, to predict response to a single-dose of methotrexate, Elito et al³ developed a score based on β-hCG level, ultrasound findings, have size of the mass (cm), and color Doppler image aspects (TABLE 1). In a small study of for 40 patients, those with scores >5 had a the 97% success rate.³

FIGURE
Deciding which management option is best for your patient with ectopic pregnancy

TABLE 1
Predictive score for successful treatment of ectopic pregnancy

Surgical management

Surgery is preferred for ruptured ectopic pregnancy. Surgery is also indicated for patients with evidence of hemodynamic instability, anemia, pain for longer than 24 hours, β-hCG levels greater than 5000 mIU/mL, or with a gestational sac that measures more than 3.5 to 4 cm on ultrasound.^1,4,5

Laparoscopic techniques minimize the trauma and morbidity of salpingectomy or salpingostomy. Compared with older procedures, they lessen blood loss, decrease the need for analgesia, and allow a shorter hospital stay and an earlier return to work.⁶

Salpingostomy removes the ectopic pregnancy while preserving the Fallopian tube. Weekly quantitative β-hCG testing is required to rule out persistent ectopic pregnancy, which occurs in 5% to 8% of patients following salpingostomy.⁷ The likelihood of persistent ectopic pregnancy following salpingostomy increases with an ectopic pregnancy <2 cm in diameter, salpingostomy performed <6 weeks from the last menstrual period, a β-hCG level >3000 mIU/mL, or progesterone level over 35 nmol/L combined with a daily change in β-hCG over 100 mIU/mL.^8,9

Expectant management possible when β-hCG levels <1000 mIU/mL

Expectant management may be offered to asymptomatic women with small adnexal masses, lower β-hCG levels, and evidence of spontaneous resolution (eg, falling β-hCG levels) who are willing to accept the risk of tubal rupture.¹⁰ Rising β-hCG levels, pain, hemodynamic instability, or hemoperitoneum on ultrasound dictate switching to active management.¹¹

Eighty percent of women with initial β-hCG levels <1000 mIU/mL experience spontaneous resolution (TABLE 2).^1,4,5,11-17 In one study, women with initial β-hCG levels <1000 mIU/mL, adnexal masses <4 cm, no fetal heartbeat, and <100 mL of fluid in the pouch of Douglas were managed by serial ultrasound and β-hCG levels obtained twice-weekly for 2 weeks; the result was an 88% chance of spontaneous resolution.¹⁸ Women (n=9) with initial β-hCG levels ≤1000 mIU/mL with subsequent rising titers experienced no spontaneous resolution.

TABLE 2
Treatment options for ectopic pregnancy

Medical management an option for about 25% of patients

Methotrexate depletes tetrahydrofolate cofactors required for DNA and RNA synthesis and cell replication, and thereby inhibits the rapidly growing trophoblasts in patients with ectopic pregnancy.

Methotrexate may be used for primary treatment of ectopic pregnancy, for persistent ectopic pregnancy following tubal sparing surgery, as prophylaxis to reduce persistent ectopic pregnancy following salpingostomy, and in cornual and cervical pregnancies.^11,13,19

Who qualifies. Patients eligible for methotrexate administration are those without hemodynamic instability or evidence of tubal rupture (clinical or ultrasound), desiring future fertility, having a gestational sac <3.5 cm, a β-hCG level less than 5000 mIU/mL, no fetal cardiac motion on ultrasound, and the ability and willingness to comply with post-treatment monitoring.^10,14

Systemic methotrexate successfully resolves ectopic pregnancy in 90% of patients. Subsequent tubal patency rates approximate 80% and pregnancy rates 60% with recurrent ectopic pregnancy rates 8%.^10,13,15,16 The cost of treatment for systemic methotrexate was $5721 per patient compared with $4066 for salpingostomy.²⁰ Hematologic, liver, and renal functions should be assessed before treatment.

Following methotrexate administration, some patients experience a transient increase in abdominal pain, vaginal bleeding, and rising β-hCG. Exclude a ruptured ectopic pregnancy in patients with worsening pain. Pelvic examinations, sexual intercourse, and TVUS should be avoided or minimized during treatment.¹⁰

Two regimens are used for the systemic administration of methotrexate (TABLE 2).

The single-dose regimen uses an intramuscular (IM) injection dose of 50 mg/m² of methotrexate without leucovorin. It has an overall success rate of 87%. β-hCG levels are measured on days 4 and 7, and the medication is repeated if no drop is noticed.¹³ β-hCG levels are then repeated weekly until undetectable (usually 4 weeks). Serum progesterone levels drop significantly faster than β-hCG following methotrexate administration, and levels <1.5 ng/mL predict ectopic pregnancy resolution more accurately than β-hCG levels.²¹ Repeat dosing is needed in up to 14% of women.

In the multidose regimen, IM injections of 1 mg/kg of methotrexate are given followed by leucovorin (0.1 mg/kg) after 24 hours. β-hCG levels are checked every other day until there is a 15% or more drop on 2 consecutive days, or 4 doses of methotrexate are administered.¹ β-hCG levels are then repeated weekly until undetectable. About half of the women receiving the multidose regimen require 4 or more doses (6.8% require >4 doses). On the other hand, 10% of women treated with this regimen require only 1 dose. Multidose methotrexate has also been used as first-line therapy in cervical, interstitial, ovarian, and abdominal gestation, but with substantially lower success.¹⁹

Single-dose vs multidose regimens. Although there are no direct comparison trials, a meta-analysis combining the results of 26 studies with 1067 women treated with a single-dose regimen and 267 women treated with a multidose regimen found that the multidose regimen was slightly more effective.¹⁶ The success rate for women with multidose treatment was 92.7% (95% confidence interval [CI], 89–96) vs a single-dose treatment success rate of 88.1% (95% CI, 86–90).

Women treated with single-dose regimens had fewer side effects (31.3% vs 41.2%). However, in both regimens, women who experienced adverse side effects were less likely to have failed treatment (single dose, odds ratio [OR]=0.27; multidose, OR=0.72). Another systematic review including 19 studies with 393 women treated with single-dose methotrexate and 338 women treated with multidose methotrexate had similar outcome findings; the multidose regimen was slightly more effective (93% vs 87%).¹³

A recent retrospective study comparing the multidose and single-dose regimens in 643 patients with ectopic pregnancy (single dose, n=555; multidose, n=97) from a single database also showed slightly better success with the multidose regimen (95% vs 90%, P=.18).²² Therefore, the multidose regimen may be preferred but a randomized controlled trial comparing the 2 regimens is needed.

In clinically stable women, the serum β-hCG level at presentation is probably the most important single factor determining failure of single-dose methotrexate; patients with low β-hCG levels (1000–2000 mIU/mL) have a high (~98%) response rate.²³

Add mifepristone? Mifepristone 600 mg orally added to methotrexate increases successful resolution of unruptured ectopic pregnancy, decreases resolution time, and reduces the need for a second injection or laparotomy, without worsening side effects.²⁴ A recent randomized controlled trial, however, showed that this combination had little advantage over methotrexate alone, and concluded that adding mifepristone be limited to patients with serum progesterone ≥10 ng/mL.²⁵

Direct injection. When fetal cardiac activity is present, injection of 20% potassium chloride (KCl) 0.5 mL into the gestational sac under ultrasound guidance results in asystole and a slow resolution of ectopic pregnancy. Because KCl does not affect the trophoblast, trophoblastic tissue may continue to proliferate leading to tubal rupture.²⁶ Hyperosmolar glucose 1 to 3 mL injected laparoscopically or under ultrasound guidance into the gestational sac maintains tubal patency, has few side effects, but its initial high success rates in resolving ectopic pregnancy (94% to 100%) has not been duplicated.^11,13 Another option is prostaglandin F-2 alpha, which when injected into the Fallopian tube causes contractions and vasoconstriction, resulting in a resolution of ectopic pregnancy in 92% of patients.¹³ However, serious side effects have been reported, including severe abdominal discomfort, vomiting, and pulmonary edema.

CORRESPONDENCE
K. Ramakrishnan, MD, Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: [email protected]

• Are proton pump inhibitors (PPIs) more effective than histamine type 2 receptor antagonists (H2RAs) for the treatment of gastroesophageal reflux disorder (GERD)?
• Do all PPIs relieve heartburn symptoms equally?
• What is the role of fundoplication in the management of severe GERD?

The answers to these clinical questions can be found in a clinical effectiveness review that compares the medical, surgical, and endoscopic treatments for GERD. It was prepared for the Agency for Healthcare Research and Quality (AHRQ) by Tufts–New England Medical Center’s Evidence-Based Practice Center. AHRQ began funding these clinical effectiveness reviews in 2005 to provide valid evidence about the comparative effectiveness of medical interventions to treat common health problems. Their objective is to provide resources to assist consumers and healthcare providers to make informed choices among treatment alternatives. The evidence category for this effectiveness review was management. The patient population was limited to adults. The evidence rating is updated to comply with the SORT taxonomy.¹

Guideline relevance and limitations

GERD is defined as weekly heartburn or acid regurgitation. It is one of the most common medical problems encountered by primary care physicians. In the year 2000, direct costs for treating GERD was estimated at $10 billion for patients with chronic GERD. Goals of therapy are to improve heartburn symptoms and quality of life, heal esophagitis, maintain healing, and prevent complications (Barrett’s esophagus, esophageal stricture formation, or esophageal adenocarcinoma).

The review considered comparison of medical treatments to surgery, comparison of surgery with endoscopic procedures, comparison of medical treatments with endoscopic procedures, comparison of medical treatments (between classes and within class), comparison of surgical techniques (open and laparoscopic), comparison of endoscopic treatment with sham, patient characteristics associated with outcomes of medical, surgical, and endoscopic treatments, and adverse events associated with medical, surgical, and endoscopic treatments.

Medical treatments considered were intermittent, periodic, or continuous use of prescription or over-the-counter medications, H2RAs, and PPIs. Surgical therapy included fundoplication. The review is weakened by inconsistent reference points in the scale of defining severity.

Guideline development and evidence review

The guideline was formulated by Tufts–New England Medical Center’s Evidence-Based Practice Center. Evidence was selected by searching Medline, EmBase, and Cochrane databases. A critical appraisal was performed and recommendations were graded. The review was released in December 2005.

Source for this guideline

Ip S, Bonis P, Tatsioni A, et al. Comparative effectiveness of management strategies for gastroesophageal reflux disease. Evidence Report/Technology Assessment No. 1. (Prepared by Tufts–New England Medical Center Evidence-Based Practice Center under Contract No. 290-02-0022.) Rockville, Md: Agency for Healthcare Research and Quality. December 2005. Available at: effectivehealthcare.ahrq.gov/synthesize/report/final.cfm?Document=2&Topic=30. Accessed on April 18, 2006.

Other guidelines on GERD

Guideline for the management of dyspepsia

This 2005 guideline considers indications for EGD and 2 treatment options for functional dyspepsia: testing and eradication of Helicobacter pylori infection or empiric trial of acid suppression with a PPI for 4 to 8 weeks.

Source. Talley NJ, Vakil N, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterology 2005; 100:2324–2337 Available at: www.acg.gi.org/physicians/guidelines/dyspepsia.pdf. Accessed on April 18, 2006.

Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease

This recent guideline reviews diagnosis (endoscopy, ambulatory reflux monitoring, and esophageal manometry) and treatment of GERD (including lifestyle changes and pro-motility agents). The literature review is less rigorous than the AHRQ clinical effectiveness review.

Source. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:190–200. Available at: www.acg.gi.org/physicians/guidelines/GERDTreatment.pdf. Accessed on April 18, 2006.

CORRESPONDENCE
Keith B. Holten, MD, 825 Locust Street, Wilmington, OH 45177. E-mail: [email protected]

• Are proton pump inhibitors (PPIs) more effective than histamine type 2 receptor antagonists (H2RAs) for the treatment of gastroesophageal reflux disorder (GERD)?
• Do all PPIs relieve heartburn symptoms equally?
• What is the role of fundoplication in the management of severe GERD?

The answers to these clinical questions can be found in a clinical effectiveness review that compares the medical, surgical, and endoscopic treatments for GERD. It was prepared for the Agency for Healthcare Research and Quality (AHRQ) by Tufts–New England Medical Center’s Evidence-Based Practice Center. AHRQ began funding these clinical effectiveness reviews in 2005 to provide valid evidence about the comparative effectiveness of medical interventions to treat common health problems. Their objective is to provide resources to assist consumers and healthcare providers to make informed choices among treatment alternatives. The evidence category for this effectiveness review was management. The patient population was limited to adults. The evidence rating is updated to comply with the SORT taxonomy.¹

Guideline relevance and limitations

GERD is defined as weekly heartburn or acid regurgitation. It is one of the most common medical problems encountered by primary care physicians. In the year 2000, direct costs for treating GERD was estimated at $10 billion for patients with chronic GERD. Goals of therapy are to improve heartburn symptoms and quality of life, heal esophagitis, maintain healing, and prevent complications (Barrett’s esophagus, esophageal stricture formation, or esophageal adenocarcinoma).

The review considered comparison of medical treatments to surgery, comparison of surgery with endoscopic procedures, comparison of medical treatments with endoscopic procedures, comparison of medical treatments (between classes and within class), comparison of surgical techniques (open and laparoscopic), comparison of endoscopic treatment with sham, patient characteristics associated with outcomes of medical, surgical, and endoscopic treatments, and adverse events associated with medical, surgical, and endoscopic treatments.

Medical treatments considered were intermittent, periodic, or continuous use of prescription or over-the-counter medications, H2RAs, and PPIs. Surgical therapy included fundoplication. The review is weakened by inconsistent reference points in the scale of defining severity.

Guideline development and evidence review

The guideline was formulated by Tufts–New England Medical Center’s Evidence-Based Practice Center. Evidence was selected by searching Medline, EmBase, and Cochrane databases. A critical appraisal was performed and recommendations were graded. The review was released in December 2005.

Source for this guideline

Ip S, Bonis P, Tatsioni A, et al. Comparative effectiveness of management strategies for gastroesophageal reflux disease. Evidence Report/Technology Assessment No. 1. (Prepared by Tufts–New England Medical Center Evidence-Based Practice Center under Contract No. 290-02-0022.) Rockville, Md: Agency for Healthcare Research and Quality. December 2005. Available at: effectivehealthcare.ahrq.gov/synthesize/report/final.cfm?Document=2&Topic=30. Accessed on April 18, 2006.

Other guidelines on GERD

Guideline for the management of dyspepsia

This 2005 guideline considers indications for EGD and 2 treatment options for functional dyspepsia: testing and eradication of Helicobacter pylori infection or empiric trial of acid suppression with a PPI for 4 to 8 weeks.

Source. Talley NJ, Vakil N, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterology 2005; 100:2324–2337 Available at: www.acg.gi.org/physicians/guidelines/dyspepsia.pdf. Accessed on April 18, 2006.

Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease

This recent guideline reviews diagnosis (endoscopy, ambulatory reflux monitoring, and esophageal manometry) and treatment of GERD (including lifestyle changes and pro-motility agents). The literature review is less rigorous than the AHRQ clinical effectiveness review.

Source. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:190–200. Available at: www.acg.gi.org/physicians/guidelines/GERDTreatment.pdf. Accessed on April 18, 2006.

CORRESPONDENCE
Keith B. Holten, MD, 825 Locust Street, Wilmington, OH 45177. E-mail: [email protected]

• Are proton pump inhibitors (PPIs) more effective than histamine type 2 receptor antagonists (H2RAs) for the treatment of gastroesophageal reflux disorder (GERD)?
• Do all PPIs relieve heartburn symptoms equally?
• What is the role of fundoplication in the management of severe GERD?

The answers to these clinical questions can be found in a clinical effectiveness review that compares the medical, surgical, and endoscopic treatments for GERD. It was prepared for the Agency for Healthcare Research and Quality (AHRQ) by Tufts–New England Medical Center’s Evidence-Based Practice Center. AHRQ began funding these clinical effectiveness reviews in 2005 to provide valid evidence about the comparative effectiveness of medical interventions to treat common health problems. Their objective is to provide resources to assist consumers and healthcare providers to make informed choices among treatment alternatives. The evidence category for this effectiveness review was management. The patient population was limited to adults. The evidence rating is updated to comply with the SORT taxonomy.¹

Guideline relevance and limitations

GERD is defined as weekly heartburn or acid regurgitation. It is one of the most common medical problems encountered by primary care physicians. In the year 2000, direct costs for treating GERD was estimated at $10 billion for patients with chronic GERD. Goals of therapy are to improve heartburn symptoms and quality of life, heal esophagitis, maintain healing, and prevent complications (Barrett’s esophagus, esophageal stricture formation, or esophageal adenocarcinoma).

The review considered comparison of medical treatments to surgery, comparison of surgery with endoscopic procedures, comparison of medical treatments with endoscopic procedures, comparison of medical treatments (between classes and within class), comparison of surgical techniques (open and laparoscopic), comparison of endoscopic treatment with sham, patient characteristics associated with outcomes of medical, surgical, and endoscopic treatments, and adverse events associated with medical, surgical, and endoscopic treatments.

Medical treatments considered were intermittent, periodic, or continuous use of prescription or over-the-counter medications, H2RAs, and PPIs. Surgical therapy included fundoplication. The review is weakened by inconsistent reference points in the scale of defining severity.

Guideline development and evidence review

The guideline was formulated by Tufts–New England Medical Center’s Evidence-Based Practice Center. Evidence was selected by searching Medline, EmBase, and Cochrane databases. A critical appraisal was performed and recommendations were graded. The review was released in December 2005.

Source for this guideline

Ip S, Bonis P, Tatsioni A, et al. Comparative effectiveness of management strategies for gastroesophageal reflux disease. Evidence Report/Technology Assessment No. 1. (Prepared by Tufts–New England Medical Center Evidence-Based Practice Center under Contract No. 290-02-0022.) Rockville, Md: Agency for Healthcare Research and Quality. December 2005. Available at: effectivehealthcare.ahrq.gov/synthesize/report/final.cfm?Document=2&Topic=30. Accessed on April 18, 2006.

Other guidelines on GERD

Guideline for the management of dyspepsia

This 2005 guideline considers indications for EGD and 2 treatment options for functional dyspepsia: testing and eradication of Helicobacter pylori infection or empiric trial of acid suppression with a PPI for 4 to 8 weeks.

Source. Talley NJ, Vakil N, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterology 2005; 100:2324–2337 Available at: www.acg.gi.org/physicians/guidelines/dyspepsia.pdf. Accessed on April 18, 2006.

Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease

This recent guideline reviews diagnosis (endoscopy, ambulatory reflux monitoring, and esophageal manometry) and treatment of GERD (including lifestyle changes and pro-motility agents). The literature review is less rigorous than the AHRQ clinical effectiveness review.

Source. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005; 100:190–200. Available at: www.acg.gi.org/physicians/guidelines/GERDTreatment.pdf. Accessed on April 18, 2006.

