Clinical Inquiries

Evidence summary

A Cochrane review of 22 trials (N=2797) comparing CMS with no CMS in uncomplicated term deliveries demonstrated no significant differences in fetal outcomes.¹ The groups showed similar rates of maternal infection and fever (relative risk [RR]=1.05; 95% confidence interval [CI], 0.68-1.65), neonatal infection (RR=0.92; 95% CI, 0.30-2.82), and Apgar scores <7 at 5 minutes (RR=1.13; 95% CI, 0.53-2.43). Two perinatal deaths were reported in each group. The review was limited by relatively small trials and heterogeneity between trial results, suggesting the possibility of publication bias.

Most of the studies included in the meta-analysis didn’t specifically include or exclude women with GBS colonization, nor did the review subanalyze patients into a GBS-positive and GBS-negative arm. Considering that GBS colonization was reported in 19% to 26% of pregnancies, it’s likely that GBS colonization was present in both CMS and control groups in the review.^2,3

Study shows no CMS effects, but may be underpowered

A randomized prospective study (N=98) included in the Cochrane review specifically considered the effects of CMS and maternal GBS colonization.⁴ Colonization rates for the study were 17% (9/44 in the study group, 8/54 in the control group). Women in the study group underwent weekly CMS beginning at 38 weeks of gestation; the control group didn’t undergo CMS. Repeat GBS testing was performed at 40 weeks for all patients with initial GBS-negative cultures.

Three patients were GBS-positive on repeat testing (one in the study group, 2 in the control group). No admissions to the neonatal intensive care unit or neonatal infections occurred in either group. The study may have been underpowered to detect any effect, however.⁴

Recommendations

The American College of Obstetricians and Gynecologists’ 2009 Practice Bulletin on induction of labor states that the data are insufficient to either recommend or discourage CMS to induce labor in women who are GBS-positive.⁵

The 2009 Department of Veterans Affairs/Department of Defense Clinical Practice Guideline for Pregnancy Management also cites insufficient data to support or oppose CMS in GBS-positive term pregnant women.⁶

Evidence summary

A Cochrane review of 22 trials (N=2797) comparing CMS with no CMS in uncomplicated term deliveries demonstrated no significant differences in fetal outcomes.¹ The groups showed similar rates of maternal infection and fever (relative risk [RR]=1.05; 95% confidence interval [CI], 0.68-1.65), neonatal infection (RR=0.92; 95% CI, 0.30-2.82), and Apgar scores <7 at 5 minutes (RR=1.13; 95% CI, 0.53-2.43). Two perinatal deaths were reported in each group. The review was limited by relatively small trials and heterogeneity between trial results, suggesting the possibility of publication bias.

Most of the studies included in the meta-analysis didn’t specifically include or exclude women with GBS colonization, nor did the review subanalyze patients into a GBS-positive and GBS-negative arm. Considering that GBS colonization was reported in 19% to 26% of pregnancies, it’s likely that GBS colonization was present in both CMS and control groups in the review.^2,3

Study shows no CMS effects, but may be underpowered

A randomized prospective study (N=98) included in the Cochrane review specifically considered the effects of CMS and maternal GBS colonization.⁴ Colonization rates for the study were 17% (9/44 in the study group, 8/54 in the control group). Women in the study group underwent weekly CMS beginning at 38 weeks of gestation; the control group didn’t undergo CMS. Repeat GBS testing was performed at 40 weeks for all patients with initial GBS-negative cultures.

Three patients were GBS-positive on repeat testing (one in the study group, 2 in the control group). No admissions to the neonatal intensive care unit or neonatal infections occurred in either group. The study may have been underpowered to detect any effect, however.⁴

Recommendations

The American College of Obstetricians and Gynecologists’ 2009 Practice Bulletin on induction of labor states that the data are insufficient to either recommend or discourage CMS to induce labor in women who are GBS-positive.⁵

The 2009 Department of Veterans Affairs/Department of Defense Clinical Practice Guideline for Pregnancy Management also cites insufficient data to support or oppose CMS in GBS-positive term pregnant women.⁶

Evidence summary

A Cochrane review of 22 trials (N=2797) comparing CMS with no CMS in uncomplicated term deliveries demonstrated no significant differences in fetal outcomes.¹ The groups showed similar rates of maternal infection and fever (relative risk [RR]=1.05; 95% confidence interval [CI], 0.68-1.65), neonatal infection (RR=0.92; 95% CI, 0.30-2.82), and Apgar scores <7 at 5 minutes (RR=1.13; 95% CI, 0.53-2.43). Two perinatal deaths were reported in each group. The review was limited by relatively small trials and heterogeneity between trial results, suggesting the possibility of publication bias.

Most of the studies included in the meta-analysis didn’t specifically include or exclude women with GBS colonization, nor did the review subanalyze patients into a GBS-positive and GBS-negative arm. Considering that GBS colonization was reported in 19% to 26% of pregnancies, it’s likely that GBS colonization was present in both CMS and control groups in the review.^2,3

Study shows no CMS effects, but may be underpowered

A randomized prospective study (N=98) included in the Cochrane review specifically considered the effects of CMS and maternal GBS colonization.⁴ Colonization rates for the study were 17% (9/44 in the study group, 8/54 in the control group). Women in the study group underwent weekly CMS beginning at 38 weeks of gestation; the control group didn’t undergo CMS. Repeat GBS testing was performed at 40 weeks for all patients with initial GBS-negative cultures.