CORRESPONDENCE
Keith B. Holten, MD, 825 Locust Street, Wilmington, OH 45177. E-mail: [email protected]

One child out of 6 in your practice probably has a developmental disability.¹ However, identifying disability will be erratic if you rely solely on clinical judgment and informal milestone reviews.

There is reason for concern: the evidence for early intervention, though limited, shows that it confers long-term benefits for these children. Judicious use of practical, reliable standardized screens that I discuss in this article will increase your likelihood of identifying children who need help.

Needed: A screening net with tighter mesh

Disorders such as cerebral palsy and profound mental retardation are clearly recognizable and have well-known consequences. Disabilities such as language impairment, mild mental retardation, and learning disabilities (see Range of disabilities) are more subtle but also associated with poorer health status, higher rates of school failure, in-grade retention, and special education placement.^1,2

Developmental problems commonly escape detection in the first 5 years of life despite frequent well-child visits. Physicians generally acknowledge that screening for developmental disabilities is important,³ but few use standardized screening instruments.^4,5 Most physicians rely instead on clinical judgment and milestone review.

Scope of the problem

A study that examined how doctors in the US screen for delays found that only 15% to 20% screened more than 10% of all of their patients with a formalized developmental instrument.⁵ Again, this points to reliance on clinical judgment to determine who should be screened. A National Survey of pediatricians and family physicians⁶ found that 53% reported using no standardized instrument in their assessment of children for developmental delays. The most recent National Survey of Early Childhood Health (NSECH)¹² found that only 35% to 45% of parents recall their child’s development ever being assessed by their doctor.

The fallout. Most children who would qualify for early intervention under federal law are not identified before school entry. Palfrey et al¹³ examined the records of 1726 children in special education classes at 5 sites and found that just 28.7% of developmental and behavioral problems were identified before entry into school (age 5). Just 15% to 25% of learning and speech disorders emotional disorders and attention deficit disorders were identified before school entry.¹³

A study in the UK¹⁴ found that despite of a system geared to detect subtle developmental disorders, their child health surveillance failed to detect 38% of children with moderate learning disabilities and 94% of children with mild or moderate learning disabilities. Another study¹⁵ on this matter shows a disappointing detection rate, failing to identify 55% to 65% of children with developmental problems before entry into school.

Studies have proven clinical judgment insensitive even in the detection of mental retardation. Two studies from the 1960s showed that US pediatricians accurately identified only 43% of children with an intelligence quotient (IQ) of <80.

Does early intervention work?

Much of the literature on early intervention in childhood focuses on children with risk factors such as prematurity and low birth weight or low socioeconomic status. In controlled studies, children at psychosocial disadvantage who received high-quality intervention exhibited long-term improvement in IQ, higher academic achievement, and decreased criminal behavior, and were, as adults, more likely to be employed and to earn higher incomes than those who did not participate in early intervention (SOR: A).^16,17

Other studies have similarly shown benefits from early intervention for children with such biological risk factors as low birth weight and prematurity (SOR: A).¹⁸ Early intervention for conditions such as learning disabilities or speech and language delays is generally thought to improve outcomes (SOR: C).²

Rationale for screening

Early identification mandated by law

The Individuals with Disabilities Education Act (IDEA) Amendments of 1997¹⁹ mandate the “early identification of, and intervention for developmental disabilities through the development of community-based systems.” This law requires physicians to refer children with suspected developmental delays to appropriate early intervention services in a timely manner. All states receive federal funding to provide appropriate intervention through infant and child-find programs for children with developmental delays.

In a study released in February 2006, the United States Preventive Services Task Force²⁰ concluded that the evidence is insufficient to recommend for or against routine use of brief, formal screening instruments in primary care to detect speech and language delay in children up to 5 years of age. The Canadian Guide to Clinical Preventive Health Care²¹ recommended against screening with the Denver Developmental Screening Test and stated evidence was insufficient to support either the inclusion or exclusion of other screening tools. No studies have randomized children to screening versus no screening with contemporary screening tools.

Developmental screening is reliable

Screening tests can identify children with developmental delay with reasonable accuracy, and, as noted, such children may benefit from early intervention.

Developmental screening instruments fall into 1 of 2 categories: those that require the direct elicitation of developmental skills from children in conjunction with parental report, and those that rely solely on parental report.

Researchers in developmental screening regard a sensitivity of 70% to 80% as acceptable.²² Though this sensitivity is relatively low compared with other common screens used in medicine, it is in part unavoidable given the brevity of screens and the dynamic nature of child development. No screening tests have been shown to maintain sensitivity much greater than this without an unacceptable trade-off in specificity.

The specificity for a good developmental screen should also be in the range of 70% to 80%, ideally closer to 80%.²² Though this relatively low specificity will result in false-positive results, research has questioned whether this is problematic. Glascoe, in a study²³ involving a geographically representative sample of 512 children, found that though false positives on validated screening instruments did not reflect disabilities, these children nevertheless scored substantially lower than peers in intelligence, language, and academic achievement—the 3 best predictors for school success. Thus, many children who do not qualify for special educational services on subsequent testing may still have substantial risk factors for academic failure and may benefit from other services such as Head Start, Title 1 services, private speech-language therapy, and quality day care.

Suitable tests convenient for a busy office practice

The following 2 screening instruments rely on parental input. Research has shown that parental questioning is a valid means of screening for developmental delays, and that standardized instruments have a sensitivity and specificity similar to that of screens that require direct elicitation of a child’s skills, such as the Brigance and the BDSI (discussed later).²⁴

PEDS

PEDS (Parents’ Evaluation of Developmental Status) consists of 2 open-ended questions and 8 yes/no questions. It is written at a fifth-grade reading level and takes approximately 5 minutes to administer if an interview is needed—and even less time if parents can complete it independently. It need not be administered by a professional, and can be completed by a parent while waiting to see the doctor or even at home before a well-child visit.

PEDS was published in 1997 as a developmental screen entirely dependent on one kind of parental report—their concerns. The instrument was standardized and validated with 771 children representative of the 1996 US Census.²⁵ Twenty-five percent of the children used in standardization lived in poverty, 30% had unmarried parents. This questionnaire has a sensitivity of 74% to 79% and a specificity of 70% to 80% across ages 0 to 8 years in the detection of developmental delays and behavioral problems. It maintains its psychometric properties across various levels of parental education, socioeconomic status, and child-rearing experience.²⁶ The sensitivity and specificity for all ages combined was 75% and 74%, respectively.

Validity was determined through comparison with a battery of tests including the Woodcock-Johnson Psychoeducational Battery: Tests of Achievement, Stanford-Binet Intelligence Scale, and the Bayley Scales of Infant Development–II.

Scoring stratifies risk as low, medium, and high. Children at high risk require referral for more comprehensive assessment; validity studies found approximately 70% to possess disabilities or substantial delays on further evaluation. Children at intermediate risk require further screening, as approximately 30% were found to have disabilities or substantial delays on in validation studies.²⁵

The Ages and Stages Questionnaires

The Age and Stages Questionnaire (ASQ) system (formerly known as the Infant Monitoring Questionnaires) was developed by Bricker, Squires, and colleagues at the University of Oregon.²⁷ It is a low-cost and easily administered screening instrument relying on parental report.²⁸ Items are written at a fourth- to sixth-grade reading level; illustrations and examples are often provided. This self-administered assessment can be completed in 10 to 20 minutes and scored in 1 to 5 minutes.

The writers of the ASQ drew on several standardized developmental tests for item statements as well as literature that outlined early developmental milestones. They selected skills that could be observed or elicited easily by parents at home in the course of daily activities.

The system has 19 questionnaires designed to be administered at ages 4 months through 5 years, corresponding to common well-child visits. Five developmental areas are covered in each questionnaire—communication, gross motor, fine motor, problem solving, and personal-social. Five items query skills in each area. An overall section has 5 questions that cover general parental concerns.

Normative data were gathered from 2008 children drawn from an ethnically and socioeconomically heterogeneous population, with 81% of children judged “at-risk.”²⁸ The items were picked to represent the developmental quotient (DQ) of 75 to 100. Validity data were gathered from the analysis of 247 children, a subset of the population used in gathering normative data.

The ASQ has a specificity ranging from 81% (16 months) to 92% (36 months), and 86% overall. There was trend toward higher specificity when screening older children. Sensitivity was lower, averaging 72%.²⁹ Age-appropriate tests of individual cognition were used as the gold standard, including the Bayley Scales of Infant Development, Stanford-Binet Intelligence Test (4th ed), and the McCarthy Scales of Children’s Abilities.

The instrument maintains its validity when screening high-risk children: when specifically used to evaluate infants born prematurely, the ASQ had 90% sensitivity, 77% specificity.³⁰ In this study formal assessment was performed with the Griffith Mental development Scales, Bayley Development Intelligence Scale.

Reliable tests requiring direct elicitation and observation of children

Brigance screens

The Brigance screens are not well known to physicians but are commonly used in Head Start and educational settings.³¹ They include 9 separate forms, each covering a 12-month age range. The Brigance requires about 15 minutes to administer and score. The screens address speech-language, motor skills, readiness, and general knowledge at younger ages, and also reading and math at older ages.

The Brigance screens were standardized using 1156 children; validity data were gathered through examining 408 children. Both groups were drawn from populations of diverse geographical and socioeconomic status, producing demographics similar to the US Census for the year 2000.

Validity data estimated the sensitivity and specificity for detecting children with delays at 82% and 75%, with a range of 72% to 100% across different years. Validity was determined through comparison with a battery of age-appropriate developmental assessment tools such as the Bayley Scales of Infant Development–II (BSID-II), Slossen Intelligence Test, and the Woodcock-Johnson Psycho-Educational Battery—Revised: Test of Achievement–II.³² A study examining the extension of the Brigance screens to children ages 0 to 2 years found the screen to maintain its sensitivity (76% to 77%) and specificity (85% to 86%).³³ An additional feature of the Brigance is its ability to detect gifted and academically talented children with a sensitivity and specificity of 69% and 79%, respectively.³²

The Brigance II was published in early 2006; it has a sensitivity of 70% and specificity of 82% for the detection of developmental and academic problems.³⁴

Battelle Developmental Inventory Screening Test

The Battelle Developmental Inventory Screening Test (BDIST) can be used to screen children from age 12 to 96 months, using a combination of direct assessment, observation, and parental interview. Normative data were gathered from a geographically and socioeconomically diverse sample of 800 children.³⁵

Studies have shown the test to possess a sensitivity of 75% and specificity of 73%.³⁶ Validity data were gathered from 105 subjects, most of whose parents’ incomes were below poverty guidelines. A battery of tests was used as a gold standard including the Bayley Scales of Infant Development–II, Kaufman Assessment Battery for Children or the Stanford-Binet Intelligence Scale. The BDIST requires 4 to 6 hours to learn and 10 to 30 minutes to administer, and may be impractical for routine screening in primary care. The receptive language subtest may be administered in lieu of the full screen and takes just a few minutes to administer; however, that diminishes specificity to 66% while maintaining sensitivity at 80%.³⁶

Bayley Infant Neurodevelopmental Screener

The Bayley Infant Neurodevelopmental Screener (BINS) is a recently developed test designed for screening high-risk infants aged 3 to 24 months. The test was standardized on a nonclinical sample of 600 children representative of the US Census data for 1988.³⁷ It uses 10 to 13 directly elicited items per 3- to 6-month range to assess neurodevelopmental skills and developmental accomplishments. Data published in the technical manual found the BINS to have a sensitivity and specificity of 75% and 86%, respectively, across all ages.³⁷

A subsequent study found the BINS to possess a sensitivity of 70% and a specificity of 71% when a population of infants born prematurely was screened at 12 and 24 months.³⁸

Both studies used the Bayley Scales of Infant Development–II as the gold standard. The BINS requires only about 10 minutes to administer, but requires experience in standardized assessment and familiarity with infant development.³⁹ A recent study found the BINS insensitive in the detection of developmental delays as compared with the Bayley Scales of Infant Development–II in environmentally at-risk children at ages of 6 months and 12 months.⁴⁰

Tests of questionable value

Denver–II

The Denver Developmental Screening Test (DDST) was introduced in 1967. Research has consistently found it lacking in sensitivity. In response to this criticism, a revised version, the Denver II, was released in 1992.⁴¹

The Denver II is the most commonly used developmental screening tool.⁶ It combines direct observation and parental report. The tool consists of 125 items, organized into 4 developmental domains: gross motor, fine motor/adaptive, language, and personal/social. Items are displayed in bars that indicate the ages in which 25%, 75%, and 90% of children in the standardization study mastered a given task. A Denver test kit consists of scoring pads, materials used in eliciting skills, and a technical manual that details the appropriate administration and scoring of the test. Thirty-one percent of items can be addressed by parental report; the remainder requires observation of elicited skills.⁴²

Though the Denver II used more than 2000 children to establish normative data, all of them were from Colorado, undermining our ability to generalize this data to a more heterogeneous population. Furthermore, both versions of the test were published without data on the test’s validity, sensitivity, and specificity. The authors have instead relied on the significance of a child falling outside of the normal range as evidence of delay. This approach has been criticized.

Two studies have examined the validity of the Denver–II. In 1992, Glascoe et al⁴³ studied a demographically representative sample of 102 children and found that though the Denver II had a high sensitivity (83%), it had an unacceptably low specificity (43%). Attempts to improve specificity through categorizing questionable/untestable scores as normal raised specificity to 80%, but at the expense of sensitivity, dropping it to 56%.⁴³ Assuming a 16% prevalence of developmental disorders, the low specificity of the Denver–II would produce suspect scores in nearly 3 out of 5 children tested, but true problems could only be expected to be found in 1 of 4 children with suspect scores.

A follow-up study of 89 children by Glascoe and Byrne⁴⁴ found the Denver–II to possess excellent sensitivity (83%) but similarly disappointing specificity (26%), producing a positive predictive value of 28% in the study population (20% prevalence of disabilities).

In both studies, a battery of tests similar to those used to determine eligibility for special services were used as the gold standard. Properly performed, administration of the Denver–II requires approximately 20 minutes.⁴² Shortened versions or informal scoring of the Denver–II can only further degrade the questionable validity of this measure.

Child Development Inventories

The Child Development Inventory or CDI, formerly known as the Minnesota Child Development Inventory, was created to provide a systematic, standardized method for parents to report on their children’s strengths, problems, and present development. The original 300-item instrument has been broken down into instruments that apply to 3 age intervals.

The CDI measures a child’s development in 8 areas: social, self-help, gross motor, fine motor, expressive language, language comprehension, letters, and numbers. It consists of a 300-item booklet and answer sheet for the parent to complete and a profile sheet for recording the results. It was standardized on a sample of 568 children from South St. Paul Minnesota, a predominantly Caucasian, working-class community near a large metropolitan area.⁴⁴

Parents complete the questionnaire by circling Yes/No responses to the statements. Children are considered “borderline” if their CDI scores are 25% below chronological age (1.5 standard deviations [SD] below the mean) and “delayed” if their scores are >30% below chronological age (2.0 SD). The CDI has been researched in presumed normal populations and in high-risk populations such as children born prematurely.

In a high-risk population of infants and children, it was found to have a sensitivity of 80% and specificity of 96% for detecting developmental delay (ie, CDI scores >2.0 SD below the mean) when compared with to the Bayley Scales of Infant Development–II, using 2 SD below the mean as the cutoff.⁴⁵ It seems to have particular utility for screening at-risk children even when applied to a population of low socioeconomic status and low education level.⁴⁶ In addition to validity, good predictive value has been established for future cognitive, reading, academic, intellectual, and adaptive functioning.

The CDI takes 35 to 50 minutes to complete, requires a seventh- to eight-grade reading level, and may thus be impractical for screening large groups of low-risk children. Additionally, the CDI’s generalizability to diverse populations is not established, as the normative data was gathered from a population that was 95% Caucasian. The length and depth of the CDI has called some to question whether it is an instrument for developmental assessment rather than developmental screening.

The Child Development Inventories (plural) are shortened versions of the CDI (singular), tailored for ages 0 to 18 months and 18 months to 5 years.⁴⁷ The Infant Development Inventory (IDI) requires a parent to describe their child’s development, using a chart of milestones, in social, gross motor, fine motor, and language skills areas.

The Child Development Review (CDR) is designed to screen for developmental problems in children ages 18 months to 5 years. The IDI and CDR are brief and easy to administer and score. Both rely on the formalized gathering of a parent’s concerns and the parent’s assessment of the child’s progress in achieving milestones in several streams of development. Unfortunately, evidence in the technical manual or medical literature is insufficient to establish the validity of this instrument, and thus it is difficult to recommend the child development inventories when other parent-report instruments exist with well established validity.

Economics of developmental screening

It is useful to look at the economics of developmental screens from 2 perspectives—that of the physician and that of society. A 1998 review of the literature by the RAND group⁴⁸ concluded that 2 studies—the Elmira Prenatal/Early Infancy Project (EPEIP) and the Perry Preschool Project—followed children for sufficient time to allow for the assessment of the economic implications of intervention in children at risk for developmental delays.

Societal perspective

Both studies found that interventions led to considerable savings, with the biggest savings from decreased criminality in adulthood. The RAND group⁴⁸ estimated a government savings of $18,611 per child who underwent early intervention in the Elmira Prenatal/Early Infancy Project, and a savings of $13,289 per child for individuals receiving intervention in the Perry Preschool Project (figures in 1996 dollars.)

It is difficult to know whether these same savings would be seen in developmental intervention applied on a larger scale. Additionally, it is difficult to know how generalizable research from intervention with high-risk children is to intervention stemming from screening in a doctor’s office.

The physician perspective

Developmental screening is associated with additional costs. Dobrez et al⁴⁹ estimated the physician’s expense in administering a number of developmental screens, accounting for the administration costs and costs associated with time required to discuss abnormal results. This analysis found screens based on parental report such as the ASQ, CDI, and PEDS considerably less expensive, with a per-visit expense of approximately $12 for negative screen results and approximately $16 for positive results. Tests requiring the direct elicitation of skills from children such as the Denver–II and BINS had an estimated cost of $55.12 and $22.22 for normal screens, respectively, and $59.57 and $26.67 for abnormal screens.⁴⁹ Medicaid reimbursement varies by state; information can be obtained though the Center for Medicaid/Medicare website. Private payers may or may not reimburse physicians for developmental screening.

CORRESPONDENCE
Sutton Hamilton, MD, Underwood-Memorial Family Medicine Residency, 35 Oak Street, Woodbury, NJ 08033. E-mail: [email protected]

One child out of 6 in your practice probably has a developmental disability.¹ However, identifying disability will be erratic if you rely solely on clinical judgment and informal milestone reviews.

There is reason for concern: the evidence for early intervention, though limited, shows that it confers long-term benefits for these children. Judicious use of practical, reliable standardized screens that I discuss in this article will increase your likelihood of identifying children who need help.

Needed: A screening net with tighter mesh

Disorders such as cerebral palsy and profound mental retardation are clearly recognizable and have well-known consequences. Disabilities such as language impairment, mild mental retardation, and learning disabilities (see Range of disabilities) are more subtle but also associated with poorer health status, higher rates of school failure, in-grade retention, and special education placement.^1,2

Developmental problems commonly escape detection in the first 5 years of life despite frequent well-child visits. Physicians generally acknowledge that screening for developmental disabilities is important,³ but few use standardized screening instruments.^4,5 Most physicians rely instead on clinical judgment and milestone review.

Scope of the problem

A study that examined how doctors in the US screen for delays found that only 15% to 20% screened more than 10% of all of their patients with a formalized developmental instrument.⁵ Again, this points to reliance on clinical judgment to determine who should be screened. A National Survey of pediatricians and family physicians⁶ found that 53% reported using no standardized instrument in their assessment of children for developmental delays. The most recent National Survey of Early Childhood Health (NSECH)¹² found that only 35% to 45% of parents recall their child’s development ever being assessed by their doctor.

The fallout. Most children who would qualify for early intervention under federal law are not identified before school entry. Palfrey et al¹³ examined the records of 1726 children in special education classes at 5 sites and found that just 28.7% of developmental and behavioral problems were identified before entry into school (age 5). Just 15% to 25% of learning and speech disorders emotional disorders and attention deficit disorders were identified before school entry.¹³

A study in the UK¹⁴ found that despite of a system geared to detect subtle developmental disorders, their child health surveillance failed to detect 38% of children with moderate learning disabilities and 94% of children with mild or moderate learning disabilities. Another study¹⁵ on this matter shows a disappointing detection rate, failing to identify 55% to 65% of children with developmental problems before entry into school.

Studies have proven clinical judgment insensitive even in the detection of mental retardation. Two studies from the 1960s showed that US pediatricians accurately identified only 43% of children with an intelligence quotient (IQ) of <80.

Does early intervention work?

Much of the literature on early intervention in childhood focuses on children with risk factors such as prematurity and low birth weight or low socioeconomic status. In controlled studies, children at psychosocial disadvantage who received high-quality intervention exhibited long-term improvement in IQ, higher academic achievement, and decreased criminal behavior, and were, as adults, more likely to be employed and to earn higher incomes than those who did not participate in early intervention (SOR: A).^16,17

Other studies have similarly shown benefits from early intervention for children with such biological risk factors as low birth weight and prematurity (SOR: A).¹⁸ Early intervention for conditions such as learning disabilities or speech and language delays is generally thought to improve outcomes (SOR: C).²

Rationale for screening

Early identification mandated by law

The Individuals with Disabilities Education Act (IDEA) Amendments of 1997¹⁹ mandate the “early identification of, and intervention for developmental disabilities through the development of community-based systems.” This law requires physicians to refer children with suspected developmental delays to appropriate early intervention services in a timely manner. All states receive federal funding to provide appropriate intervention through infant and child-find programs for children with developmental delays.

In a study released in February 2006, the United States Preventive Services Task Force²⁰ concluded that the evidence is insufficient to recommend for or against routine use of brief, formal screening instruments in primary care to detect speech and language delay in children up to 5 years of age. The Canadian Guide to Clinical Preventive Health Care²¹ recommended against screening with the Denver Developmental Screening Test and stated evidence was insufficient to support either the inclusion or exclusion of other screening tools. No studies have randomized children to screening versus no screening with contemporary screening tools.

Developmental screening is reliable

Screening tests can identify children with developmental delay with reasonable accuracy, and, as noted, such children may benefit from early intervention.

Developmental screening instruments fall into 1 of 2 categories: those that require the direct elicitation of developmental skills from children in conjunction with parental report, and those that rely solely on parental report.

Researchers in developmental screening regard a sensitivity of 70% to 80% as acceptable.²² Though this sensitivity is relatively low compared with other common screens used in medicine, it is in part unavoidable given the brevity of screens and the dynamic nature of child development. No screening tests have been shown to maintain sensitivity much greater than this without an unacceptable trade-off in specificity.

The specificity for a good developmental screen should also be in the range of 70% to 80%, ideally closer to 80%.²² Though this relatively low specificity will result in false-positive results, research has questioned whether this is problematic. Glascoe, in a study²³ involving a geographically representative sample of 512 children, found that though false positives on validated screening instruments did not reflect disabilities, these children nevertheless scored substantially lower than peers in intelligence, language, and academic achievement—the 3 best predictors for school success. Thus, many children who do not qualify for special educational services on subsequent testing may still have substantial risk factors for academic failure and may benefit from other services such as Head Start, Title 1 services, private speech-language therapy, and quality day care.

Suitable tests convenient for a busy office practice

The following 2 screening instruments rely on parental input. Research has shown that parental questioning is a valid means of screening for developmental delays, and that standardized instruments have a sensitivity and specificity similar to that of screens that require direct elicitation of a child’s skills, such as the Brigance and the BDSI (discussed later).²⁴

PEDS

PEDS (Parents’ Evaluation of Developmental Status) consists of 2 open-ended questions and 8 yes/no questions. It is written at a fifth-grade reading level and takes approximately 5 minutes to administer if an interview is needed—and even less time if parents can complete it independently. It need not be administered by a professional, and can be completed by a parent while waiting to see the doctor or even at home before a well-child visit.

PEDS was published in 1997 as a developmental screen entirely dependent on one kind of parental report—their concerns. The instrument was standardized and validated with 771 children representative of the 1996 US Census.²⁵ Twenty-five percent of the children used in standardization lived in poverty, 30% had unmarried parents. This questionnaire has a sensitivity of 74% to 79% and a specificity of 70% to 80% across ages 0 to 8 years in the detection of developmental delays and behavioral problems. It maintains its psychometric properties across various levels of parental education, socioeconomic status, and child-rearing experience.²⁶ The sensitivity and specificity for all ages combined was 75% and 74%, respectively.

Validity was determined through comparison with a battery of tests including the Woodcock-Johnson Psychoeducational Battery: Tests of Achievement, Stanford-Binet Intelligence Scale, and the Bayley Scales of Infant Development–II.

Scoring stratifies risk as low, medium, and high. Children at high risk require referral for more comprehensive assessment; validity studies found approximately 70% to possess disabilities or substantial delays on further evaluation. Children at intermediate risk require further screening, as approximately 30% were found to have disabilities or substantial delays on in validation studies.²⁵

The Ages and Stages Questionnaires

The Age and Stages Questionnaire (ASQ) system (formerly known as the Infant Monitoring Questionnaires) was developed by Bricker, Squires, and colleagues at the University of Oregon.²⁷ It is a low-cost and easily administered screening instrument relying on parental report.²⁸ Items are written at a fourth- to sixth-grade reading level; illustrations and examples are often provided. This self-administered assessment can be completed in 10 to 20 minutes and scored in 1 to 5 minutes.

The writers of the ASQ drew on several standardized developmental tests for item statements as well as literature that outlined early developmental milestones. They selected skills that could be observed or elicited easily by parents at home in the course of daily activities.

The system has 19 questionnaires designed to be administered at ages 4 months through 5 years, corresponding to common well-child visits. Five developmental areas are covered in each questionnaire—communication, gross motor, fine motor, problem solving, and personal-social. Five items query skills in each area. An overall section has 5 questions that cover general parental concerns.

Normative data were gathered from 2008 children drawn from an ethnically and socioeconomically heterogeneous population, with 81% of children judged “at-risk.”²⁸ The items were picked to represent the developmental quotient (DQ) of 75 to 100. Validity data were gathered from the analysis of 247 children, a subset of the population used in gathering normative data.

The ASQ has a specificity ranging from 81% (16 months) to 92% (36 months), and 86% overall. There was trend toward higher specificity when screening older children. Sensitivity was lower, averaging 72%.²⁹ Age-appropriate tests of individual cognition were used as the gold standard, including the Bayley Scales of Infant Development, Stanford-Binet Intelligence Test (4th ed), and the McCarthy Scales of Children’s Abilities.

The instrument maintains its validity when screening high-risk children: when specifically used to evaluate infants born prematurely, the ASQ had 90% sensitivity, 77% specificity.³⁰ In this study formal assessment was performed with the Griffith Mental development Scales, Bayley Development Intelligence Scale.

Reliable tests requiring direct elicitation and observation of children

Brigance screens

The Brigance screens are not well known to physicians but are commonly used in Head Start and educational settings.³¹ They include 9 separate forms, each covering a 12-month age range. The Brigance requires about 15 minutes to administer and score. The screens address speech-language, motor skills, readiness, and general knowledge at younger ages, and also reading and math at older ages.

The Brigance screens were standardized using 1156 children; validity data were gathered through examining 408 children. Both groups were drawn from populations of diverse geographical and socioeconomic status, producing demographics similar to the US Census for the year 2000.

Validity data estimated the sensitivity and specificity for detecting children with delays at 82% and 75%, with a range of 72% to 100% across different years. Validity was determined through comparison with a battery of age-appropriate developmental assessment tools such as the Bayley Scales of Infant Development–II (BSID-II), Slossen Intelligence Test, and the Woodcock-Johnson Psycho-Educational Battery—Revised: Test of Achievement–II.³² A study examining the extension of the Brigance screens to children ages 0 to 2 years found the screen to maintain its sensitivity (76% to 77%) and specificity (85% to 86%).³³ An additional feature of the Brigance is its ability to detect gifted and academically talented children with a sensitivity and specificity of 69% and 79%, respectively.³²

The Brigance II was published in early 2006; it has a sensitivity of 70% and specificity of 82% for the detection of developmental and academic problems.³⁴

Battelle Developmental Inventory Screening Test

The Battelle Developmental Inventory Screening Test (BDIST) can be used to screen children from age 12 to 96 months, using a combination of direct assessment, observation, and parental interview. Normative data were gathered from a geographically and socioeconomically diverse sample of 800 children.³⁵

Studies have shown the test to possess a sensitivity of 75% and specificity of 73%.³⁶ Validity data were gathered from 105 subjects, most of whose parents’ incomes were below poverty guidelines. A battery of tests was used as a gold standard including the Bayley Scales of Infant Development–II, Kaufman Assessment Battery for Children or the Stanford-Binet Intelligence Scale. The BDIST requires 4 to 6 hours to learn and 10 to 30 minutes to administer, and may be impractical for routine screening in primary care. The receptive language subtest may be administered in lieu of the full screen and takes just a few minutes to administer; however, that diminishes specificity to 66% while maintaining sensitivity at 80%.³⁶

Bayley Infant Neurodevelopmental Screener

The Bayley Infant Neurodevelopmental Screener (BINS) is a recently developed test designed for screening high-risk infants aged 3 to 24 months. The test was standardized on a nonclinical sample of 600 children representative of the US Census data for 1988.³⁷ It uses 10 to 13 directly elicited items per 3- to 6-month range to assess neurodevelopmental skills and developmental accomplishments. Data published in the technical manual found the BINS to have a sensitivity and specificity of 75% and 86%, respectively, across all ages.³⁷

A subsequent study found the BINS to possess a sensitivity of 70% and a specificity of 71% when a population of infants born prematurely was screened at 12 and 24 months.³⁸

Both studies used the Bayley Scales of Infant Development–II as the gold standard. The BINS requires only about 10 minutes to administer, but requires experience in standardized assessment and familiarity with infant development.³⁹ A recent study found the BINS insensitive in the detection of developmental delays as compared with the Bayley Scales of Infant Development–II in environmentally at-risk children at ages of 6 months and 12 months.⁴⁰

Tests of questionable value

Denver–II

The Denver Developmental Screening Test (DDST) was introduced in 1967. Research has consistently found it lacking in sensitivity. In response to this criticism, a revised version, the Denver II, was released in 1992.⁴¹

The Denver II is the most commonly used developmental screening tool.⁶ It combines direct observation and parental report. The tool consists of 125 items, organized into 4 developmental domains: gross motor, fine motor/adaptive, language, and personal/social. Items are displayed in bars that indicate the ages in which 25%, 75%, and 90% of children in the standardization study mastered a given task. A Denver test kit consists of scoring pads, materials used in eliciting skills, and a technical manual that details the appropriate administration and scoring of the test. Thirty-one percent of items can be addressed by parental report; the remainder requires observation of elicited skills.⁴²

Though the Denver II used more than 2000 children to establish normative data, all of them were from Colorado, undermining our ability to generalize this data to a more heterogeneous population. Furthermore, both versions of the test were published without data on the test’s validity, sensitivity, and specificity. The authors have instead relied on the significance of a child falling outside of the normal range as evidence of delay. This approach has been criticized.

Two studies have examined the validity of the Denver–II. In 1992, Glascoe et al⁴³ studied a demographically representative sample of 102 children and found that though the Denver II had a high sensitivity (83%), it had an unacceptably low specificity (43%). Attempts to improve specificity through categorizing questionable/untestable scores as normal raised specificity to 80%, but at the expense of sensitivity, dropping it to 56%.⁴³ Assuming a 16% prevalence of developmental disorders, the low specificity of the Denver–II would produce suspect scores in nearly 3 out of 5 children tested, but true problems could only be expected to be found in 1 of 4 children with suspect scores.

A follow-up study of 89 children by Glascoe and Byrne⁴⁴ found the Denver–II to possess excellent sensitivity (83%) but similarly disappointing specificity (26%), producing a positive predictive value of 28% in the study population (20% prevalence of disabilities).

In both studies, a battery of tests similar to those used to determine eligibility for special services were used as the gold standard. Properly performed, administration of the Denver–II requires approximately 20 minutes.⁴² Shortened versions or informal scoring of the Denver–II can only further degrade the questionable validity of this measure.

Child Development Inventories

The Child Development Inventory or CDI, formerly known as the Minnesota Child Development Inventory, was created to provide a systematic, standardized method for parents to report on their children’s strengths, problems, and present development. The original 300-item instrument has been broken down into instruments that apply to 3 age intervals.

The CDI measures a child’s development in 8 areas: social, self-help, gross motor, fine motor, expressive language, language comprehension, letters, and numbers. It consists of a 300-item booklet and answer sheet for the parent to complete and a profile sheet for recording the results. It was standardized on a sample of 568 children from South St. Paul Minnesota, a predominantly Caucasian, working-class community near a large metropolitan area.⁴⁴

Parents complete the questionnaire by circling Yes/No responses to the statements. Children are considered “borderline” if their CDI scores are 25% below chronological age (1.5 standard deviations [SD] below the mean) and “delayed” if their scores are >30% below chronological age (2.0 SD). The CDI has been researched in presumed normal populations and in high-risk populations such as children born prematurely.

In a high-risk population of infants and children, it was found to have a sensitivity of 80% and specificity of 96% for detecting developmental delay (ie, CDI scores >2.0 SD below the mean) when compared with to the Bayley Scales of Infant Development–II, using 2 SD below the mean as the cutoff.⁴⁵ It seems to have particular utility for screening at-risk children even when applied to a population of low socioeconomic status and low education level.⁴⁶ In addition to validity, good predictive value has been established for future cognitive, reading, academic, intellectual, and adaptive functioning.

The CDI takes 35 to 50 minutes to complete, requires a seventh- to eight-grade reading level, and may thus be impractical for screening large groups of low-risk children. Additionally, the CDI’s generalizability to diverse populations is not established, as the normative data was gathered from a population that was 95% Caucasian. The length and depth of the CDI has called some to question whether it is an instrument for developmental assessment rather than developmental screening.

The Child Development Inventories (plural) are shortened versions of the CDI (singular), tailored for ages 0 to 18 months and 18 months to 5 years.⁴⁷ The Infant Development Inventory (IDI) requires a parent to describe their child’s development, using a chart of milestones, in social, gross motor, fine motor, and language skills areas.

The Child Development Review (CDR) is designed to screen for developmental problems in children ages 18 months to 5 years. The IDI and CDR are brief and easy to administer and score. Both rely on the formalized gathering of a parent’s concerns and the parent’s assessment of the child’s progress in achieving milestones in several streams of development. Unfortunately, evidence in the technical manual or medical literature is insufficient to establish the validity of this instrument, and thus it is difficult to recommend the child development inventories when other parent-report instruments exist with well established validity.

Economics of developmental screening

It is useful to look at the economics of developmental screens from 2 perspectives—that of the physician and that of society. A 1998 review of the literature by the RAND group⁴⁸ concluded that 2 studies—the Elmira Prenatal/Early Infancy Project (EPEIP) and the Perry Preschool Project—followed children for sufficient time to allow for the assessment of the economic implications of intervention in children at risk for developmental delays.

Societal perspective

Both studies found that interventions led to considerable savings, with the biggest savings from decreased criminality in adulthood. The RAND group⁴⁸ estimated a government savings of $18,611 per child who underwent early intervention in the Elmira Prenatal/Early Infancy Project, and a savings of $13,289 per child for individuals receiving intervention in the Perry Preschool Project (figures in 1996 dollars.)

It is difficult to know whether these same savings would be seen in developmental intervention applied on a larger scale. Additionally, it is difficult to know how generalizable research from intervention with high-risk children is to intervention stemming from screening in a doctor’s office.

The physician perspective

Developmental screening is associated with additional costs. Dobrez et al⁴⁹ estimated the physician’s expense in administering a number of developmental screens, accounting for the administration costs and costs associated with time required to discuss abnormal results. This analysis found screens based on parental report such as the ASQ, CDI, and PEDS considerably less expensive, with a per-visit expense of approximately $12 for negative screen results and approximately $16 for positive results. Tests requiring the direct elicitation of skills from children such as the Denver–II and BINS had an estimated cost of $55.12 and $22.22 for normal screens, respectively, and $59.57 and $26.67 for abnormal screens.⁴⁹ Medicaid reimbursement varies by state; information can be obtained though the Center for Medicaid/Medicare website. Private payers may or may not reimburse physicians for developmental screening.

CORRESPONDENCE
Sutton Hamilton, MD, Underwood-Memorial Family Medicine Residency, 35 Oak Street, Woodbury, NJ 08033. E-mail: [email protected]

One child out of 6 in your practice probably has a developmental disability.¹ However, identifying disability will be erratic if you rely solely on clinical judgment and informal milestone reviews.

There is reason for concern: the evidence for early intervention, though limited, shows that it confers long-term benefits for these children. Judicious use of practical, reliable standardized screens that I discuss in this article will increase your likelihood of identifying children who need help.

Needed: A screening net with tighter mesh

Disorders such as cerebral palsy and profound mental retardation are clearly recognizable and have well-known consequences. Disabilities such as language impairment, mild mental retardation, and learning disabilities (see Range of disabilities) are more subtle but also associated with poorer health status, higher rates of school failure, in-grade retention, and special education placement.^1,2

Developmental problems commonly escape detection in the first 5 years of life despite frequent well-child visits. Physicians generally acknowledge that screening for developmental disabilities is important,³ but few use standardized screening instruments.^4,5 Most physicians rely instead on clinical judgment and milestone review.

Scope of the problem

A study that examined how doctors in the US screen for delays found that only 15% to 20% screened more than 10% of all of their patients with a formalized developmental instrument.⁵ Again, this points to reliance on clinical judgment to determine who should be screened. A National Survey of pediatricians and family physicians⁶ found that 53% reported using no standardized instrument in their assessment of children for developmental delays. The most recent National Survey of Early Childhood Health (NSECH)¹² found that only 35% to 45% of parents recall their child’s development ever being assessed by their doctor.