Three patients were GBS-positive on repeat testing (one in the study group, 2 in the control group). No admissions to the neonatal intensive care unit or neonatal infections occurred in either group. The study may have been underpowered to detect any effect, however.⁴

Recommendations

The American College of Obstetricians and Gynecologists’ 2009 Practice Bulletin on induction of labor states that the data are insufficient to either recommend or discourage CMS to induce labor in women who are GBS-positive.⁵

The 2009 Department of Veterans Affairs/Department of Defense Clinical Practice Guideline for Pregnancy Management also cites insufficient data to support or oppose CMS in GBS-positive term pregnant women.⁶

Evidence summary

A nonsystematic review of 11 prospective cohort studies (N=2804) reported that ferning was both sensitive and specific for the presence of amniotic fluid in laboring women who reported fluid loss. Labor was defined as contractions with subsequent delivery of a baby. Ferning had a mean sensitivity of 96% (range, 74%-100%) and a mean specificity of 96.2% (range, 77%-100%).¹

Helpful in laboring women, but less so in those who are nonlaboring
A prospective cohort study evaluated the sensitivity and specificity of ferning among women reporting fluid loss who were in labor compared with women who weren’t in labor. Investigators classified laboring women (n=51) as having continued fluid loss and no fetal membranes covering the presenting part and progressing to delivery. They considered women to be nonlaboring (n=100) if they had minimal fluid loss and fetal membranes covering the presenting part or didn’t progress to delivery (investigators diagnosed 39 women with ruptured membranes on clinical grounds). Ferning was 98% sensitive and 88.2% specific in laboring women, and 51.3% sensitive and 70.5% specific in nonlaboring women.¹

Ferning occurs from 14 weeks of gestation onward
A prospective case series (N=400) determined that amniotic fluid would fern at all gestational ages between 14 and 41 weeks. Investigators obtained fluid samples by amniocentesis and confirmed that they were 100% nitrazine-positive.² They found more consistent ferning in samples dried on a slide for 10 minutes than samples dried over a flame (100% vs 86.7% of 112 samples).

Some contaminants in amniotic samples affect ferning
In vitro studies evaluated ferning in samples of amniotic fluid mixed with blood, meconium, or vaginal fluids. Blood contamination didn’t affect ferning unless the sample contained more than 10% blood.^3-5 Meconium (which itself verifies ruptured membranes) didn’t change the fern pattern at any dilution,⁶ nor did vaginal discharge.³

Antiseptic solution may cause false-positive results, as may semen, fingerprints, and cervical mucus—although none of these show the fine arborization or discrete crystallization seen in uncontaminated amniotic fluid.^6,7

Recommendations

The American College of Obstetricians and Gynecologists says that ferning is a confirmatory test for ruptured membranes, to be used along with pooling in the vaginal vault, and that premature membrane rupture is confirmed by fluid passing from the cervical canal.⁸

Evidence summary

A nonsystematic review of 11 prospective cohort studies (N=2804) reported that ferning was both sensitive and specific for the presence of amniotic fluid in laboring women who reported fluid loss. Labor was defined as contractions with subsequent delivery of a baby. Ferning had a mean sensitivity of 96% (range, 74%-100%) and a mean specificity of 96.2% (range, 77%-100%).¹

Helpful in laboring women, but less so in those who are nonlaboring
A prospective cohort study evaluated the sensitivity and specificity of ferning among women reporting fluid loss who were in labor compared with women who weren’t in labor. Investigators classified laboring women (n=51) as having continued fluid loss and no fetal membranes covering the presenting part and progressing to delivery. They considered women to be nonlaboring (n=100) if they had minimal fluid loss and fetal membranes covering the presenting part or didn’t progress to delivery (investigators diagnosed 39 women with ruptured membranes on clinical grounds). Ferning was 98% sensitive and 88.2% specific in laboring women, and 51.3% sensitive and 70.5% specific in nonlaboring women.¹

Ferning occurs from 14 weeks of gestation onward
A prospective case series (N=400) determined that amniotic fluid would fern at all gestational ages between 14 and 41 weeks. Investigators obtained fluid samples by amniocentesis and confirmed that they were 100% nitrazine-positive.² They found more consistent ferning in samples dried on a slide for 10 minutes than samples dried over a flame (100% vs 86.7% of 112 samples).

Some contaminants in amniotic samples affect ferning
In vitro studies evaluated ferning in samples of amniotic fluid mixed with blood, meconium, or vaginal fluids. Blood contamination didn’t affect ferning unless the sample contained more than 10% blood.^3-5 Meconium (which itself verifies ruptured membranes) didn’t change the fern pattern at any dilution,⁶ nor did vaginal discharge.³

Antiseptic solution may cause false-positive results, as may semen, fingerprints, and cervical mucus—although none of these show the fine arborization or discrete crystallization seen in uncontaminated amniotic fluid.^6,7

Recommendations

The American College of Obstetricians and Gynecologists says that ferning is a confirmatory test for ruptured membranes, to be used along with pooling in the vaginal vault, and that premature membrane rupture is confirmed by fluid passing from the cervical canal.⁸

Evidence summary

A nonsystematic review of 11 prospective cohort studies (N=2804) reported that ferning was both sensitive and specific for the presence of amniotic fluid in laboring women who reported fluid loss. Labor was defined as contractions with subsequent delivery of a baby. Ferning had a mean sensitivity of 96% (range, 74%-100%) and a mean specificity of 96.2% (range, 77%-100%).¹