The fallout. Most children who would qualify for early intervention under federal law are not identified before school entry. Palfrey et al¹³ examined the records of 1726 children in special education classes at 5 sites and found that just 28.7% of developmental and behavioral problems were identified before entry into school (age 5). Just 15% to 25% of learning and speech disorders emotional disorders and attention deficit disorders were identified before school entry.¹³

A study in the UK¹⁴ found that despite of a system geared to detect subtle developmental disorders, their child health surveillance failed to detect 38% of children with moderate learning disabilities and 94% of children with mild or moderate learning disabilities. Another study¹⁵ on this matter shows a disappointing detection rate, failing to identify 55% to 65% of children with developmental problems before entry into school.

Studies have proven clinical judgment insensitive even in the detection of mental retardation. Two studies from the 1960s showed that US pediatricians accurately identified only 43% of children with an intelligence quotient (IQ) of <80.

Does early intervention work?

Much of the literature on early intervention in childhood focuses on children with risk factors such as prematurity and low birth weight or low socioeconomic status. In controlled studies, children at psychosocial disadvantage who received high-quality intervention exhibited long-term improvement in IQ, higher academic achievement, and decreased criminal behavior, and were, as adults, more likely to be employed and to earn higher incomes than those who did not participate in early intervention (SOR: A).^16,17

Other studies have similarly shown benefits from early intervention for children with such biological risk factors as low birth weight and prematurity (SOR: A).¹⁸ Early intervention for conditions such as learning disabilities or speech and language delays is generally thought to improve outcomes (SOR: C).²

Rationale for screening

Early identification mandated by law

The Individuals with Disabilities Education Act (IDEA) Amendments of 1997¹⁹ mandate the “early identification of, and intervention for developmental disabilities through the development of community-based systems.” This law requires physicians to refer children with suspected developmental delays to appropriate early intervention services in a timely manner. All states receive federal funding to provide appropriate intervention through infant and child-find programs for children with developmental delays.

In a study released in February 2006, the United States Preventive Services Task Force²⁰ concluded that the evidence is insufficient to recommend for or against routine use of brief, formal screening instruments in primary care to detect speech and language delay in children up to 5 years of age. The Canadian Guide to Clinical Preventive Health Care²¹ recommended against screening with the Denver Developmental Screening Test and stated evidence was insufficient to support either the inclusion or exclusion of other screening tools. No studies have randomized children to screening versus no screening with contemporary screening tools.

Developmental screening is reliable

Screening tests can identify children with developmental delay with reasonable accuracy, and, as noted, such children may benefit from early intervention.

Developmental screening instruments fall into 1 of 2 categories: those that require the direct elicitation of developmental skills from children in conjunction with parental report, and those that rely solely on parental report.

Researchers in developmental screening regard a sensitivity of 70% to 80% as acceptable.²² Though this sensitivity is relatively low compared with other common screens used in medicine, it is in part unavoidable given the brevity of screens and the dynamic nature of child development. No screening tests have been shown to maintain sensitivity much greater than this without an unacceptable trade-off in specificity.

The specificity for a good developmental screen should also be in the range of 70% to 80%, ideally closer to 80%.²² Though this relatively low specificity will result in false-positive results, research has questioned whether this is problematic. Glascoe, in a study²³ involving a geographically representative sample of 512 children, found that though false positives on validated screening instruments did not reflect disabilities, these children nevertheless scored substantially lower than peers in intelligence, language, and academic achievement—the 3 best predictors for school success. Thus, many children who do not qualify for special educational services on subsequent testing may still have substantial risk factors for academic failure and may benefit from other services such as Head Start, Title 1 services, private speech-language therapy, and quality day care.

Suitable tests convenient for a busy office practice

The following 2 screening instruments rely on parental input. Research has shown that parental questioning is a valid means of screening for developmental delays, and that standardized instruments have a sensitivity and specificity similar to that of screens that require direct elicitation of a child’s skills, such as the Brigance and the BDSI (discussed later).²⁴

PEDS

PEDS (Parents’ Evaluation of Developmental Status) consists of 2 open-ended questions and 8 yes/no questions. It is written at a fifth-grade reading level and takes approximately 5 minutes to administer if an interview is needed—and even less time if parents can complete it independently. It need not be administered by a professional, and can be completed by a parent while waiting to see the doctor or even at home before a well-child visit.

PEDS was published in 1997 as a developmental screen entirely dependent on one kind of parental report—their concerns. The instrument was standardized and validated with 771 children representative of the 1996 US Census.²⁵ Twenty-five percent of the children used in standardization lived in poverty, 30% had unmarried parents. This questionnaire has a sensitivity of 74% to 79% and a specificity of 70% to 80% across ages 0 to 8 years in the detection of developmental delays and behavioral problems. It maintains its psychometric properties across various levels of parental education, socioeconomic status, and child-rearing experience.²⁶ The sensitivity and specificity for all ages combined was 75% and 74%, respectively.

Validity was determined through comparison with a battery of tests including the Woodcock-Johnson Psychoeducational Battery: Tests of Achievement, Stanford-Binet Intelligence Scale, and the Bayley Scales of Infant Development–II.

Scoring stratifies risk as low, medium, and high. Children at high risk require referral for more comprehensive assessment; validity studies found approximately 70% to possess disabilities or substantial delays on further evaluation. Children at intermediate risk require further screening, as approximately 30% were found to have disabilities or substantial delays on in validation studies.²⁵

The Ages and Stages Questionnaires

The Age and Stages Questionnaire (ASQ) system (formerly known as the Infant Monitoring Questionnaires) was developed by Bricker, Squires, and colleagues at the University of Oregon.²⁷ It is a low-cost and easily administered screening instrument relying on parental report.²⁸ Items are written at a fourth- to sixth-grade reading level; illustrations and examples are often provided. This self-administered assessment can be completed in 10 to 20 minutes and scored in 1 to 5 minutes.

The writers of the ASQ drew on several standardized developmental tests for item statements as well as literature that outlined early developmental milestones. They selected skills that could be observed or elicited easily by parents at home in the course of daily activities.

The system has 19 questionnaires designed to be administered at ages 4 months through 5 years, corresponding to common well-child visits. Five developmental areas are covered in each questionnaire—communication, gross motor, fine motor, problem solving, and personal-social. Five items query skills in each area. An overall section has 5 questions that cover general parental concerns.

Normative data were gathered from 2008 children drawn from an ethnically and socioeconomically heterogeneous population, with 81% of children judged “at-risk.”²⁸ The items were picked to represent the developmental quotient (DQ) of 75 to 100. Validity data were gathered from the analysis of 247 children, a subset of the population used in gathering normative data.

The ASQ has a specificity ranging from 81% (16 months) to 92% (36 months), and 86% overall. There was trend toward higher specificity when screening older children. Sensitivity was lower, averaging 72%.²⁹ Age-appropriate tests of individual cognition were used as the gold standard, including the Bayley Scales of Infant Development, Stanford-Binet Intelligence Test (4th ed), and the McCarthy Scales of Children’s Abilities.

The instrument maintains its validity when screening high-risk children: when specifically used to evaluate infants born prematurely, the ASQ had 90% sensitivity, 77% specificity.³⁰ In this study formal assessment was performed with the Griffith Mental development Scales, Bayley Development Intelligence Scale.

Reliable tests requiring direct elicitation and observation of children

Brigance screens

The Brigance screens are not well known to physicians but are commonly used in Head Start and educational settings.³¹ They include 9 separate forms, each covering a 12-month age range. The Brigance requires about 15 minutes to administer and score. The screens address speech-language, motor skills, readiness, and general knowledge at younger ages, and also reading and math at older ages.

The Brigance screens were standardized using 1156 children; validity data were gathered through examining 408 children. Both groups were drawn from populations of diverse geographical and socioeconomic status, producing demographics similar to the US Census for the year 2000.

Validity data estimated the sensitivity and specificity for detecting children with delays at 82% and 75%, with a range of 72% to 100% across different years. Validity was determined through comparison with a battery of age-appropriate developmental assessment tools such as the Bayley Scales of Infant Development–II (BSID-II), Slossen Intelligence Test, and the Woodcock-Johnson Psycho-Educational Battery—Revised: Test of Achievement–II.³² A study examining the extension of the Brigance screens to children ages 0 to 2 years found the screen to maintain its sensitivity (76% to 77%) and specificity (85% to 86%).³³ An additional feature of the Brigance is its ability to detect gifted and academically talented children with a sensitivity and specificity of 69% and 79%, respectively.³²

The Brigance II was published in early 2006; it has a sensitivity of 70% and specificity of 82% for the detection of developmental and academic problems.³⁴

Battelle Developmental Inventory Screening Test

The Battelle Developmental Inventory Screening Test (BDIST) can be used to screen children from age 12 to 96 months, using a combination of direct assessment, observation, and parental interview. Normative data were gathered from a geographically and socioeconomically diverse sample of 800 children.³⁵

Studies have shown the test to possess a sensitivity of 75% and specificity of 73%.³⁶ Validity data were gathered from 105 subjects, most of whose parents’ incomes were below poverty guidelines. A battery of tests was used as a gold standard including the Bayley Scales of Infant Development–II, Kaufman Assessment Battery for Children or the Stanford-Binet Intelligence Scale. The BDIST requires 4 to 6 hours to learn and 10 to 30 minutes to administer, and may be impractical for routine screening in primary care. The receptive language subtest may be administered in lieu of the full screen and takes just a few minutes to administer; however, that diminishes specificity to 66% while maintaining sensitivity at 80%.³⁶

Bayley Infant Neurodevelopmental Screener

The Bayley Infant Neurodevelopmental Screener (BINS) is a recently developed test designed for screening high-risk infants aged 3 to 24 months. The test was standardized on a nonclinical sample of 600 children representative of the US Census data for 1988.³⁷ It uses 10 to 13 directly elicited items per 3- to 6-month range to assess neurodevelopmental skills and developmental accomplishments. Data published in the technical manual found the BINS to have a sensitivity and specificity of 75% and 86%, respectively, across all ages.³⁷

A subsequent study found the BINS to possess a sensitivity of 70% and a specificity of 71% when a population of infants born prematurely was screened at 12 and 24 months.³⁸

Both studies used the Bayley Scales of Infant Development–II as the gold standard. The BINS requires only about 10 minutes to administer, but requires experience in standardized assessment and familiarity with infant development.³⁹ A recent study found the BINS insensitive in the detection of developmental delays as compared with the Bayley Scales of Infant Development–II in environmentally at-risk children at ages of 6 months and 12 months.⁴⁰

Tests of questionable value

Denver–II

The Denver Developmental Screening Test (DDST) was introduced in 1967. Research has consistently found it lacking in sensitivity. In response to this criticism, a revised version, the Denver II, was released in 1992.⁴¹

The Denver II is the most commonly used developmental screening tool.⁶ It combines direct observation and parental report. The tool consists of 125 items, organized into 4 developmental domains: gross motor, fine motor/adaptive, language, and personal/social. Items are displayed in bars that indicate the ages in which 25%, 75%, and 90% of children in the standardization study mastered a given task. A Denver test kit consists of scoring pads, materials used in eliciting skills, and a technical manual that details the appropriate administration and scoring of the test. Thirty-one percent of items can be addressed by parental report; the remainder requires observation of elicited skills.⁴²

Though the Denver II used more than 2000 children to establish normative data, all of them were from Colorado, undermining our ability to generalize this data to a more heterogeneous population. Furthermore, both versions of the test were published without data on the test’s validity, sensitivity, and specificity. The authors have instead relied on the significance of a child falling outside of the normal range as evidence of delay. This approach has been criticized.

Two studies have examined the validity of the Denver–II. In 1992, Glascoe et al⁴³ studied a demographically representative sample of 102 children and found that though the Denver II had a high sensitivity (83%), it had an unacceptably low specificity (43%). Attempts to improve specificity through categorizing questionable/untestable scores as normal raised specificity to 80%, but at the expense of sensitivity, dropping it to 56%.⁴³ Assuming a 16% prevalence of developmental disorders, the low specificity of the Denver–II would produce suspect scores in nearly 3 out of 5 children tested, but true problems could only be expected to be found in 1 of 4 children with suspect scores.

A follow-up study of 89 children by Glascoe and Byrne⁴⁴ found the Denver–II to possess excellent sensitivity (83%) but similarly disappointing specificity (26%), producing a positive predictive value of 28% in the study population (20% prevalence of disabilities).

In both studies, a battery of tests similar to those used to determine eligibility for special services were used as the gold standard. Properly performed, administration of the Denver–II requires approximately 20 minutes.⁴² Shortened versions or informal scoring of the Denver–II can only further degrade the questionable validity of this measure.

Child Development Inventories

The Child Development Inventory or CDI, formerly known as the Minnesota Child Development Inventory, was created to provide a systematic, standardized method for parents to report on their children’s strengths, problems, and present development. The original 300-item instrument has been broken down into instruments that apply to 3 age intervals.

The CDI measures a child’s development in 8 areas: social, self-help, gross motor, fine motor, expressive language, language comprehension, letters, and numbers. It consists of a 300-item booklet and answer sheet for the parent to complete and a profile sheet for recording the results. It was standardized on a sample of 568 children from South St. Paul Minnesota, a predominantly Caucasian, working-class community near a large metropolitan area.⁴⁴

Parents complete the questionnaire by circling Yes/No responses to the statements. Children are considered “borderline” if their CDI scores are 25% below chronological age (1.5 standard deviations [SD] below the mean) and “delayed” if their scores are >30% below chronological age (2.0 SD). The CDI has been researched in presumed normal populations and in high-risk populations such as children born prematurely.

In a high-risk population of infants and children, it was found to have a sensitivity of 80% and specificity of 96% for detecting developmental delay (ie, CDI scores >2.0 SD below the mean) when compared with to the Bayley Scales of Infant Development–II, using 2 SD below the mean as the cutoff.⁴⁵ It seems to have particular utility for screening at-risk children even when applied to a population of low socioeconomic status and low education level.⁴⁶ In addition to validity, good predictive value has been established for future cognitive, reading, academic, intellectual, and adaptive functioning.

The CDI takes 35 to 50 minutes to complete, requires a seventh- to eight-grade reading level, and may thus be impractical for screening large groups of low-risk children. Additionally, the CDI’s generalizability to diverse populations is not established, as the normative data was gathered from a population that was 95% Caucasian. The length and depth of the CDI has called some to question whether it is an instrument for developmental assessment rather than developmental screening.

The Child Development Inventories (plural) are shortened versions of the CDI (singular), tailored for ages 0 to 18 months and 18 months to 5 years.⁴⁷ The Infant Development Inventory (IDI) requires a parent to describe their child’s development, using a chart of milestones, in social, gross motor, fine motor, and language skills areas.

The Child Development Review (CDR) is designed to screen for developmental problems in children ages 18 months to 5 years. The IDI and CDR are brief and easy to administer and score. Both rely on the formalized gathering of a parent’s concerns and the parent’s assessment of the child’s progress in achieving milestones in several streams of development. Unfortunately, evidence in the technical manual or medical literature is insufficient to establish the validity of this instrument, and thus it is difficult to recommend the child development inventories when other parent-report instruments exist with well established validity.

Economics of developmental screening

It is useful to look at the economics of developmental screens from 2 perspectives—that of the physician and that of society. A 1998 review of the literature by the RAND group⁴⁸ concluded that 2 studies—the Elmira Prenatal/Early Infancy Project (EPEIP) and the Perry Preschool Project—followed children for sufficient time to allow for the assessment of the economic implications of intervention in children at risk for developmental delays.

Societal perspective

Both studies found that interventions led to considerable savings, with the biggest savings from decreased criminality in adulthood. The RAND group⁴⁸ estimated a government savings of $18,611 per child who underwent early intervention in the Elmira Prenatal/Early Infancy Project, and a savings of $13,289 per child for individuals receiving intervention in the Perry Preschool Project (figures in 1996 dollars.)

It is difficult to know whether these same savings would be seen in developmental intervention applied on a larger scale. Additionally, it is difficult to know how generalizable research from intervention with high-risk children is to intervention stemming from screening in a doctor’s office.

The physician perspective

Developmental screening is associated with additional costs. Dobrez et al⁴⁹ estimated the physician’s expense in administering a number of developmental screens, accounting for the administration costs and costs associated with time required to discuss abnormal results. This analysis found screens based on parental report such as the ASQ, CDI, and PEDS considerably less expensive, with a per-visit expense of approximately $12 for negative screen results and approximately $16 for positive results. Tests requiring the direct elicitation of skills from children such as the Denver–II and BINS had an estimated cost of $55.12 and $22.22 for normal screens, respectively, and $59.57 and $26.67 for abnormal screens.⁴⁹ Medicaid reimbursement varies by state; information can be obtained though the Center for Medicaid/Medicare website. Private payers may or may not reimburse physicians for developmental screening.

CORRESPONDENCE
Sutton Hamilton, MD, Underwood-Memorial Family Medicine Residency, 35 Oak Street, Woodbury, NJ 08033. E-mail: [email protected]

An 80-year-old woman with diabetes who has been your patient for many years is in failing health and may need dialysis for deteriorating kidney function. She refuses even to consider further evaluation.

A 37-year-old man has, according to his family, become increasingly depressed and makes comments suggesting suicidal ideation. They are afraid for his safety. He says he’s just going through a rough period and doesn’t need help.

Would you be prepared to handle instances of treatment refusal such as these? Treatment refusal can be challenging, creating conflicts among patients, families, and health care providers, and raising important ethical considerations. A patient’s autonomy may be undermined if her wishes are overridden. Inappropriately confining, restraining, or treating patients may cause harm. Failing to obtain a surrogate when indicated may result in a missed opportunity to benefit a patient. Refusal of treatment, when unaddressed or mishandled, may lead to patient dissatisfaction, substandard care, increased litigation, or disparities in care.

Clearer guidelines are needed to help clinicians evaluate and manage patients who refuse treatment. Building on previous work in treatment refusal, informed consent, and competency theory, we propose an approach to treatment refusal that provides 3 unique contributions:

• First, our model integrates medical and psychiatric treatment refusal practices—usually found in separate literature bases—into one model.
• Second, it emphasizes that evaluations of both decisional capacity and dangerousness (both defined later) are crucial to determining the appropriate response to treatment refusal.
• Third, it provides concrete guidance for how to decide between 3 actions: 1) respect the treatment refusal, 2) obtain a surrogate, or 3) mandate hospitalization and possibly treatment.

How to assess and manage treatment refusal

Step 1: Evaluate both decisional capacity and dangerousness

Grisso and Appelbaum have described an empirically tested model of how to evaluate decisional capacity.¹Decisional capacity refers to the ability to make a choice about treatment, and it is determined by the presence and extent of functional abilities, which are hierarchical, from the simplest to the most complex:

1. Making a choice (“I’d like to have the cardiac catheterization”)
2. Understanding relevant details, such as diagnosis, prognosis, the benefits and burdens of different treatment alternatives, and what will happen without treatment
3. Appreciating that the relevant details apply to oneself and will mean something for one’s own future
4. Rationally describing why a choice was made (such as explaining why one would prefer a particular set of risks, benefits, or burdens from one treatment alternative over another).

Many factors may interfere with these abilities and they should be assessed,¹ but additional discussion is beyond the scope of this article.

Not all patients with mental illness have impaired decisional capacity. On the contrary, there is significant variability in the decisional capacity of people with serious mental illness.² One instrument to evaluate decisional capacity for treatment decisions has been studied, but time constraints may limit its widespread application in clinical practice.³

Dangerousness in the clinical setting is generally defined as the intent to harm oneself or others, creating imminent risk. For the purposes of our model, this will be called “psychiatric dangerousness.” Other sources describe the assessment of psychiatric dangerousness in more detail,⁴ but the assessment typically includes a thorough psychosocial history, an evaluation for mental illness, a determination of risk factors for suicide, and often corroborating history from family or friends. “Medical dangerousness” is defined as the risk of morbidity or mortality that accompanies medical intervention or non-intervention.

In cases of treatment refusal, explicitly assess both decisional capacity and dangerousness. There are 3 benefits in doing so. First, it helps avoid the tendency to assess dangerousness only in the psychiatric context and decisional capacity in the general medical context. Second, it provides a useful way to approach treatment refusal when the cause of symptoms or complaints is ambiguous. Third, it helps when a patient exhibits both medical and psychiatric symptoms of illness.

Step 2: Determine the need for involuntary hospitalization and treatment

The ideal threshold for involuntary confinement is the point at which those who will harm themselves or others are confined and protected, while those who will not harm themselves or others are not. Determining the ideal threshold for involuntary treatment is difficult. Besides the challenges in predicting dangerousness,⁵ this determination involves a balance between potentially competing goals: respecting individual liberties, enhancing quality of life, and protecting patients and others from harm.

In general, there is greater justification for involuntary hospitalization with increasing “psychiatric dangerousness.” States vary on what requirements must be met for involuntary psychiatric hospitalization. Many jurisdictions have additional requirements to force psychiatric treatment; in some jurisdictions, forcing psychiatric treatment is not permitted.

Step 3: Determine the need for a surrogate decision-maker

The strength of the case for surrogate decision-making increases as decisional capacity decreases. A surrogate decision-maker is the person authorized to make decisions for a person who is not fully autonomous because of impaired decisional capacity. The ethical justification for obtaining a surrogate is to respect the patient’s prior ability to be informed and make a choice. Some patients share decision-making with other family or friends and this should be respected.

In our view, a surrogate should be obtained for a patient with impaired decisional capacity even when significant “psychiatric dangerousness” is present and involuntary hospitalization or treatment is pursued. The principle of equal respect for persons supports the view that since incompetent patients with medical problems are afforded a surrogate, so should incompetent patients with psychiatric problems.

Some might argue that the judge ordering the mandatory hospitalization or treatment is the surrogate. However, others who know the patient better and are more familiar with their values are more likely to provide authentic substituted judgment. At the same time, safety concerns for the patient (in the case of suicidal intent) or others (in the case of homicidal intent) require that surrogate decision-making be restricted. Surprisingly, no law or regulation in the US, to our knowledge, mandates appointing a surrogate for a patient who is involuntarily hospitalized or treated.

Managing treatment refusal in practice

Evaluating decisional capacity and dangerousness leads to 3 possible decisions: 1) respect the treatment refusal, 2) obtain a surrogate, or 3) mandate hospitalization and possibly treatment. FIGURES 1 AND 2 depict such decisions for psychiatric and medical dangerousness, respectively. The important question during evaluation is not, “Is there decisional capacity or dangerousness?” but is rather, “How much decisional capacity or dangerousness is present?” Even if different evaluators agree which decision-making abilities are present or how much psychiatric dangerousness exists, a value judgment must be made to decide the threshold at which a surrogate is obtained or the court is petitioned for involuntary hospitalization or treatment.

Similarities in the assessments of medical and psychiatric dangerousness.

When a patient exhibits adequate decisional capacity and insufficient dangerousness of either type, treatment refusal is respected. When decisional capacity is judged to be impaired, a surrogate should be obtained regardless of the type of dangerousness that is present.

FIGURE 1
Decisional capacity and psychiatric dangerousness

FIGURE 2
Decisional capacity and medical dangerousness

Decisional capacity

Differences in the assessments. Two boxes in the figures deserve comment. First, the bottom right box of FIGURE 1 recommends a departure from current practice. As described earlier, we recommend obtaining a surrogate for patients who have impaired decisional capacity and are involuntarily hospitalized for psychiatric dangerousness. Second, in the bottom left box of FIGURE 2, treatment refusal by a patient who has decisional capacity and “medical dangerousness” may be respected or overridden depending on contextual factors. The long history of respect for liberty, and the requirement not to invade another’s body without consent generally supports respecting treatment refusal.

When decisions may be overridden in a patient with adequate decisional capacity and medical dangerousness. During a public health emergency, such as a tuberculosis or SARS outbreak, ensuring the public’s safety may outweigh respect for individual liberties. When someone with tuberculosis refuses treatment and has adequate decisional capacity, legal precedent and ethical justification exist to defend involuntary confinement or treatment in certain circumstances.⁶

When the threshold for adequate decisional capacity changes based on the level of medical dangerousness. With increasing medical dangerousness, a given level of decisional capacity may be regarded as inadequate, and treatment refusal may be appropriately questioned and consideration given to naming a surrogate.^7,8 Alternatively, when there is little “medical dangerousness,” less decisional capacity may be required for a treatment refusal to be respected. This approach is controversial because it involves a modifiable notion of decisional capacity.⁹

In addition, this approach is not appropriate in all contexts. For example, in patients who are imminently dying with irreversible terminal illness, “medical dangerousness” may be very high, but the threshold for adequate decisional capacity should not necessarily be very high.

Dealing with uncertainty

Sometimes the degree of “medical dangerousness” is difficult to quantify, in part because the diagnosis may be uncertain; or even when the diagnosis is known, prognostication may be difficult.¹⁰

In instances of uncertainty, considering the possibility that there may be a serious underlying condition is important both medically (in case immediate intervention can prevent a negative outcome) and ethically (to benefit the patient and preserve autonomy by preventing morbidity that may be impairing). Thus, shifting the standard for decisional capacity to require a higher level of understanding and appreciation may be justified.

In such cases, even though a patient has some level of decisional capacity, a surrogate may be needed. One approach might be to attempt shared decision-making between the patient and surrogate, although ultimate decision-making should be left to the surrogate.

Careful documentation is important

As with other medical issues, in cases of treatment refusal, thoroughly document the process, whether or not treatment refusal is ultimately honored. Note findings from the evaluation including decisional capacity and medical and psychiatric dangerousness, thinking associated with the assessment, and specific management plans.

Record any decision for involuntary hospitalization or treatment because of psychiatric dangerousness or the need for a surrogate decision-maker because of impaired decisional capacity. Finally, describe your reasons for a course of action in the special situations noted above.

Benefits of this model

This approach to treatment refusal is consistent and involves clear standards and processes for evaluation, regardless of setting, problem, type of patient, or practitioner. It facilitates respect for persons, equal treatment independent of diagnosis, and appropriate involvement of surrogate decision-makers and the courts.

Acknowledgments

Earlier versions of this work have been presented at the following meetings:

Bekelman D, Carrese J (2003). Treatment refusal and decisional competence assessment. Concurrent Session, Clinical Ethics Consultation: First International Summit, Cleveland, Ohio.

Bekelman D (2002). Treatment refusal: Conceptual models and clinical approaches. Workshop, 49th annual meeting of the Academy of Psychosomatic Medicine, Tucson, Arizona.

CORRESPONDENCE
David Bekelman, MD, MPH, Division of General Internal Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East 9th Avenue, B180, Denver, CO 80262. E-mail: [email protected]

An 80-year-old woman with diabetes who has been your patient for many years is in failing health and may need dialysis for deteriorating kidney function. She refuses even to consider further evaluation.

A 37-year-old man has, according to his family, become increasingly depressed and makes comments suggesting suicidal ideation. They are afraid for his safety. He says he’s just going through a rough period and doesn’t need help.

Would you be prepared to handle instances of treatment refusal such as these? Treatment refusal can be challenging, creating conflicts among patients, families, and health care providers, and raising important ethical considerations. A patient’s autonomy may be undermined if her wishes are overridden. Inappropriately confining, restraining, or treating patients may cause harm. Failing to obtain a surrogate when indicated may result in a missed opportunity to benefit a patient. Refusal of treatment, when unaddressed or mishandled, may lead to patient dissatisfaction, substandard care, increased litigation, or disparities in care.

Clearer guidelines are needed to help clinicians evaluate and manage patients who refuse treatment. Building on previous work in treatment refusal, informed consent, and competency theory, we propose an approach to treatment refusal that provides 3 unique contributions:

• First, our model integrates medical and psychiatric treatment refusal practices—usually found in separate literature bases—into one model.
• Second, it emphasizes that evaluations of both decisional capacity and dangerousness (both defined later) are crucial to determining the appropriate response to treatment refusal.
• Third, it provides concrete guidance for how to decide between 3 actions: 1) respect the treatment refusal, 2) obtain a surrogate, or 3) mandate hospitalization and possibly treatment.

How to assess and manage treatment refusal

Step 1: Evaluate both decisional capacity and dangerousness

Grisso and Appelbaum have described an empirically tested model of how to evaluate decisional capacity.¹Decisional capacity refers to the ability to make a choice about treatment, and it is determined by the presence and extent of functional abilities, which are hierarchical, from the simplest to the most complex:

1. Making a choice (“I’d like to have the cardiac catheterization”)
2. Understanding relevant details, such as diagnosis, prognosis, the benefits and burdens of different treatment alternatives, and what will happen without treatment
3. Appreciating that the relevant details apply to oneself and will mean something for one’s own future
4. Rationally describing why a choice was made (such as explaining why one would prefer a particular set of risks, benefits, or burdens from one treatment alternative over another).

Many factors may interfere with these abilities and they should be assessed,¹ but additional discussion is beyond the scope of this article.

Not all patients with mental illness have impaired decisional capacity. On the contrary, there is significant variability in the decisional capacity of people with serious mental illness.² One instrument to evaluate decisional capacity for treatment decisions has been studied, but time constraints may limit its widespread application in clinical practice.³

Dangerousness in the clinical setting is generally defined as the intent to harm oneself or others, creating imminent risk. For the purposes of our model, this will be called “psychiatric dangerousness.” Other sources describe the assessment of psychiatric dangerousness in more detail,⁴ but the assessment typically includes a thorough psychosocial history, an evaluation for mental illness, a determination of risk factors for suicide, and often corroborating history from family or friends. “Medical dangerousness” is defined as the risk of morbidity or mortality that accompanies medical intervention or non-intervention.

In cases of treatment refusal, explicitly assess both decisional capacity and dangerousness. There are 3 benefits in doing so. First, it helps avoid the tendency to assess dangerousness only in the psychiatric context and decisional capacity in the general medical context. Second, it provides a useful way to approach treatment refusal when the cause of symptoms or complaints is ambiguous. Third, it helps when a patient exhibits both medical and psychiatric symptoms of illness.

Step 2: Determine the need for involuntary hospitalization and treatment

The ideal threshold for involuntary confinement is the point at which those who will harm themselves or others are confined and protected, while those who will not harm themselves or others are not. Determining the ideal threshold for involuntary treatment is difficult. Besides the challenges in predicting dangerousness,⁵ this determination involves a balance between potentially competing goals: respecting individual liberties, enhancing quality of life, and protecting patients and others from harm.

In general, there is greater justification for involuntary hospitalization with increasing “psychiatric dangerousness.” States vary on what requirements must be met for involuntary psychiatric hospitalization. Many jurisdictions have additional requirements to force psychiatric treatment; in some jurisdictions, forcing psychiatric treatment is not permitted.

Step 3: Determine the need for a surrogate decision-maker

The strength of the case for surrogate decision-making increases as decisional capacity decreases. A surrogate decision-maker is the person authorized to make decisions for a person who is not fully autonomous because of impaired decisional capacity. The ethical justification for obtaining a surrogate is to respect the patient’s prior ability to be informed and make a choice. Some patients share decision-making with other family or friends and this should be respected.

In our view, a surrogate should be obtained for a patient with impaired decisional capacity even when significant “psychiatric dangerousness” is present and involuntary hospitalization or treatment is pursued. The principle of equal respect for persons supports the view that since incompetent patients with medical problems are afforded a surrogate, so should incompetent patients with psychiatric problems.

Some might argue that the judge ordering the mandatory hospitalization or treatment is the surrogate. However, others who know the patient better and are more familiar with their values are more likely to provide authentic substituted judgment. At the same time, safety concerns for the patient (in the case of suicidal intent) or others (in the case of homicidal intent) require that surrogate decision-making be restricted. Surprisingly, no law or regulation in the US, to our knowledge, mandates appointing a surrogate for a patient who is involuntarily hospitalized or treated.

Managing treatment refusal in practice

Evaluating decisional capacity and dangerousness leads to 3 possible decisions: 1) respect the treatment refusal, 2) obtain a surrogate, or 3) mandate hospitalization and possibly treatment. FIGURES 1 AND 2 depict such decisions for psychiatric and medical dangerousness, respectively. The important question during evaluation is not, “Is there decisional capacity or dangerousness?” but is rather, “How much decisional capacity or dangerousness is present?” Even if different evaluators agree which decision-making abilities are present or how much psychiatric dangerousness exists, a value judgment must be made to decide the threshold at which a surrogate is obtained or the court is petitioned for involuntary hospitalization or treatment.

Similarities in the assessments of medical and psychiatric dangerousness.

When a patient exhibits adequate decisional capacity and insufficient dangerousness of either type, treatment refusal is respected. When decisional capacity is judged to be impaired, a surrogate should be obtained regardless of the type of dangerousness that is present.

FIGURE 1
Decisional capacity and psychiatric dangerousness

FIGURE 2
Decisional capacity and medical dangerousness

Decisional capacity

Differences in the assessments. Two boxes in the figures deserve comment. First, the bottom right box of FIGURE 1 recommends a departure from current practice. As described earlier, we recommend obtaining a surrogate for patients who have impaired decisional capacity and are involuntarily hospitalized for psychiatric dangerousness. Second, in the bottom left box of FIGURE 2, treatment refusal by a patient who has decisional capacity and “medical dangerousness” may be respected or overridden depending on contextual factors. The long history of respect for liberty, and the requirement not to invade another’s body without consent generally supports respecting treatment refusal.

When decisions may be overridden in a patient with adequate decisional capacity and medical dangerousness. During a public health emergency, such as a tuberculosis or SARS outbreak, ensuring the public’s safety may outweigh respect for individual liberties. When someone with tuberculosis refuses treatment and has adequate decisional capacity, legal precedent and ethical justification exist to defend involuntary confinement or treatment in certain circumstances.⁶

When the threshold for adequate decisional capacity changes based on the level of medical dangerousness. With increasing medical dangerousness, a given level of decisional capacity may be regarded as inadequate, and treatment refusal may be appropriately questioned and consideration given to naming a surrogate.^7,8 Alternatively, when there is little “medical dangerousness,” less decisional capacity may be required for a treatment refusal to be respected. This approach is controversial because it involves a modifiable notion of decisional capacity.⁹

In addition, this approach is not appropriate in all contexts. For example, in patients who are imminently dying with irreversible terminal illness, “medical dangerousness” may be very high, but the threshold for adequate decisional capacity should not necessarily be very high.

Dealing with uncertainty

Sometimes the degree of “medical dangerousness” is difficult to quantify, in part because the diagnosis may be uncertain; or even when the diagnosis is known, prognostication may be difficult.¹⁰

In instances of uncertainty, considering the possibility that there may be a serious underlying condition is important both medically (in case immediate intervention can prevent a negative outcome) and ethically (to benefit the patient and preserve autonomy by preventing morbidity that may be impairing). Thus, shifting the standard for decisional capacity to require a higher level of understanding and appreciation may be justified.

In such cases, even though a patient has some level of decisional capacity, a surrogate may be needed. One approach might be to attempt shared decision-making between the patient and surrogate, although ultimate decision-making should be left to the surrogate.

Careful documentation is important

As with other medical issues, in cases of treatment refusal, thoroughly document the process, whether or not treatment refusal is ultimately honored. Note findings from the evaluation including decisional capacity and medical and psychiatric dangerousness, thinking associated with the assessment, and specific management plans.

Record any decision for involuntary hospitalization or treatment because of psychiatric dangerousness or the need for a surrogate decision-maker because of impaired decisional capacity. Finally, describe your reasons for a course of action in the special situations noted above.

Benefits of this model

This approach to treatment refusal is consistent and involves clear standards and processes for evaluation, regardless of setting, problem, type of patient, or practitioner. It facilitates respect for persons, equal treatment independent of diagnosis, and appropriate involvement of surrogate decision-makers and the courts.

Acknowledgments

Earlier versions of this work have been presented at the following meetings:

Bekelman D, Carrese J (2003). Treatment refusal and decisional competence assessment. Concurrent Session, Clinical Ethics Consultation: First International Summit, Cleveland, Ohio.

Bekelman D (2002). Treatment refusal: Conceptual models and clinical approaches. Workshop, 49th annual meeting of the Academy of Psychosomatic Medicine, Tucson, Arizona.

CORRESPONDENCE
David Bekelman, MD, MPH, Division of General Internal Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East 9th Avenue, B180, Denver, CO 80262. E-mail: [email protected]

An 80-year-old woman with diabetes who has been your patient for many years is in failing health and may need dialysis for deteriorating kidney function. She refuses even to consider further evaluation.

A 37-year-old man has, according to his family, become increasingly depressed and makes comments suggesting suicidal ideation. They are afraid for his safety. He says he’s just going through a rough period and doesn’t need help.

Would you be prepared to handle instances of treatment refusal such as these? Treatment refusal can be challenging, creating conflicts among patients, families, and health care providers, and raising important ethical considerations. A patient’s autonomy may be undermined if her wishes are overridden. Inappropriately confining, restraining, or treating patients may cause harm. Failing to obtain a surrogate when indicated may result in a missed opportunity to benefit a patient. Refusal of treatment, when unaddressed or mishandled, may lead to patient dissatisfaction, substandard care, increased litigation, or disparities in care.

Clearer guidelines are needed to help clinicians evaluate and manage patients who refuse treatment. Building on previous work in treatment refusal, informed consent, and competency theory, we propose an approach to treatment refusal that provides 3 unique contributions:

• First, our model integrates medical and psychiatric treatment refusal practices—usually found in separate literature bases—into one model.
• Second, it emphasizes that evaluations of both decisional capacity and dangerousness (both defined later) are crucial to determining the appropriate response to treatment refusal.
• Third, it provides concrete guidance for how to decide between 3 actions: 1) respect the treatment refusal, 2) obtain a surrogate, or 3) mandate hospitalization and possibly treatment.