Helpful in laboring women, but less so in those who are nonlaboring
A prospective cohort study evaluated the sensitivity and specificity of ferning among women reporting fluid loss who were in labor compared with women who weren’t in labor. Investigators classified laboring women (n=51) as having continued fluid loss and no fetal membranes covering the presenting part and progressing to delivery. They considered women to be nonlaboring (n=100) if they had minimal fluid loss and fetal membranes covering the presenting part or didn’t progress to delivery (investigators diagnosed 39 women with ruptured membranes on clinical grounds). Ferning was 98% sensitive and 88.2% specific in laboring women, and 51.3% sensitive and 70.5% specific in nonlaboring women.¹

Ferning occurs from 14 weeks of gestation onward
A prospective case series (N=400) determined that amniotic fluid would fern at all gestational ages between 14 and 41 weeks. Investigators obtained fluid samples by amniocentesis and confirmed that they were 100% nitrazine-positive.² They found more consistent ferning in samples dried on a slide for 10 minutes than samples dried over a flame (100% vs 86.7% of 112 samples).

Some contaminants in amniotic samples affect ferning
In vitro studies evaluated ferning in samples of amniotic fluid mixed with blood, meconium, or vaginal fluids. Blood contamination didn’t affect ferning unless the sample contained more than 10% blood.^3-5 Meconium (which itself verifies ruptured membranes) didn’t change the fern pattern at any dilution,⁶ nor did vaginal discharge.³

Antiseptic solution may cause false-positive results, as may semen, fingerprints, and cervical mucus—although none of these show the fine arborization or discrete crystallization seen in uncontaminated amniotic fluid.^6,7

Recommendations

The American College of Obstetricians and Gynecologists says that ferning is a confirmatory test for ruptured membranes, to be used along with pooling in the vaginal vault, and that premature membrane rupture is confirmed by fluid passing from the cervical canal.⁸

Evidence summary

Nonulcer dyspepsia is defined by upper abdominal symptoms (nausea, bloating, and abdominal pain) in the absence of an ulcer.¹ A prospective study evaluating the natural history of 209 Taiwanese patients with nonulcer dyspepsia found a 45% prevalence of H pylori. The patients presented with dyspeptic symptoms and had no history of peptic ulcer disease or treatment for H pylori. Investigators performed an initial endoscopy to establish a diagnosis of nonulcer dyspepsia and followed the patients for 24 months. Patients with H pylori infection were more likely to develop peptic ulcer disease (odds ratio [OR]=3.59; 95% confidence interval [CI], 1.07-12.05; P=.039).²

In addition, a prospective cohort study of Japanese patients with nonulcer dyspepsia found that 4.7% of patients infected with H pylori developed gastric cancer after 10 years.³

Eradicating H pylori doesn’t prevent peptic ulcer disease
A prospective, placebo-controlled trial found that therapy to eradicate H pylori didn’t reduce peptic ulcer disease in patients with functional dyspepsia. Investigators recruited 161 patients with H pylori infection who had had functional dyspepsia symptoms for 3 months and no peptic ulcer disease at baseline. They gave lansoprazole, metronidazole, and tetracycline for 1 week to the treatment group and placebo antibiotics and lansoprazole to the placebo group. Fewer of the treated patients developed peptic ulcers by 12 months, but the difference wasn’t significant (2.5% treatment vs 7.5% placebo; P=.167).⁴

Eradication improves symptoms, but not quality of life
A Cochrane systematic review of 17 RCTs (total N=3566) compared drugs known to eradicate H pylori with placebo or drugs known to be ineffective against H pylori for patients with nonulcer dyspepsia. Investigators evaluated individual and global dyspeptic symptom scores and quality-of-life measures. At 3 to 12 months of follow-up, treated patients reported improved symptom scores (number needed to treat=14; 95% CI, 10-25). Three studies that evaluated quality-of-life indicators found no significant benefit with H pylori eradication.⁵

Evidence for outcomes beyond 12 months is limited. An RCT evaluated 100 patients with nonulcer dyspepsia who received bismuth subcitrate for 4 weeks or metronidazole and tetracycline for 7 days or placebo. At 5 years, investigators performed urea breath testing on 64 patients and found that 67% were negative for H pylori. More H pylori-negative patients reported complete symptom resolution than patients who were still infected (34% vs 8.3%; chi-square <0.001). However, investigators grouped patients at 5-year follow-up according to their H pylori status at that time and not by their original treatment group.⁶

H pylori eradication is low cost
A 2000 systematic review with economic analysis found that eradicating H pylori would cost less than $50 per patient per year compared with antisecretory therapy alone.⁷

Recommendations

The European Helicobacter Study Group states that treatment of H pylori in nonulcer dyspepsia is appropriate.⁸ The American College of Gastroenterology agrees that offering treatment for H pylori in nonulcer dyspepsia is acceptable.⁹

The American Gastroenterological Association recommends a “test and treat” strategy for H pylori in dyspeptic patients.¹

Evidence summary

Nonulcer dyspepsia is defined by upper abdominal symptoms (nausea, bloating, and abdominal pain) in the absence of an ulcer.¹ A prospective study evaluating the natural history of 209 Taiwanese patients with nonulcer dyspepsia found a 45% prevalence of H pylori. The patients presented with dyspeptic symptoms and had no history of peptic ulcer disease or treatment for H pylori. Investigators performed an initial endoscopy to establish a diagnosis of nonulcer dyspepsia and followed the patients for 24 months. Patients with H pylori infection were more likely to develop peptic ulcer disease (odds ratio [OR]=3.59; 95% confidence interval [CI], 1.07-12.05; P=.039).²

In addition, a prospective cohort study of Japanese patients with nonulcer dyspepsia found that 4.7% of patients infected with H pylori developed gastric cancer after 10 years.³

Eradicating H pylori doesn’t prevent peptic ulcer disease
A prospective, placebo-controlled trial found that therapy to eradicate H pylori didn’t reduce peptic ulcer disease in patients with functional dyspepsia. Investigators recruited 161 patients with H pylori infection who had had functional dyspepsia symptoms for 3 months and no peptic ulcer disease at baseline. They gave lansoprazole, metronidazole, and tetracycline for 1 week to the treatment group and placebo antibiotics and lansoprazole to the placebo group. Fewer of the treated patients developed peptic ulcers by 12 months, but the difference wasn’t significant (2.5% treatment vs 7.5% placebo; P=.167).⁴

Eradication improves symptoms, but not quality of life
A Cochrane systematic review of 17 RCTs (total N=3566) compared drugs known to eradicate H pylori with placebo or drugs known to be ineffective against H pylori for patients with nonulcer dyspepsia. Investigators evaluated individual and global dyspeptic symptom scores and quality-of-life measures. At 3 to 12 months of follow-up, treated patients reported improved symptom scores (number needed to treat=14; 95% CI, 10-25). Three studies that evaluated quality-of-life indicators found no significant benefit with H pylori eradication.⁵

Evidence for outcomes beyond 12 months is limited. An RCT evaluated 100 patients with nonulcer dyspepsia who received bismuth subcitrate for 4 weeks or metronidazole and tetracycline for 7 days or placebo. At 5 years, investigators performed urea breath testing on 64 patients and found that 67% were negative for H pylori. More H pylori-negative patients reported complete symptom resolution than patients who were still infected (34% vs 8.3%; chi-square <0.001). However, investigators grouped patients at 5-year follow-up according to their H pylori status at that time and not by their original treatment group.⁶

H pylori eradication is low cost
A 2000 systematic review with economic analysis found that eradicating H pylori would cost less than $50 per patient per year compared with antisecretory therapy alone.⁷

Recommendations

The European Helicobacter Study Group states that treatment of H pylori in nonulcer dyspepsia is appropriate.⁸ The American College of Gastroenterology agrees that offering treatment for H pylori in nonulcer dyspepsia is acceptable.⁹

The American Gastroenterological Association recommends a “test and treat” strategy for H pylori in dyspeptic patients.¹

Evidence summary

Nonulcer dyspepsia is defined by upper abdominal symptoms (nausea, bloating, and abdominal pain) in the absence of an ulcer.¹ A prospective study evaluating the natural history of 209 Taiwanese patients with nonulcer dyspepsia found a 45% prevalence of H pylori. The patients presented with dyspeptic symptoms and had no history of peptic ulcer disease or treatment for H pylori. Investigators performed an initial endoscopy to establish a diagnosis of nonulcer dyspepsia and followed the patients for 24 months. Patients with H pylori infection were more likely to develop peptic ulcer disease (odds ratio [OR]=3.59; 95% confidence interval [CI], 1.07-12.05; P=.039).²

In addition, a prospective cohort study of Japanese patients with nonulcer dyspepsia found that 4.7% of patients infected with H pylori developed gastric cancer after 10 years.³

Eradicating H pylori doesn’t prevent peptic ulcer disease
A prospective, placebo-controlled trial found that therapy to eradicate H pylori didn’t reduce peptic ulcer disease in patients with functional dyspepsia. Investigators recruited 161 patients with H pylori infection who had had functional dyspepsia symptoms for 3 months and no peptic ulcer disease at baseline. They gave lansoprazole, metronidazole, and tetracycline for 1 week to the treatment group and placebo antibiotics and lansoprazole to the placebo group. Fewer of the treated patients developed peptic ulcers by 12 months, but the difference wasn’t significant (2.5% treatment vs 7.5% placebo; P=.167).⁴

Eradication improves symptoms, but not quality of life
A Cochrane systematic review of 17 RCTs (total N=3566) compared drugs known to eradicate H pylori with placebo or drugs known to be ineffective against H pylori for patients with nonulcer dyspepsia. Investigators evaluated individual and global dyspeptic symptom scores and quality-of-life measures. At 3 to 12 months of follow-up, treated patients reported improved symptom scores (number needed to treat=14; 95% CI, 10-25). Three studies that evaluated quality-of-life indicators found no significant benefit with H pylori eradication.⁵

Evidence for outcomes beyond 12 months is limited. An RCT evaluated 100 patients with nonulcer dyspepsia who received bismuth subcitrate for 4 weeks or metronidazole and tetracycline for 7 days or placebo. At 5 years, investigators performed urea breath testing on 64 patients and found that 67% were negative for H pylori. More H pylori-negative patients reported complete symptom resolution than patients who were still infected (34% vs 8.3%; chi-square <0.001). However, investigators grouped patients at 5-year follow-up according to their H pylori status at that time and not by their original treatment group.⁶

H pylori eradication is low cost
A 2000 systematic review with economic analysis found that eradicating H pylori would cost less than $50 per patient per year compared with antisecretory therapy alone.⁷