How to assess and manage treatment refusal

Step 1: Evaluate both decisional capacity and dangerousness

Grisso and Appelbaum have described an empirically tested model of how to evaluate decisional capacity.¹Decisional capacity refers to the ability to make a choice about treatment, and it is determined by the presence and extent of functional abilities, which are hierarchical, from the simplest to the most complex:

1. Making a choice (“I’d like to have the cardiac catheterization”)
2. Understanding relevant details, such as diagnosis, prognosis, the benefits and burdens of different treatment alternatives, and what will happen without treatment
3. Appreciating that the relevant details apply to oneself and will mean something for one’s own future
4. Rationally describing why a choice was made (such as explaining why one would prefer a particular set of risks, benefits, or burdens from one treatment alternative over another).

Many factors may interfere with these abilities and they should be assessed,¹ but additional discussion is beyond the scope of this article.

Not all patients with mental illness have impaired decisional capacity. On the contrary, there is significant variability in the decisional capacity of people with serious mental illness.² One instrument to evaluate decisional capacity for treatment decisions has been studied, but time constraints may limit its widespread application in clinical practice.³

Dangerousness in the clinical setting is generally defined as the intent to harm oneself or others, creating imminent risk. For the purposes of our model, this will be called “psychiatric dangerousness.” Other sources describe the assessment of psychiatric dangerousness in more detail,⁴ but the assessment typically includes a thorough psychosocial history, an evaluation for mental illness, a determination of risk factors for suicide, and often corroborating history from family or friends. “Medical dangerousness” is defined as the risk of morbidity or mortality that accompanies medical intervention or non-intervention.

In cases of treatment refusal, explicitly assess both decisional capacity and dangerousness. There are 3 benefits in doing so. First, it helps avoid the tendency to assess dangerousness only in the psychiatric context and decisional capacity in the general medical context. Second, it provides a useful way to approach treatment refusal when the cause of symptoms or complaints is ambiguous. Third, it helps when a patient exhibits both medical and psychiatric symptoms of illness.

Step 2: Determine the need for involuntary hospitalization and treatment

The ideal threshold for involuntary confinement is the point at which those who will harm themselves or others are confined and protected, while those who will not harm themselves or others are not. Determining the ideal threshold for involuntary treatment is difficult. Besides the challenges in predicting dangerousness,⁵ this determination involves a balance between potentially competing goals: respecting individual liberties, enhancing quality of life, and protecting patients and others from harm.

In general, there is greater justification for involuntary hospitalization with increasing “psychiatric dangerousness.” States vary on what requirements must be met for involuntary psychiatric hospitalization. Many jurisdictions have additional requirements to force psychiatric treatment; in some jurisdictions, forcing psychiatric treatment is not permitted.

Step 3: Determine the need for a surrogate decision-maker

The strength of the case for surrogate decision-making increases as decisional capacity decreases. A surrogate decision-maker is the person authorized to make decisions for a person who is not fully autonomous because of impaired decisional capacity. The ethical justification for obtaining a surrogate is to respect the patient’s prior ability to be informed and make a choice. Some patients share decision-making with other family or friends and this should be respected.

In our view, a surrogate should be obtained for a patient with impaired decisional capacity even when significant “psychiatric dangerousness” is present and involuntary hospitalization or treatment is pursued. The principle of equal respect for persons supports the view that since incompetent patients with medical problems are afforded a surrogate, so should incompetent patients with psychiatric problems.

Some might argue that the judge ordering the mandatory hospitalization or treatment is the surrogate. However, others who know the patient better and are more familiar with their values are more likely to provide authentic substituted judgment. At the same time, safety concerns for the patient (in the case of suicidal intent) or others (in the case of homicidal intent) require that surrogate decision-making be restricted. Surprisingly, no law or regulation in the US, to our knowledge, mandates appointing a surrogate for a patient who is involuntarily hospitalized or treated.

Managing treatment refusal in practice

Evaluating decisional capacity and dangerousness leads to 3 possible decisions: 1) respect the treatment refusal, 2) obtain a surrogate, or 3) mandate hospitalization and possibly treatment. FIGURES 1 AND 2 depict such decisions for psychiatric and medical dangerousness, respectively. The important question during evaluation is not, “Is there decisional capacity or dangerousness?” but is rather, “How much decisional capacity or dangerousness is present?” Even if different evaluators agree which decision-making abilities are present or how much psychiatric dangerousness exists, a value judgment must be made to decide the threshold at which a surrogate is obtained or the court is petitioned for involuntary hospitalization or treatment.

Similarities in the assessments of medical and psychiatric dangerousness.

When a patient exhibits adequate decisional capacity and insufficient dangerousness of either type, treatment refusal is respected. When decisional capacity is judged to be impaired, a surrogate should be obtained regardless of the type of dangerousness that is present.

FIGURE 1
Decisional capacity and psychiatric dangerousness

FIGURE 2
Decisional capacity and medical dangerousness

Decisional capacity

Differences in the assessments. Two boxes in the figures deserve comment. First, the bottom right box of FIGURE 1 recommends a departure from current practice. As described earlier, we recommend obtaining a surrogate for patients who have impaired decisional capacity and are involuntarily hospitalized for psychiatric dangerousness. Second, in the bottom left box of FIGURE 2, treatment refusal by a patient who has decisional capacity and “medical dangerousness” may be respected or overridden depending on contextual factors. The long history of respect for liberty, and the requirement not to invade another’s body without consent generally supports respecting treatment refusal.

When decisions may be overridden in a patient with adequate decisional capacity and medical dangerousness. During a public health emergency, such as a tuberculosis or SARS outbreak, ensuring the public’s safety may outweigh respect for individual liberties. When someone with tuberculosis refuses treatment and has adequate decisional capacity, legal precedent and ethical justification exist to defend involuntary confinement or treatment in certain circumstances.⁶

When the threshold for adequate decisional capacity changes based on the level of medical dangerousness. With increasing medical dangerousness, a given level of decisional capacity may be regarded as inadequate, and treatment refusal may be appropriately questioned and consideration given to naming a surrogate.^7,8 Alternatively, when there is little “medical dangerousness,” less decisional capacity may be required for a treatment refusal to be respected. This approach is controversial because it involves a modifiable notion of decisional capacity.⁹

In addition, this approach is not appropriate in all contexts. For example, in patients who are imminently dying with irreversible terminal illness, “medical dangerousness” may be very high, but the threshold for adequate decisional capacity should not necessarily be very high.

Dealing with uncertainty

Sometimes the degree of “medical dangerousness” is difficult to quantify, in part because the diagnosis may be uncertain; or even when the diagnosis is known, prognostication may be difficult.¹⁰

In instances of uncertainty, considering the possibility that there may be a serious underlying condition is important both medically (in case immediate intervention can prevent a negative outcome) and ethically (to benefit the patient and preserve autonomy by preventing morbidity that may be impairing). Thus, shifting the standard for decisional capacity to require a higher level of understanding and appreciation may be justified.

In such cases, even though a patient has some level of decisional capacity, a surrogate may be needed. One approach might be to attempt shared decision-making between the patient and surrogate, although ultimate decision-making should be left to the surrogate.

Careful documentation is important

As with other medical issues, in cases of treatment refusal, thoroughly document the process, whether or not treatment refusal is ultimately honored. Note findings from the evaluation including decisional capacity and medical and psychiatric dangerousness, thinking associated with the assessment, and specific management plans.

Record any decision for involuntary hospitalization or treatment because of psychiatric dangerousness or the need for a surrogate decision-maker because of impaired decisional capacity. Finally, describe your reasons for a course of action in the special situations noted above.

Benefits of this model

This approach to treatment refusal is consistent and involves clear standards and processes for evaluation, regardless of setting, problem, type of patient, or practitioner. It facilitates respect for persons, equal treatment independent of diagnosis, and appropriate involvement of surrogate decision-makers and the courts.

Acknowledgments

Earlier versions of this work have been presented at the following meetings:

Bekelman D, Carrese J (2003). Treatment refusal and decisional competence assessment. Concurrent Session, Clinical Ethics Consultation: First International Summit, Cleveland, Ohio.

Bekelman D (2002). Treatment refusal: Conceptual models and clinical approaches. Workshop, 49th annual meeting of the Academy of Psychosomatic Medicine, Tucson, Arizona.

CORRESPONDENCE
David Bekelman, MD, MPH, Division of General Internal Medicine, University of Colorado at Denver and Health Sciences Center, 4200 East 9th Avenue, B180, Denver, CO 80262. E-mail: [email protected]

Despite advanced detection methods, ectopic pregnancy may be missed in 40% to 50% of patients on an initial visit.¹ Most women with ectopic pregnancy have no risk factors (TABLE 1),^2-5 and the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding is absent in more than half of cases.

Early diagnosis not only decreases maternal mortality and morbidity; it also helps preserve future reproductive capacity—only one third of women with ectopic pregnancy have subsequent live births.²

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.⁶ Using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal. In part 2 of this article (coming in the June 2006 Journal of Family Practice), we provide a decision protocol for management of ectopic pregnancy.

TABLE 1
Risk factors for ectopic pregnancy

Evaluation

Clinical features of ectopic pregnancy highly variable

No single clinical feature accurately indicates ectopic pregnancy. Less than half of women with ectopic pregnancy exhibit the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding.¹ And, unfortunately, these features are seen commonly in patients with both viable (50%) and nonviable (25%) intrauterine pregnancies, as well as in threatened abortion, cervical irritation, infection, and trauma.⁷

Set a low threshold for suspicion. For any woman of childbearing age with abdominal pain and vaginal bleeding, consider pregnancy and take steps to rule out ectopic pregnancy. Abdominal pain and vaginal bleeding are highly sensitive for ectopic pregnancy but are not specific for the disorder (TABLE 2).^8-17 Pain located in the hypogastrium or iliac fossa may be mild to severe. Vaginal bleeding, present in 50% to 80% of patients with ectopic pregnancy, can be mistaken for a normal menstrual period.^2,6 Pregnancy-associated symptoms of nausea and vomiting, breast tenderness, and fatigue may be present.

Lower abdominal and adnexal tenderness can be elicited in most women with ectopic pregnancy. Cervical motion tenderness, peritoneal signs, and adnexal masses are most specific for ectopic pregnancy, but are not sensitive.⁸ An adnexal mass is palpable in less than 10% of cases; when it is detected, one third of patients will have a contralateral ectopic pregnancy on ultrasonography.¹⁸ Symptoms of hemodynamic compromise (orthostasis, hypotension, shock) are becoming uncommon with earlier diagnosis of ectopic pregnancy, facilitated by improved detection methods.

TABLE 2
Significance of features associated with ectopic pregnancy

Laboratory tests

In an early normal pregnancy, the beta-human chorionic gonadotropin (β-hCG) level doubles every 1.8 to 3 days, rising to 1000 mIU/mL IRP (International Reference Preparation, measured by radioimmunoassay) by 5 weeks, to 2500 mIU/mL by 6 weeks, and to 13,000 mIU/mL (±3000) by 7 weeks. A single quantitative β-hCG level is not always helpful, as it can range from less than 100 mIU/mL to greater than 50,000 mIU/mL with both ruptured and unruptured ectopic pregnancies.¹⁹

Rethinking the rate of rise in β-hCG. The oft-quoted maxim that ectopic pregnancy or impending miscarriage is associated with a rise in β-hCG of less than 66% in 48 hours arose from a 1981 study that included only 20 women and that was based on an 85% confidence interval (CI).²⁰ A recent study of 287 women suggests that the minimal expected rise in 2 days for a viable intrauterine pregnancy (based on a 99% CI) should be at least 53%.²¹

Combining β-hCG levels and ultrasound findings to improve diagnosis. Because the exact gestational age is often unknown in women presenting with features of ectopic pregnancy, the β-hCG level is used to determine whether a gestational sac can be identified on ultrasound. With a β-hCG level of 6500 mIU/mL, a gestational sac should be visible on abdominal ultrasound in the uterus of a woman with an intrauterine pregnancy; the sac should be absent in ectopic pregnancy. This β-hCG level is designated the discriminatory zone.²²

With a high-resolution transvaginal ultrasound (TVUS), the gestational sac of a normal single intrauterine pregnancy should be visible at a β-hCG level above 1000–1500 mIU/mL, depending on equipment and technical expertise.^2,7 In multiple gestations the discriminatory zone is observed to be above 2300 mIU/mL.² Various ultrasonography findings have been combined with β-hCG levels to more accurately diagnose ectopic pregnancy (TABLE 2 and FIGURE).

Serial β-hCG measurements. If TVUS findings are indeterminate, serial measurements of β-hCG levels at 48-hour intervals may be useful in managing suspected ectopic pregnancy. Dart et al¹⁷ found that a rise in β-hCG level of 66% or more was usually associated with a viable intrauterine pregnancy, though 22% of women in that study had an ectopic pregnancy. Mol et al¹³ found similar results using a cutoff of a β-hCG level rise of 50% or more; 35% had an ectopic pregnancy. Increases in the β-hCG level less than these cutoffs almost always indicated an abnormal pregnancy, and about half of these women had an ectopic pregnancy.^13,17 Also a fall in the β-hCG level by less than 50% was almost always associated with an abnormal pregnancy, but only 19% of these women had an ectopic pregnancy. ^13,17 Alternatively, decreases in β-hCG level of greater than 50% reduced the chance that patients had an ectopic pregnancy to less than 3%.^13,17

Scope of the problem

Ectopic pregnancy is defined as the implantation of the fertilized egg that occurs outside the uterine cavity. It is practically synonymous with tubal pregnancy, as 97% occur in the Fallopian tube.^6,23 Ectopic pregnancy occurs in 2% of all pregnancies in the United States, affecting more than 100,000 patients each year. It is a leading cause of pregnancy-related death in the first trimester,² with a yearly monetary impact of greater than 1 billion dollars. The incidence has increased almost six-fold since 1970 due to delayed child-bearing, rising prevalence of sexually transmitted diseases, and sterilization procedures.⁶

FIGURE
Diagnostic protocol with high sensitivity and specificity for ectopic pregnancy

Serum progesterone levels may have limited usefulness. Serum progesterone measurements are not considered accurate enough to diagnose ectopic pregnancy.²⁴ However, progesterone levels may be helpful if they are either very high or very low. Levels less than 22 ng/mL have a sensitivity of 100% for ectopic pregnancy.²⁵ Only 5 of 1615 patients (0.3%) in 13 studies with progesterone levels below 5 ng/mL had a viable intrauterine pregnancy.²⁴ By establishing the low likelihood of a viable intrauterine pregnancy, serum progesterone measurements may also be useful when β-hCG levels have reached 1000–1500 mIU/mL and the TVUS is equivocal.²⁵

When D&C may help. Dilation and curettage (D&C) is an option for patients with an indeterminate ultrasound result and progesterone levels less than 5 ng/mL, as it can rule out an ectopic pregnancy with only a small chance of interrupting a viable intrauterine pregnancy. The presence of chorionic villi rules out an ectopic pregnancy. In the absence of villi, if β-hCG levels subsequently plateau or increase, it is presumptive of ectopic pregnancy. Chorionic villous sampling by pipelle curette has both insufficient sensitivity and predictive value in diagnosing ectopic pregnancy, and should not be considered a substitute for D&C.²⁶

Other tests that have limited use. Patients with ectopic pregnancy may have elevated serum markers of smooth muscle destruction such as creatinine phosphokinase (CPK), myoglobin, and smooth muscle heavy-chain myosin (SMHC). However, these tests are of limited value in diagnosing ectopic pregnancy.²⁷ SMHC may be of use in evaluating pregnancies less than 5 weeks’ gestation when the TVUS is not diagnostic. Serum vascular endothelial growth factor is another marker elevated in women with ectopic pregnancy; levels greater than 200 pg/mL distinguish ectopic pregnancy from intrauterine pregnancy (sensitivity=60%, specificity=90%).²⁸

Imaging

In normal pregnancies, a gestational sac is seen on TVUS between 4 and 5 weeks’ gestation;²⁹ the yolk sac is visible at around 6 weeks; and an embryo can be detected between 6 and 7 weeks. A gestational sac greater than 10 mm in diameter without a yolk sac, or greater than 25 mm without an embryo, indicates an abnormal regnancy.^9,29 Presence of an intrauterine pregnancy on ultrasound effectively rules out ectopic pregnancy because heterotopic pregnancy is rare (1 in 2600–30,000 pregnancies).³⁰ Hormonal changes associated with pregnancy result in a uterine endometrial fluid collection (pseudo-sac) in 8% of ectopic pregnancies.³¹

Specific diagnostic finding for ectopic pregnancy. A gestational sac visible on ultrasound with a yolk sac or fetal pole outside the endometrial cavity (TABLE 2) is diagnostic of ectopic pregnancy. The initial ultrasound is indeterminate in 15% to 20% of women with clinical features suggesting ectopic pregnancy.^14,15 Dart et al³² developed a subclassification system of indeterminate ultrasound including 5 categories that stratify the risk of ectopic pregnancy (TABLE 3).

Endometrial stripe thickness of dubious value. For patients with an empty uterus on TVUS and a β-hCG level below the discriminatory zone, endometrial stripe thickness may identify an abnormal pregnancy. In a retrospective study of 117 patients with β-hCG levels less than 1500 mIU/mL, stripe thickness <6 mm had a sensitivity of 100% in identifying ectopic pregnancy or miscarriage; at >13 mm, it had a specificity of 100%.³³

Two recent studies, however, have called into question the value of stripe thickness in identifying ectopic pregnancy. One suggested it was of little value with β-hCG levels <1500 mIU/mL,³⁴ and the other concluded its predictive value for ectopic pregnancy and the likelihood of obtaining chorionic villi on D&C is confined to β-hCG values at or below 1000 mIU/mL.³⁵

Color-enhanced sonography. The addition of endovaginal color-flow imaging to sonography enables exclusion of ectopic pregnancy by establishing findings consistent with a nonviable intrauterine pregnancy: an intrauterine gestational sac, nonvisualization of an adnexal mass, and absent placental blood flow (sensitivity=95%, specificity=98%).¹² Color-flow Doppler imaging shows enhanced blood flow to the affected tube. A cutoff value of 8% change in tubal blood flow has been used to diagnose ectopic pregnancy (sensitivity=85%, specificity=96%).³⁶ In cases where the gestational sac is questionable or absent, color-flow Doppler may expedite diagnosis and possibly identify candidates for expectant or medical management.

When an MRI might help. Magnetic resonance imaging (MRI), in a small study of 37 patients, allowed recognition of tubal wall enhancements and fresh tubal hematoma, and was diagnostic in 21 patients.³⁷ An MRI may be useful when precise and early diagnosis of ectopic pregnancy is imperative, such as pre-existing damage to the contralateral tube where preservation of tubal patency is paramount and when prior TVUS is inconclusive.³⁷

TABLE 3
Detecting ectopic pregnancy with ultrasound and β-hCG levels

A practical evaluation algorithm

Prediction models based on clinical presentation, which classify patients into high-, intermediate-, and low-risk groups, are useful for estimating the risk of ectopic pregnancy in first-trimester patients (FIGURE). Diagnostic pathways incorporating physical findings, quantitative β-hCG levels, and ultrasound results have been developed to manage possible ectopic pregnancy.^38,39 A protocol created by Barnhart using β-hCG and TVUS was accurate and safe when applied to women presenting in emergency settings (sensitivity=100%, specificity=99.9%).³⁰ If β-hCG levels were greater than 1500 mIU/mL, ultrasound was performed. Clinically stable patients with β-hCG levels below 1500 mIU/mL were followed with serial β-hCG levels.