Recommendations

The European Helicobacter Study Group states that treatment of H pylori in nonulcer dyspepsia is appropriate.⁸ The American College of Gastroenterology agrees that offering treatment for H pylori in nonulcer dyspepsia is acceptable.⁹

The American Gastroenterological Association recommends a “test and treat” strategy for H pylori in dyspeptic patients.¹

Evidence summary

Although most parvovirus infections in pregnant women don’t harm the fetus, human parvovirus B19 (B19V) may cause severe fetal anemia and cardiac failure, potentially leading to nonimmune fetal hydrops. Transplacental transmission occurs in as many as 33% of cases, with the highest risk of fetal infection occurring between the 9th and 20th weeks of gestation and within 2 to 4 weeks of maternal infection.^1,2

A quarter of infections are asymptomatic; the remainder present as a self-limited flu-like syndrome. Infected people may transmit the virus for 5 to 10 days before developing symptoms.^1-3

Infection raises risk of death, but not later developmental delay
First- and second-trimester parvovirus infections carry an excess fetal loss risk of 10% above baseline (5%), but a low risk of long-term sequelae during childhood.⁴ A prospective cohort study of 1018 pregnant German women, confirmed to be immunoglobulin M-positive and followed by targeted ultrasound for 10 weeks, found a 6.3% incidence of fetal death and a 3.9% incidence of hydrops fetalis.³ Fetal death occurred only with B19V infection before 20 weeks’ gestation. Although more cases (67.5%) of fetal hydrops occurred before 20 weeks, cases were seen throughout all gestational periods.

A similar prospective cohort study of 427 pregnant women from England and Wales reported 14% and 1.7% incidences of fetal death and hydrops fetalis, respectively.⁴ In following up on 182 infants (1 year of age) and 129 children (7-10.5 years of age), investigators found 3 children (2%) with developmental delays in each cohort—consistent with expected numbers for any unselected group of children. They found no congenital abnormalities attributable to B19V infections.

Occupational exposure doesn’t pose significant danger
Few prospective studies have examined prevention of parvovirus infection because of the difficulty of detecting infection during the initial asymptomatic phase. In an effort to determine potential modifiable risk factors, a prospective cohort study of a convenience sample at a referral clinic with no power analysis examined infection rates among 618 pregnant women in various occupations who were exposed to infected children.⁵

Exposure to children in the household produced the highest risk of infection (29.4% vs 16.7% overall incidence; P<.001). Primary school teachers and daycare workers had an increased risk of infection that didn’t reach statistical significance (23%, P=.5).⁵ None of the occupations examined (school teacher, daycare worker, office professional, homemaker, and health care worker) demonstrated significantly increased risk (P=.5). Because of the lack of difference in infection rates among studied occupations, the authors recommended against routine workplace exclusion.⁵ Subsequent Danish population-based cohort studies (N=32,300) found that nursery school teachers had an odds ratio of 3.0 for acute infection, but it was reduced to 1.82 after accounting for infections in their own children.⁶

The TABLE summarizes current consensus guidelines for initial evaluation, clinical surveillance, and management of pregnant women potentially exposed to B19V.²

TABLE
Managing suspected parvovirus B19 infections in pregnancy: Consensus recommendations

Recommendations

The Centers for Disease Control and Prevention and a 2000 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) don’t recommend routinely excluding pregnant women from the workplace during endemic outbreaks of parvovirus to reduce exposure risk. They do, however, encourage women to discuss their individual risk with their physician.^7,8

ACOG and the Society of Obstetricians and Gynaecologists of Canada concur with consensus guidelines for evaluating and managing women suspected of exposure or infection.^1,7

Evidence summary

Although most parvovirus infections in pregnant women don’t harm the fetus, human parvovirus B19 (B19V) may cause severe fetal anemia and cardiac failure, potentially leading to nonimmune fetal hydrops. Transplacental transmission occurs in as many as 33% of cases, with the highest risk of fetal infection occurring between the 9th and 20th weeks of gestation and within 2 to 4 weeks of maternal infection.^1,2

A quarter of infections are asymptomatic; the remainder present as a self-limited flu-like syndrome. Infected people may transmit the virus for 5 to 10 days before developing symptoms.^1-3

Infection raises risk of death, but not later developmental delay
First- and second-trimester parvovirus infections carry an excess fetal loss risk of 10% above baseline (5%), but a low risk of long-term sequelae during childhood.⁴ A prospective cohort study of 1018 pregnant German women, confirmed to be immunoglobulin M-positive and followed by targeted ultrasound for 10 weeks, found a 6.3% incidence of fetal death and a 3.9% incidence of hydrops fetalis.³ Fetal death occurred only with B19V infection before 20 weeks’ gestation. Although more cases (67.5%) of fetal hydrops occurred before 20 weeks, cases were seen throughout all gestational periods.

A similar prospective cohort study of 427 pregnant women from England and Wales reported 14% and 1.7% incidences of fetal death and hydrops fetalis, respectively.⁴ In following up on 182 infants (1 year of age) and 129 children (7-10.5 years of age), investigators found 3 children (2%) with developmental delays in each cohort—consistent with expected numbers for any unselected group of children. They found no congenital abnormalities attributable to B19V infections.

Occupational exposure doesn’t pose significant danger
Few prospective studies have examined prevention of parvovirus infection because of the difficulty of detecting infection during the initial asymptomatic phase. In an effort to determine potential modifiable risk factors, a prospective cohort study of a convenience sample at a referral clinic with no power analysis examined infection rates among 618 pregnant women in various occupations who were exposed to infected children.⁵

Exposure to children in the household produced the highest risk of infection (29.4% vs 16.7% overall incidence; P<.001). Primary school teachers and daycare workers had an increased risk of infection that didn’t reach statistical significance (23%, P=.5).⁵ None of the occupations examined (school teacher, daycare worker, office professional, homemaker, and health care worker) demonstrated significantly increased risk (P=.5). Because of the lack of difference in infection rates among studied occupations, the authors recommended against routine workplace exclusion.⁵ Subsequent Danish population-based cohort studies (N=32,300) found that nursery school teachers had an odds ratio of 3.0 for acute infection, but it was reduced to 1.82 after accounting for infections in their own children.⁶

The TABLE summarizes current consensus guidelines for initial evaluation, clinical surveillance, and management of pregnant women potentially exposed to B19V.²

TABLE
Managing suspected parvovirus B19 infections in pregnancy: Consensus recommendations

Recommendations

The Centers for Disease Control and Prevention and a 2000 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) don’t recommend routinely excluding pregnant women from the workplace during endemic outbreaks of parvovirus to reduce exposure risk. They do, however, encourage women to discuss their individual risk with their physician.^7,8

ACOG and the Society of Obstetricians and Gynaecologists of Canada concur with consensus guidelines for evaluating and managing women suspected of exposure or infection.^1,7

Evidence summary

Although most parvovirus infections in pregnant women don’t harm the fetus, human parvovirus B19 (B19V) may cause severe fetal anemia and cardiac failure, potentially leading to nonimmune fetal hydrops. Transplacental transmission occurs in as many as 33% of cases, with the highest risk of fetal infection occurring between the 9th and 20th weeks of gestation and within 2 to 4 weeks of maternal infection.^1,2

A quarter of infections are asymptomatic; the remainder present as a self-limited flu-like syndrome. Infected people may transmit the virus for 5 to 10 days before developing symptoms.^1-3

Infection raises risk of death, but not later developmental delay
First- and second-trimester parvovirus infections carry an excess fetal loss risk of 10% above baseline (5%), but a low risk of long-term sequelae during childhood.⁴ A prospective cohort study of 1018 pregnant German women, confirmed to be immunoglobulin M-positive and followed by targeted ultrasound for 10 weeks, found a 6.3% incidence of fetal death and a 3.9% incidence of hydrops fetalis.³ Fetal death occurred only with B19V infection before 20 weeks’ gestation. Although more cases (67.5%) of fetal hydrops occurred before 20 weeks, cases were seen throughout all gestational periods.

A similar prospective cohort study of 427 pregnant women from England and Wales reported 14% and 1.7% incidences of fetal death and hydrops fetalis, respectively.⁴ In following up on 182 infants (1 year of age) and 129 children (7-10.5 years of age), investigators found 3 children (2%) with developmental delays in each cohort—consistent with expected numbers for any unselected group of children. They found no congenital abnormalities attributable to B19V infections.

Occupational exposure doesn’t pose significant danger
Few prospective studies have examined prevention of parvovirus infection because of the difficulty of detecting infection during the initial asymptomatic phase. In an effort to determine potential modifiable risk factors, a prospective cohort study of a convenience sample at a referral clinic with no power analysis examined infection rates among 618 pregnant women in various occupations who were exposed to infected children.⁵

Exposure to children in the household produced the highest risk of infection (29.4% vs 16.7% overall incidence; P<.001). Primary school teachers and daycare workers had an increased risk of infection that didn’t reach statistical significance (23%, P=.5).⁵ None of the occupations examined (school teacher, daycare worker, office professional, homemaker, and health care worker) demonstrated significantly increased risk (P=.5). Because of the lack of difference in infection rates among studied occupations, the authors recommended against routine workplace exclusion.⁵ Subsequent Danish population-based cohort studies (N=32,300) found that nursery school teachers had an odds ratio of 3.0 for acute infection, but it was reduced to 1.82 after accounting for infections in their own children.⁶

The TABLE summarizes current consensus guidelines for initial evaluation, clinical surveillance, and management of pregnant women potentially exposed to B19V.²

TABLE
Managing suspected parvovirus B19 infections in pregnancy: Consensus recommendations

Recommendations

The Centers for Disease Control and Prevention and a 2000 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) don’t recommend routinely excluding pregnant women from the workplace during endemic outbreaks of parvovirus to reduce exposure risk. They do, however, encourage women to discuss their individual risk with their physician.^7,8

ACOG and the Society of Obstetricians and Gynaecologists of Canada concur with consensus guidelines for evaluating and managing women suspected of exposure or infection.^1,7

Evidence summary

The TABLE summarizes the evidence for the best-studied treatments.^1-5 A systematic review of 396 studies, 36 of which were included in an accompanying meta-analysis, concluded that, overall, any treatment gave patients a 70% (95% confidence interval [CI], 49%-91%) chance of improvement.⁶ The mean improvement in scar appearance or symptoms was 60% for all the studies combined (no CI reported).

The review found no statistically significant difference between outcomes of 27 different treatments or combinations of treatments. The authors concluded that no optimal evidence-based therapy exists and recommended choosing treatment based on cost and adverse effect profile.⁶

TABLE
What the evidence tells us about these scar treatments

Many studies have limitations
Studies often don’t distinguish between hypertrophic and keloid scars, although much evidence supports important differences in their natural histories and response to therapy.⁷ Hypertrophic scars may resolve spontaneously, can improve with surgical revision, and are less likely to recur.