A decision model comparing 6 possible diagnostic strategies that combined clinical examination, TVUS, β-hCG, serum progesterone, and D&C showed that TVUS followed by serial serum β-hCGs in those with initial nondiagnostic ultrasound scans was the most accurate and efficient model.⁴⁰ By using this strategy, all ectopic pregnancies would be detected, fewer than 1 in 100 normal pregnancies would be interrupted, and diagnostic lag would average only 1.46 days.

CORRESPONDENCE
K. Ramakrishnan, MD, Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: [email protected]

Despite advanced detection methods, ectopic pregnancy may be missed in 40% to 50% of patients on an initial visit.¹ Most women with ectopic pregnancy have no risk factors (TABLE 1),^2-5 and the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding is absent in more than half of cases.

Early diagnosis not only decreases maternal mortality and morbidity; it also helps preserve future reproductive capacity—only one third of women with ectopic pregnancy have subsequent live births.²

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.⁶ Using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal. In part 2 of this article (coming in the June 2006 Journal of Family Practice), we provide a decision protocol for management of ectopic pregnancy.

TABLE 1
Risk factors for ectopic pregnancy

Evaluation

Clinical features of ectopic pregnancy highly variable

No single clinical feature accurately indicates ectopic pregnancy. Less than half of women with ectopic pregnancy exhibit the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding.¹ And, unfortunately, these features are seen commonly in patients with both viable (50%) and nonviable (25%) intrauterine pregnancies, as well as in threatened abortion, cervical irritation, infection, and trauma.⁷

Set a low threshold for suspicion. For any woman of childbearing age with abdominal pain and vaginal bleeding, consider pregnancy and take steps to rule out ectopic pregnancy. Abdominal pain and vaginal bleeding are highly sensitive for ectopic pregnancy but are not specific for the disorder (TABLE 2).^8-17 Pain located in the hypogastrium or iliac fossa may be mild to severe. Vaginal bleeding, present in 50% to 80% of patients with ectopic pregnancy, can be mistaken for a normal menstrual period.^2,6 Pregnancy-associated symptoms of nausea and vomiting, breast tenderness, and fatigue may be present.

Lower abdominal and adnexal tenderness can be elicited in most women with ectopic pregnancy. Cervical motion tenderness, peritoneal signs, and adnexal masses are most specific for ectopic pregnancy, but are not sensitive.⁸ An adnexal mass is palpable in less than 10% of cases; when it is detected, one third of patients will have a contralateral ectopic pregnancy on ultrasonography.¹⁸ Symptoms of hemodynamic compromise (orthostasis, hypotension, shock) are becoming uncommon with earlier diagnosis of ectopic pregnancy, facilitated by improved detection methods.

TABLE 2
Significance of features associated with ectopic pregnancy

Laboratory tests

In an early normal pregnancy, the beta-human chorionic gonadotropin (β-hCG) level doubles every 1.8 to 3 days, rising to 1000 mIU/mL IRP (International Reference Preparation, measured by radioimmunoassay) by 5 weeks, to 2500 mIU/mL by 6 weeks, and to 13,000 mIU/mL (±3000) by 7 weeks. A single quantitative β-hCG level is not always helpful, as it can range from less than 100 mIU/mL to greater than 50,000 mIU/mL with both ruptured and unruptured ectopic pregnancies.¹⁹

Rethinking the rate of rise in β-hCG. The oft-quoted maxim that ectopic pregnancy or impending miscarriage is associated with a rise in β-hCG of less than 66% in 48 hours arose from a 1981 study that included only 20 women and that was based on an 85% confidence interval (CI).²⁰ A recent study of 287 women suggests that the minimal expected rise in 2 days for a viable intrauterine pregnancy (based on a 99% CI) should be at least 53%.²¹

Combining β-hCG levels and ultrasound findings to improve diagnosis. Because the exact gestational age is often unknown in women presenting with features of ectopic pregnancy, the β-hCG level is used to determine whether a gestational sac can be identified on ultrasound. With a β-hCG level of 6500 mIU/mL, a gestational sac should be visible on abdominal ultrasound in the uterus of a woman with an intrauterine pregnancy; the sac should be absent in ectopic pregnancy. This β-hCG level is designated the discriminatory zone.²²

With a high-resolution transvaginal ultrasound (TVUS), the gestational sac of a normal single intrauterine pregnancy should be visible at a β-hCG level above 1000–1500 mIU/mL, depending on equipment and technical expertise.^2,7 In multiple gestations the discriminatory zone is observed to be above 2300 mIU/mL.² Various ultrasonography findings have been combined with β-hCG levels to more accurately diagnose ectopic pregnancy (TABLE 2 and FIGURE).

Serial β-hCG measurements. If TVUS findings are indeterminate, serial measurements of β-hCG levels at 48-hour intervals may be useful in managing suspected ectopic pregnancy. Dart et al¹⁷ found that a rise in β-hCG level of 66% or more was usually associated with a viable intrauterine pregnancy, though 22% of women in that study had an ectopic pregnancy. Mol et al¹³ found similar results using a cutoff of a β-hCG level rise of 50% or more; 35% had an ectopic pregnancy. Increases in the β-hCG level less than these cutoffs almost always indicated an abnormal pregnancy, and about half of these women had an ectopic pregnancy.^13,17 Also a fall in the β-hCG level by less than 50% was almost always associated with an abnormal pregnancy, but only 19% of these women had an ectopic pregnancy. ^13,17 Alternatively, decreases in β-hCG level of greater than 50% reduced the chance that patients had an ectopic pregnancy to less than 3%.^13,17

Scope of the problem

Ectopic pregnancy is defined as the implantation of the fertilized egg that occurs outside the uterine cavity. It is practically synonymous with tubal pregnancy, as 97% occur in the Fallopian tube.^6,23 Ectopic pregnancy occurs in 2% of all pregnancies in the United States, affecting more than 100,000 patients each year. It is a leading cause of pregnancy-related death in the first trimester,² with a yearly monetary impact of greater than 1 billion dollars. The incidence has increased almost six-fold since 1970 due to delayed child-bearing, rising prevalence of sexually transmitted diseases, and sterilization procedures.⁶

FIGURE
Diagnostic protocol with high sensitivity and specificity for ectopic pregnancy

Serum progesterone levels may have limited usefulness. Serum progesterone measurements are not considered accurate enough to diagnose ectopic pregnancy.²⁴ However, progesterone levels may be helpful if they are either very high or very low. Levels less than 22 ng/mL have a sensitivity of 100% for ectopic pregnancy.²⁵ Only 5 of 1615 patients (0.3%) in 13 studies with progesterone levels below 5 ng/mL had a viable intrauterine pregnancy.²⁴ By establishing the low likelihood of a viable intrauterine pregnancy, serum progesterone measurements may also be useful when β-hCG levels have reached 1000–1500 mIU/mL and the TVUS is equivocal.²⁵

When D&C may help. Dilation and curettage (D&C) is an option for patients with an indeterminate ultrasound result and progesterone levels less than 5 ng/mL, as it can rule out an ectopic pregnancy with only a small chance of interrupting a viable intrauterine pregnancy. The presence of chorionic villi rules out an ectopic pregnancy. In the absence of villi, if β-hCG levels subsequently plateau or increase, it is presumptive of ectopic pregnancy. Chorionic villous sampling by pipelle curette has both insufficient sensitivity and predictive value in diagnosing ectopic pregnancy, and should not be considered a substitute for D&C.²⁶

Other tests that have limited use. Patients with ectopic pregnancy may have elevated serum markers of smooth muscle destruction such as creatinine phosphokinase (CPK), myoglobin, and smooth muscle heavy-chain myosin (SMHC). However, these tests are of limited value in diagnosing ectopic pregnancy.²⁷ SMHC may be of use in evaluating pregnancies less than 5 weeks’ gestation when the TVUS is not diagnostic. Serum vascular endothelial growth factor is another marker elevated in women with ectopic pregnancy; levels greater than 200 pg/mL distinguish ectopic pregnancy from intrauterine pregnancy (sensitivity=60%, specificity=90%).²⁸

Imaging

In normal pregnancies, a gestational sac is seen on TVUS between 4 and 5 weeks’ gestation;²⁹ the yolk sac is visible at around 6 weeks; and an embryo can be detected between 6 and 7 weeks. A gestational sac greater than 10 mm in diameter without a yolk sac, or greater than 25 mm without an embryo, indicates an abnormal regnancy.^9,29 Presence of an intrauterine pregnancy on ultrasound effectively rules out ectopic pregnancy because heterotopic pregnancy is rare (1 in 2600–30,000 pregnancies).³⁰ Hormonal changes associated with pregnancy result in a uterine endometrial fluid collection (pseudo-sac) in 8% of ectopic pregnancies.³¹

Specific diagnostic finding for ectopic pregnancy. A gestational sac visible on ultrasound with a yolk sac or fetal pole outside the endometrial cavity (TABLE 2) is diagnostic of ectopic pregnancy. The initial ultrasound is indeterminate in 15% to 20% of women with clinical features suggesting ectopic pregnancy.^14,15 Dart et al³² developed a subclassification system of indeterminate ultrasound including 5 categories that stratify the risk of ectopic pregnancy (TABLE 3).

Endometrial stripe thickness of dubious value. For patients with an empty uterus on TVUS and a β-hCG level below the discriminatory zone, endometrial stripe thickness may identify an abnormal pregnancy. In a retrospective study of 117 patients with β-hCG levels less than 1500 mIU/mL, stripe thickness <6 mm had a sensitivity of 100% in identifying ectopic pregnancy or miscarriage; at >13 mm, it had a specificity of 100%.³³

Two recent studies, however, have called into question the value of stripe thickness in identifying ectopic pregnancy. One suggested it was of little value with β-hCG levels <1500 mIU/mL,³⁴ and the other concluded its predictive value for ectopic pregnancy and the likelihood of obtaining chorionic villi on D&C is confined to β-hCG values at or below 1000 mIU/mL.³⁵

Color-enhanced sonography. The addition of endovaginal color-flow imaging to sonography enables exclusion of ectopic pregnancy by establishing findings consistent with a nonviable intrauterine pregnancy: an intrauterine gestational sac, nonvisualization of an adnexal mass, and absent placental blood flow (sensitivity=95%, specificity=98%).¹² Color-flow Doppler imaging shows enhanced blood flow to the affected tube. A cutoff value of 8% change in tubal blood flow has been used to diagnose ectopic pregnancy (sensitivity=85%, specificity=96%).³⁶ In cases where the gestational sac is questionable or absent, color-flow Doppler may expedite diagnosis and possibly identify candidates for expectant or medical management.

When an MRI might help. Magnetic resonance imaging (MRI), in a small study of 37 patients, allowed recognition of tubal wall enhancements and fresh tubal hematoma, and was diagnostic in 21 patients.³⁷ An MRI may be useful when precise and early diagnosis of ectopic pregnancy is imperative, such as pre-existing damage to the contralateral tube where preservation of tubal patency is paramount and when prior TVUS is inconclusive.³⁷

TABLE 3
Detecting ectopic pregnancy with ultrasound and β-hCG levels

A practical evaluation algorithm

Prediction models based on clinical presentation, which classify patients into high-, intermediate-, and low-risk groups, are useful for estimating the risk of ectopic pregnancy in first-trimester patients (FIGURE). Diagnostic pathways incorporating physical findings, quantitative β-hCG levels, and ultrasound results have been developed to manage possible ectopic pregnancy.^38,39 A protocol created by Barnhart using β-hCG and TVUS was accurate and safe when applied to women presenting in emergency settings (sensitivity=100%, specificity=99.9%).³⁰ If β-hCG levels were greater than 1500 mIU/mL, ultrasound was performed. Clinically stable patients with β-hCG levels below 1500 mIU/mL were followed with serial β-hCG levels.

A decision model comparing 6 possible diagnostic strategies that combined clinical examination, TVUS, β-hCG, serum progesterone, and D&C showed that TVUS followed by serial serum β-hCGs in those with initial nondiagnostic ultrasound scans was the most accurate and efficient model.⁴⁰ By using this strategy, all ectopic pregnancies would be detected, fewer than 1 in 100 normal pregnancies would be interrupted, and diagnostic lag would average only 1.46 days.

CORRESPONDENCE
K. Ramakrishnan, MD, Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: [email protected]

Despite advanced detection methods, ectopic pregnancy may be missed in 40% to 50% of patients on an initial visit.¹ Most women with ectopic pregnancy have no risk factors (TABLE 1),^2-5 and the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding is absent in more than half of cases.

Early diagnosis not only decreases maternal mortality and morbidity; it also helps preserve future reproductive capacity—only one third of women with ectopic pregnancy have subsequent live births.²

Management strategies for patients with ectopic pregnancy have evolved rapidly, with ambulatory medical therapy becoming an option for more patients.⁶ Using a practical decision protocol, we discuss the physical findings that most reliably suggest ectopic pregnancy, describe sensible use of laboratory and imaging studies, and explain what to do when results are equivocal. In part 2 of this article (coming in the June 2006 Journal of Family Practice), we provide a decision protocol for management of ectopic pregnancy.

TABLE 1
Risk factors for ectopic pregnancy

Evaluation

Clinical features of ectopic pregnancy highly variable

No single clinical feature accurately indicates ectopic pregnancy. Less than half of women with ectopic pregnancy exhibit the classic triad of a history of amenorrhea, abdominal pain, and irregular vaginal bleeding.¹ And, unfortunately, these features are seen commonly in patients with both viable (50%) and nonviable (25%) intrauterine pregnancies, as well as in threatened abortion, cervical irritation, infection, and trauma.⁷

Set a low threshold for suspicion. For any woman of childbearing age with abdominal pain and vaginal bleeding, consider pregnancy and take steps to rule out ectopic pregnancy. Abdominal pain and vaginal bleeding are highly sensitive for ectopic pregnancy but are not specific for the disorder (TABLE 2).^8-17 Pain located in the hypogastrium or iliac fossa may be mild to severe. Vaginal bleeding, present in 50% to 80% of patients with ectopic pregnancy, can be mistaken for a normal menstrual period.^2,6 Pregnancy-associated symptoms of nausea and vomiting, breast tenderness, and fatigue may be present.

Lower abdominal and adnexal tenderness can be elicited in most women with ectopic pregnancy. Cervical motion tenderness, peritoneal signs, and adnexal masses are most specific for ectopic pregnancy, but are not sensitive.⁸ An adnexal mass is palpable in less than 10% of cases; when it is detected, one third of patients will have a contralateral ectopic pregnancy on ultrasonography.¹⁸ Symptoms of hemodynamic compromise (orthostasis, hypotension, shock) are becoming uncommon with earlier diagnosis of ectopic pregnancy, facilitated by improved detection methods.

TABLE 2
Significance of features associated with ectopic pregnancy

Laboratory tests

In an early normal pregnancy, the beta-human chorionic gonadotropin (β-hCG) level doubles every 1.8 to 3 days, rising to 1000 mIU/mL IRP (International Reference Preparation, measured by radioimmunoassay) by 5 weeks, to 2500 mIU/mL by 6 weeks, and to 13,000 mIU/mL (±3000) by 7 weeks. A single quantitative β-hCG level is not always helpful, as it can range from less than 100 mIU/mL to greater than 50,000 mIU/mL with both ruptured and unruptured ectopic pregnancies.¹⁹

Rethinking the rate of rise in β-hCG. The oft-quoted maxim that ectopic pregnancy or impending miscarriage is associated with a rise in β-hCG of less than 66% in 48 hours arose from a 1981 study that included only 20 women and that was based on an 85% confidence interval (CI).²⁰ A recent study of 287 women suggests that the minimal expected rise in 2 days for a viable intrauterine pregnancy (based on a 99% CI) should be at least 53%.²¹

Combining β-hCG levels and ultrasound findings to improve diagnosis. Because the exact gestational age is often unknown in women presenting with features of ectopic pregnancy, the β-hCG level is used to determine whether a gestational sac can be identified on ultrasound. With a β-hCG level of 6500 mIU/mL, a gestational sac should be visible on abdominal ultrasound in the uterus of a woman with an intrauterine pregnancy; the sac should be absent in ectopic pregnancy. This β-hCG level is designated the discriminatory zone.²²

With a high-resolution transvaginal ultrasound (TVUS), the gestational sac of a normal single intrauterine pregnancy should be visible at a β-hCG level above 1000–1500 mIU/mL, depending on equipment and technical expertise.^2,7 In multiple gestations the discriminatory zone is observed to be above 2300 mIU/mL.² Various ultrasonography findings have been combined with β-hCG levels to more accurately diagnose ectopic pregnancy (TABLE 2 and FIGURE).