Moreover, many studies looked only at initial response, although good initial response to therapy doesn’t translate into a low recurrence rate, particularly for keloid scars. Studies were also flawed by lack of controls, nonvalidated outcome measures, and small size.

No available evidence supports using over-the-counter products such as Mederma and other creams, gels, and oils, to treat scars.

Recommendations

The American Academy of Dermatology does not make any recommendations about hypertrophic or keloid scars.

The International Clinical Recommendations on Scar Management (written for the International Advisory Panel on Scar Management) recommend silicone gel sheeting and intralesional corticosteroids as first-line therapy, based on a systematic review of the clinical literature. For secondary management, the authors accepted localized pressure therapy, specific wavelength laser therapy, and surgical revision with adjuvant silicone gel therapy as standard practice based on expert opinion. They conclude that many standard practices and emerging therapies need to be studied in well-designed trials before being conclusively recommended.⁸

Evidence summary

The TABLE summarizes the evidence for the best-studied treatments.^1-5 A systematic review of 396 studies, 36 of which were included in an accompanying meta-analysis, concluded that, overall, any treatment gave patients a 70% (95% confidence interval [CI], 49%-91%) chance of improvement.⁶ The mean improvement in scar appearance or symptoms was 60% for all the studies combined (no CI reported).

The review found no statistically significant difference between outcomes of 27 different treatments or combinations of treatments. The authors concluded that no optimal evidence-based therapy exists and recommended choosing treatment based on cost and adverse effect profile.⁶

TABLE
What the evidence tells us about these scar treatments

Many studies have limitations
Studies often don’t distinguish between hypertrophic and keloid scars, although much evidence supports important differences in their natural histories and response to therapy.⁷ Hypertrophic scars may resolve spontaneously, can improve with surgical revision, and are less likely to recur.

Moreover, many studies looked only at initial response, although good initial response to therapy doesn’t translate into a low recurrence rate, particularly for keloid scars. Studies were also flawed by lack of controls, nonvalidated outcome measures, and small size.

No available evidence supports using over-the-counter products such as Mederma and other creams, gels, and oils, to treat scars.

Recommendations

The American Academy of Dermatology does not make any recommendations about hypertrophic or keloid scars.

The International Clinical Recommendations on Scar Management (written for the International Advisory Panel on Scar Management) recommend silicone gel sheeting and intralesional corticosteroids as first-line therapy, based on a systematic review of the clinical literature. For secondary management, the authors accepted localized pressure therapy, specific wavelength laser therapy, and surgical revision with adjuvant silicone gel therapy as standard practice based on expert opinion. They conclude that many standard practices and emerging therapies need to be studied in well-designed trials before being conclusively recommended.⁸

Evidence summary

The TABLE summarizes the evidence for the best-studied treatments.^1-5 A systematic review of 396 studies, 36 of which were included in an accompanying meta-analysis, concluded that, overall, any treatment gave patients a 70% (95% confidence interval [CI], 49%-91%) chance of improvement.⁶ The mean improvement in scar appearance or symptoms was 60% for all the studies combined (no CI reported).

The review found no statistically significant difference between outcomes of 27 different treatments or combinations of treatments. The authors concluded that no optimal evidence-based therapy exists and recommended choosing treatment based on cost and adverse effect profile.⁶

TABLE
What the evidence tells us about these scar treatments

Many studies have limitations
Studies often don’t distinguish between hypertrophic and keloid scars, although much evidence supports important differences in their natural histories and response to therapy.⁷ Hypertrophic scars may resolve spontaneously, can improve with surgical revision, and are less likely to recur.

Moreover, many studies looked only at initial response, although good initial response to therapy doesn’t translate into a low recurrence rate, particularly for keloid scars. Studies were also flawed by lack of controls, nonvalidated outcome measures, and small size.

No available evidence supports using over-the-counter products such as Mederma and other creams, gels, and oils, to treat scars.

Recommendations

The American Academy of Dermatology does not make any recommendations about hypertrophic or keloid scars.

The International Clinical Recommendations on Scar Management (written for the International Advisory Panel on Scar Management) recommend silicone gel sheeting and intralesional corticosteroids as first-line therapy, based on a systematic review of the clinical literature. For secondary management, the authors accepted localized pressure therapy, specific wavelength laser therapy, and surgical revision with adjuvant silicone gel therapy as standard practice based on expert opinion. They conclude that many standard practices and emerging therapies need to be studied in well-designed trials before being conclusively recommended.⁸

Evidence summary

A meta-analysis of 147 RCTs with a total of 464,000 patients demonstrated better cardiovascular outcomes for combination therapy vs monotherapy among patients 60 to 69 years of age with diastolic blood pressures 90 mm Hg or higher. Investigators randomized participants with no history of vascular disease, a history of coronary heart disease, or a history of stroke to monotherapy or a combination of 3 drugs from any class at half-standard doses. Combination therapy reduced both coronary heart disease and stroke (number needed to treat [NNT] to prevent 1 new case of coronary heart disease=4, NNT to prevent 1 stroke=3).¹

Another meta-analysis of 61 prospective observational studies with a total of 1 million patients showed that for every coronary event or stroke prevented by doubling the dose of a single drug, 4 events were prevented by using combination therapy.² A 3-point reduction in systolic blood pressure resulted in a 5% to 10% reduction in heart disease and stroke.¹