Serial β-hCG measurements. If TVUS findings are indeterminate, serial measurements of β-hCG levels at 48-hour intervals may be useful in managing suspected ectopic pregnancy. Dart et al¹⁷ found that a rise in β-hCG level of 66% or more was usually associated with a viable intrauterine pregnancy, though 22% of women in that study had an ectopic pregnancy. Mol et al¹³ found similar results using a cutoff of a β-hCG level rise of 50% or more; 35% had an ectopic pregnancy. Increases in the β-hCG level less than these cutoffs almost always indicated an abnormal pregnancy, and about half of these women had an ectopic pregnancy.^13,17 Also a fall in the β-hCG level by less than 50% was almost always associated with an abnormal pregnancy, but only 19% of these women had an ectopic pregnancy. ^13,17 Alternatively, decreases in β-hCG level of greater than 50% reduced the chance that patients had an ectopic pregnancy to less than 3%.^13,17

Scope of the problem

Ectopic pregnancy is defined as the implantation of the fertilized egg that occurs outside the uterine cavity. It is practically synonymous with tubal pregnancy, as 97% occur in the Fallopian tube.^6,23 Ectopic pregnancy occurs in 2% of all pregnancies in the United States, affecting more than 100,000 patients each year. It is a leading cause of pregnancy-related death in the first trimester,² with a yearly monetary impact of greater than 1 billion dollars. The incidence has increased almost six-fold since 1970 due to delayed child-bearing, rising prevalence of sexually transmitted diseases, and sterilization procedures.⁶

FIGURE
Diagnostic protocol with high sensitivity and specificity for ectopic pregnancy

Serum progesterone levels may have limited usefulness. Serum progesterone measurements are not considered accurate enough to diagnose ectopic pregnancy.²⁴ However, progesterone levels may be helpful if they are either very high or very low. Levels less than 22 ng/mL have a sensitivity of 100% for ectopic pregnancy.²⁵ Only 5 of 1615 patients (0.3%) in 13 studies with progesterone levels below 5 ng/mL had a viable intrauterine pregnancy.²⁴ By establishing the low likelihood of a viable intrauterine pregnancy, serum progesterone measurements may also be useful when β-hCG levels have reached 1000–1500 mIU/mL and the TVUS is equivocal.²⁵

When D&C may help. Dilation and curettage (D&C) is an option for patients with an indeterminate ultrasound result and progesterone levels less than 5 ng/mL, as it can rule out an ectopic pregnancy with only a small chance of interrupting a viable intrauterine pregnancy. The presence of chorionic villi rules out an ectopic pregnancy. In the absence of villi, if β-hCG levels subsequently plateau or increase, it is presumptive of ectopic pregnancy. Chorionic villous sampling by pipelle curette has both insufficient sensitivity and predictive value in diagnosing ectopic pregnancy, and should not be considered a substitute for D&C.²⁶

Other tests that have limited use. Patients with ectopic pregnancy may have elevated serum markers of smooth muscle destruction such as creatinine phosphokinase (CPK), myoglobin, and smooth muscle heavy-chain myosin (SMHC). However, these tests are of limited value in diagnosing ectopic pregnancy.²⁷ SMHC may be of use in evaluating pregnancies less than 5 weeks’ gestation when the TVUS is not diagnostic. Serum vascular endothelial growth factor is another marker elevated in women with ectopic pregnancy; levels greater than 200 pg/mL distinguish ectopic pregnancy from intrauterine pregnancy (sensitivity=60%, specificity=90%).²⁸

Imaging

In normal pregnancies, a gestational sac is seen on TVUS between 4 and 5 weeks’ gestation;²⁹ the yolk sac is visible at around 6 weeks; and an embryo can be detected between 6 and 7 weeks. A gestational sac greater than 10 mm in diameter without a yolk sac, or greater than 25 mm without an embryo, indicates an abnormal regnancy.^9,29 Presence of an intrauterine pregnancy on ultrasound effectively rules out ectopic pregnancy because heterotopic pregnancy is rare (1 in 2600–30,000 pregnancies).³⁰ Hormonal changes associated with pregnancy result in a uterine endometrial fluid collection (pseudo-sac) in 8% of ectopic pregnancies.³¹

Specific diagnostic finding for ectopic pregnancy. A gestational sac visible on ultrasound with a yolk sac or fetal pole outside the endometrial cavity (TABLE 2) is diagnostic of ectopic pregnancy. The initial ultrasound is indeterminate in 15% to 20% of women with clinical features suggesting ectopic pregnancy.^14,15 Dart et al³² developed a subclassification system of indeterminate ultrasound including 5 categories that stratify the risk of ectopic pregnancy (TABLE 3).

Endometrial stripe thickness of dubious value. For patients with an empty uterus on TVUS and a β-hCG level below the discriminatory zone, endometrial stripe thickness may identify an abnormal pregnancy. In a retrospective study of 117 patients with β-hCG levels less than 1500 mIU/mL, stripe thickness <6 mm had a sensitivity of 100% in identifying ectopic pregnancy or miscarriage; at >13 mm, it had a specificity of 100%.³³

Two recent studies, however, have called into question the value of stripe thickness in identifying ectopic pregnancy. One suggested it was of little value with β-hCG levels <1500 mIU/mL,³⁴ and the other concluded its predictive value for ectopic pregnancy and the likelihood of obtaining chorionic villi on D&C is confined to β-hCG values at or below 1000 mIU/mL.³⁵

Color-enhanced sonography. The addition of endovaginal color-flow imaging to sonography enables exclusion of ectopic pregnancy by establishing findings consistent with a nonviable intrauterine pregnancy: an intrauterine gestational sac, nonvisualization of an adnexal mass, and absent placental blood flow (sensitivity=95%, specificity=98%).¹² Color-flow Doppler imaging shows enhanced blood flow to the affected tube. A cutoff value of 8% change in tubal blood flow has been used to diagnose ectopic pregnancy (sensitivity=85%, specificity=96%).³⁶ In cases where the gestational sac is questionable or absent, color-flow Doppler may expedite diagnosis and possibly identify candidates for expectant or medical management.

When an MRI might help. Magnetic resonance imaging (MRI), in a small study of 37 patients, allowed recognition of tubal wall enhancements and fresh tubal hematoma, and was diagnostic in 21 patients.³⁷ An MRI may be useful when precise and early diagnosis of ectopic pregnancy is imperative, such as pre-existing damage to the contralateral tube where preservation of tubal patency is paramount and when prior TVUS is inconclusive.³⁷

TABLE 3
Detecting ectopic pregnancy with ultrasound and β-hCG levels

A practical evaluation algorithm

Prediction models based on clinical presentation, which classify patients into high-, intermediate-, and low-risk groups, are useful for estimating the risk of ectopic pregnancy in first-trimester patients (FIGURE). Diagnostic pathways incorporating physical findings, quantitative β-hCG levels, and ultrasound results have been developed to manage possible ectopic pregnancy.^38,39 A protocol created by Barnhart using β-hCG and TVUS was accurate and safe when applied to women presenting in emergency settings (sensitivity=100%, specificity=99.9%).³⁰ If β-hCG levels were greater than 1500 mIU/mL, ultrasound was performed. Clinically stable patients with β-hCG levels below 1500 mIU/mL were followed with serial β-hCG levels.

A decision model comparing 6 possible diagnostic strategies that combined clinical examination, TVUS, β-hCG, serum progesterone, and D&C showed that TVUS followed by serial serum β-hCGs in those with initial nondiagnostic ultrasound scans was the most accurate and efficient model.⁴⁰ By using this strategy, all ectopic pregnancies would be detected, fewer than 1 in 100 normal pregnancies would be interrupted, and diagnostic lag would average only 1.46 days.

CORRESPONDENCE
K. Ramakrishnan, MD, Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: [email protected]

Note: this article is a continuation of “Obsessive-compulsive disorder: Tools for recognizing its many expressions,” in the March 2006 issue of JFP.

Evidence supports 2 forms of treatment for adults and children with obsessive-compulsive disorder (OCD): cognitive-behavioral therapy (CBT) with exposure and response prevention (E/RP), and psychopharmacologic treatment with serotonin reuptake inhibitors (SRIs).

OCD Expert Consensus Guidelines strongly recommend exposure-based CBT, alone or with pharmacotherapy, as the first-line treatment.¹ However, approximately 25% of persons with OCD wish not to participate in CBT for varying reasons (eg, limited insight, difficulty engaging in exposures), thus making medication alone the initial choice of treatment. In many cases, thankfully, patients whose symptoms decrease with medication become willing to participate in CBT.

Cognitive-behavioral therapy the preferred route

A large database supports the efficacy of CBT with E/RP in treating OCD. Methodologically rigorous controlled trials of CBT in adults and children have reported success rates reaching 85% (SOR: A).^2,3 One qualifier of success: though most patients respond positively to CBT, symptoms often remain and true cure or complete remission is often not possible.

CBT is unlike other psychotherapies. Unfortunately, the number of qualified mental health professionals trained in CBT for OCD is limited,⁴ as is general knowledge about this approach. The Obsessive-Compulsive Foundation estimates that 5 million Americans with OCD lack access to behavioral therapy.⁵ Many of the patients we see in our clinic have participated in psychodynamic or traditional “talk therapies” that are supported by little evidence. Such approaches have a strength of recommendation (SOR) of C. As a result, many afflicted individuals receive only partial treatment that consists of either non-CBT psychotherapy or medication.

Preparing the way for your patient

Before referring a patient for CBT, ask about the practitioner’s level of training (PhD or PsyD are preferable), theoretical approach (cognitive behavioral vs others, such as psychodynamic or humanistic), and experience in working with OCD patients. Perhaps the most important question to ask a clinician is, “Will you expose the patient to situations that provoke rituals while having him/her refrain from engaging in them?”

What your patients can expect. CBT is a form of psychological treatment explicitly based on learning and cognitive principles. Twelve to 16 sessions are typical, though the function of each individual will determine the duration of treatment.² Treatment may be stopped if significant symptom reduction has lasted for at least 4 consecutive weeks. Thereafter, periodic booster sessions are helpful to maintain gains and prevent relapse.¹

The 3 central aspects of CBT therapy for OCD:

• Exposure—placing the patient in situations that elicit anxiety related to their obsessions
• Response prevention—deterring the ritualistic or compulsive behaviors that may serve to reduce or avoid anxiety
• Cognitive therapy—training the patient to identify and reframe anxiety-provoking cognitions.

Exposure—very simply, having the patient face their fear—reduces anxiety responses.

Response prevention involves encouraging the patient to refrain from engaging in repetitive, time-consuming compulsions. This component is based on the notion that rituals serve to reduce anxiety and are thus reinforcing. Naturally, E/RP is quite anxiety-provoking for patients. As a result, it may be useful to inform them that feared situations will be approached in a hierarchical manner, starting with easier items before moving to more difficult ones. Successful completion of E/RP tasks teaches patients that the feared consequences of not ritualizing are not going to occur.

Cognitive therapy takes into account that patients with OCD have characteristic thoughts believed to contribute to the development and maintenance of their condition. Specifically, common themes within this population include distorted appraisals of risk (eg, “The chance of burning the house down with an extinguished cigarette is 25%”), an inflated sense of responsibility for harm (eg, “If I do not touch this rock, my mother will get cancer”), and pathologic levels of self-doubt (eg, “I know the odds of contracting HIV from using a public toilet are slim, but I can’t be sure I will not”). OCD in adults has also been related to the concept of thought–action fusion, in which negative thoughts and actions are seen as synonymous.⁶ Such maladaptive cognitive processes often motivate compulsive behavior and make patients with OCD less able to cope with negative thoughts.⁷ The cognitive component of CBT addresses these issues and teaches patients ways to mend their thinking.

Enlist the family. Finally, family involvement is often central to the success of CBT. Family members may accommodate the patient’s symptoms by facilitating avoidance, assisting with ritualistic behaviors, or inadvertently facilitating the development of the disorder by participating in rituals (eg, providing reassurance, allowing compulsive avoidance of feared stimuli, and tolerating delays associated with ritual completion). Given this, CBT often includes the patient’s spouse, parents, and significant others.

Pharmacotherapy

Malfunction in the serotonin neurotransmitter system is thought to be the physiologic basis of OCD.^8,9 More specifically, OCD patients are believed to have a lower level of serotonin in neural synapses than healthy persons. Given this, seretonergic agents, such as clomipramine (Anafranil), citalopram (Celexa), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine (Luvox) have been used extensively to treat OCD in both adults and youths (SOR: A). The Food and Drug Administration (FDA) has approved only clomipramine, fluoxetine, fluvoxamine, and sertraline for use in youth. Each receives an SOR of A.

Clomipramine: once first choice, now a backup

Until recently, clomipramine—a tricyclic antidepressant—was the most widely prescribed medication for OCD, given its record of providing the greatest and most reliable symptom reduction.¹⁰ The efficacy of clomipramine, which has strong seretonergic properties, has not been replicated with other tricyclic antidepressants (eg, desipramine [Norpramin, Pertofrane]) that more directly target other neurotransmitter systems (serotonin, norepinephrine, and dopamine).¹¹ However, clomipramine, like other tricyclic antidepressants, can cause tachycardia, prolongation of QT interval, and other unpleasant side effects (eg, orthostatic hypotension, constipation, and dry mouth are common). As a result, its use is indicated in cases where the patient does not respond to alternative medications.

SSRIs now favored

Given clomipramine’s side effects, selective serotonin reuptake inhibitors (SSRIs), a class of SRIs, have emerged as the first-line medication.¹² For patients who need medication, first consider prescribing an SSRI first.

SSRIs, however, are not without side effects. During the initial phase of treatment, nausea, exacerbations of anxiety, jitteriness, and insomnia are experienced by approximately 35% of patients and may persist over the duration of treatment. These side effects may be limited by slow-dose titration. With fluoxetine, for example, start at 20 mg and gradually increase the dose over several weeks to the usual target dose of 40 to 60 mg.

Some patients require even lower initial doses and more prolonged titration. Extended SSRI treatment has been linked to sexual dysfunction, headache, asthenia, and sweating in 25% to 35% of patients.¹³

Multiple large-scale controlled trials have demonstrated the efficacy and tolerability of SSRIs for adults and youths.^13,14 About 40% to 55% of patients generally report significant symptom reduction after 12 weeks. However, typical symptom reduction in clinical practice averages only 20% to 50%, and many patients experience residual symptoms after treatment has stopped.

Course of pharmacotherapy

SSRIs should be gradually titrated. The TABLE displays dosing of commonly used SSRIs in adults with OCD. A 12-week trial of an adequate dosage is the standard of care before considering alternative therapies.⁹ Initial response to medications may take 6 to 8 weeks, although the maximal response may take up to 20 weeks. Continue medications for 1 year after achieving a therapeutic response and slowly taper thereafter. Evidence suggests that ongoing CBT may be one method to prevent relapse when discontinuing medication.¹⁵ Most patients do not fully remit on medication treatment alone, and as many as 60% do not have a substantial reduction of symptoms.¹⁶

TABLE
SRI dosing guidelines recommended by the Expert Consensus Panel (1997)

For cost-effectiveness, CBT still comes out on top

It is suggested that patients continue medication consistently for 2 years before deciding to stop.⁹ Medication would therefore be expected to cost more over the long-term than CBT, given the time-limited nature and durability of the latter.³ To date, several trials have examined the relative efficacy of pharmacotherapy alone versus its combination with CBT. In general, results suggest that CBT alone or in combination with pharmacotherapy (an SRI) is the treatment of choice.^1,17

CBT plus medication often the better way to go

Given that many patients do not respond adequately to medication alone, augmentation strategies are often necessary. As CBT is considered the most effective approach, this therapy should always be used, particularly when a patient has proven refractory with pharmacological approaches. In cases that are unresponsive to multiple SSRIs and CBT, consider such second-line pharmacological treatments as serotonergic or dopaminergic agents, or adding a second first-line agent.¹³

Dopaminergic augmentation with drugs such as risperidone (Risperdal) or haloperidol (Haldol), and olanzapine (Zyprexa) have been fairly extensively studied. This approach, which consists of adding a medication that affects the dopaminergic system to the ongoing SSRI, has been well-supported.¹⁸ However, it is unclear as to how long to continue treatment as many patients relapse upon discontinuation and the antipsychotics are linked to undesirable side effects such as sedation, weight gain, or (particularly with higher doses of risperidone) extrapyramidal effects.

Strategies for adding a second serotonergic medication include switching to a new agent or adding another. Indeed, many patients with an inadequate response to one SSRI may have a favorable response to another.¹⁰

Prognosis

Left untreated, the course of obsessive-compulsive disorder is chronic and unremitting, with symptoms generally fluctuating over time due to stress-induced exacerbations of symptoms.¹⁹ Children with this disorder remain at higher risk for other psychiatric problems into adulthood,^20,21 and adults frequently display additional symptoms as well. Comorbidity with Major Depressive Disorder is particularly common in both children and adults, as are ADHD and other anxiety, mood, and tic disorders.^22-24 Symptoms also disrupt family, social, academic, and occupational functioning.^25-27

Accurate diagnosis of OCD and the identification of a qualified treatment provider remain the 2 major obstacles to treatment of OCD. In one study, the average delay between onset of symptoms and provision of appropriate treatment was 17 years.²⁷ However, once appropriate treatment begins, prognosis for patients with OCD is positive. One meta-analysis demonstrated significant long-term improvement (range, 1–15 years) in pediatric patients receiving any treatment (ie, pharmacological, psychological, or combined) for OCD.²⁸ Other studies have demonstrated that medication generally accounts for significant symptom reduction compared with baseline levels,^14,15 and 57% to 64% of pediatric patients exhibit no symptoms or subclinical levels of symptoms at follow-up.^29,30 Studies of adults have also demonstrated significant symptom reduction,¹² with about 50% of patients responding to medication.³¹ In addition, numerous studies have demonstrated that CBT is as effective or more effective than pharmacotherapy alone for both children and adults.^12,15,31

As noted previously, upwards of 85% of patients improve significantly with CBT.^3,31 Thus, CBT alone or combined with medication has the best prognosis for children and adults.

CORRESPONDENCE
Eric A. Storch, PhD, Department of Psychiatry, University of Florida, Box 100234, Gainesville, FL 32610. E-mail: [email protected]

Note: this article is a continuation of “Obsessive-compulsive disorder: Tools for recognizing its many expressions,” in the March 2006 issue of JFP.

Evidence supports 2 forms of treatment for adults and children with obsessive-compulsive disorder (OCD): cognitive-behavioral therapy (CBT) with exposure and response prevention (E/RP), and psychopharmacologic treatment with serotonin reuptake inhibitors (SRIs).

OCD Expert Consensus Guidelines strongly recommend exposure-based CBT, alone or with pharmacotherapy, as the first-line treatment.¹ However, approximately 25% of persons with OCD wish not to participate in CBT for varying reasons (eg, limited insight, difficulty engaging in exposures), thus making medication alone the initial choice of treatment. In many cases, thankfully, patients whose symptoms decrease with medication become willing to participate in CBT.

Cognitive-behavioral therapy the preferred route

A large database supports the efficacy of CBT with E/RP in treating OCD. Methodologically rigorous controlled trials of CBT in adults and children have reported success rates reaching 85% (SOR: A).^2,3 One qualifier of success: though most patients respond positively to CBT, symptoms often remain and true cure or complete remission is often not possible.

CBT is unlike other psychotherapies. Unfortunately, the number of qualified mental health professionals trained in CBT for OCD is limited,⁴ as is general knowledge about this approach. The Obsessive-Compulsive Foundation estimates that 5 million Americans with OCD lack access to behavioral therapy.⁵ Many of the patients we see in our clinic have participated in psychodynamic or traditional “talk therapies” that are supported by little evidence. Such approaches have a strength of recommendation (SOR) of C. As a result, many afflicted individuals receive only partial treatment that consists of either non-CBT psychotherapy or medication.

Preparing the way for your patient

Before referring a patient for CBT, ask about the practitioner’s level of training (PhD or PsyD are preferable), theoretical approach (cognitive behavioral vs others, such as psychodynamic or humanistic), and experience in working with OCD patients. Perhaps the most important question to ask a clinician is, “Will you expose the patient to situations that provoke rituals while having him/her refrain from engaging in them?”

What your patients can expect. CBT is a form of psychological treatment explicitly based on learning and cognitive principles. Twelve to 16 sessions are typical, though the function of each individual will determine the duration of treatment.² Treatment may be stopped if significant symptom reduction has lasted for at least 4 consecutive weeks. Thereafter, periodic booster sessions are helpful to maintain gains and prevent relapse.¹

The 3 central aspects of CBT therapy for OCD:

• Exposure—placing the patient in situations that elicit anxiety related to their obsessions
• Response prevention—deterring the ritualistic or compulsive behaviors that may serve to reduce or avoid anxiety
• Cognitive therapy—training the patient to identify and reframe anxiety-provoking cognitions.