A meta-analysis of 42 trials with a total of almost 11,000 patients found that combining any 2 drug classes at low doses decreased diastolic blood pressure more than doubling the dose of a single drug (9 mm Hg vs 6 mm Hg).³

ACE-I plus ß-blocker or calcium channnel blocker outperforms thiazide combos
The combination of an ACE-I plus a ß-blocker lowered systolic blood pressure more than ACE-I monotherapy (22.9 mm Hg vs 12.5 mm Hg) in an RCT with 48 patients.⁴ More patients taking an ACE-I plus a calcium channel blocker achieved the primary end point (reductions in systolic blood pressure ≥25 mm Hg) than did patients randomized to monotherapy (74.2% vs 53.9%; NNT=5).⁵

In an RCT of 11,506 patients, benazepril plus amlodipine decreased blood pressure more than benazepril plus hydrochlorothiazide (difference=0.9 mm Hg systolic, 1.1 mm Hg diastolic) and improved the composite outcome of cardiovascular events and deaths (absolute risk reduction=2.2%; NNT=45).⁶ Rates of adverse drug reactions were similar among patients taking ACE-I monotherapy and combinations of benazepril plus amlodipine or benazepril plus hydrochlorothiazide.^4-6

ARB plus a thiazide lowers BP more than monotherapy
Five short-term RCTs comparing ARB-thiazide combinations with monotherapy measured changes in blood pressure rather than morbidity and mortality. In these studies, sponsored by pharmaceutical companies, combination treatment more often produced blood pressures within the goals of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII) than monotherapy (62% vs 37%; NNT to reach goal=4 [approximately]).^7-8 An ARB plus hydrochlorothiazide lowered blood pressure more effectively than either drug alone but produced more dizziness (8.5% vs 4.7%; P=.002).⁷

In an RCT of 926 patients who had failed monotherapy with an ARB, 74.8% treated with an ARB plus a calcium channel blocker achieved blood pressures <140/90.⁹ Adding a calcium channel blocker decreased blood pressures by about 19 mm Hg systolic and 11 mm Hg diastolic with few adverse drug reactions.

How safe is combination therapy?
Participants in a 6-year RCT of 25,260 patients had more adverse outcomes with an ARB plus ACE-I combination than monotherapy (number needed to harm=100 to cause composite endpoint of death, dialysis, or creatinine doubling).¹⁰ For most other combinations, the safety profile is unknown or similar to monotherapy.

The TABLE summarizes the efficacy and safety profiles of antihypertensive drug combinations.^4-10

TABLE
Efficacy and safety of drug combinations for essential hypertension*

Recommendations

Both the 2003 JNC-VII and the 2008 Canadian Hypertension Education Program recommendations for managing hypertension advise lowering blood pressure to <140/90 mm Hg in all patients and <130/80 mm Hg in patients with diabetes and chronic kidney disease.^11,12 Both guidelines also suggest starting therapy with 2 drugs when blood pressure is more than 20 mm Hg above systolic goal or 10 mm Hg above diastolic goal, but they do not endorse specific combinations.

Evidence summary

A meta-analysis of 147 RCTs with a total of 464,000 patients demonstrated better cardiovascular outcomes for combination therapy vs monotherapy among patients 60 to 69 years of age with diastolic blood pressures 90 mm Hg or higher. Investigators randomized participants with no history of vascular disease, a history of coronary heart disease, or a history of stroke to monotherapy or a combination of 3 drugs from any class at half-standard doses. Combination therapy reduced both coronary heart disease and stroke (number needed to treat [NNT] to prevent 1 new case of coronary heart disease=4, NNT to prevent 1 stroke=3).¹

Another meta-analysis of 61 prospective observational studies with a total of 1 million patients showed that for every coronary event or stroke prevented by doubling the dose of a single drug, 4 events were prevented by using combination therapy.² A 3-point reduction in systolic blood pressure resulted in a 5% to 10% reduction in heart disease and stroke.¹

A meta-analysis of 42 trials with a total of almost 11,000 patients found that combining any 2 drug classes at low doses decreased diastolic blood pressure more than doubling the dose of a single drug (9 mm Hg vs 6 mm Hg).³

ACE-I plus ß-blocker or calcium channnel blocker outperforms thiazide combos
The combination of an ACE-I plus a ß-blocker lowered systolic blood pressure more than ACE-I monotherapy (22.9 mm Hg vs 12.5 mm Hg) in an RCT with 48 patients.⁴ More patients taking an ACE-I plus a calcium channel blocker achieved the primary end point (reductions in systolic blood pressure ≥25 mm Hg) than did patients randomized to monotherapy (74.2% vs 53.9%; NNT=5).⁵

In an RCT of 11,506 patients, benazepril plus amlodipine decreased blood pressure more than benazepril plus hydrochlorothiazide (difference=0.9 mm Hg systolic, 1.1 mm Hg diastolic) and improved the composite outcome of cardiovascular events and deaths (absolute risk reduction=2.2%; NNT=45).⁶ Rates of adverse drug reactions were similar among patients taking ACE-I monotherapy and combinations of benazepril plus amlodipine or benazepril plus hydrochlorothiazide.^4-6

ARB plus a thiazide lowers BP more than monotherapy
Five short-term RCTs comparing ARB-thiazide combinations with monotherapy measured changes in blood pressure rather than morbidity and mortality. In these studies, sponsored by pharmaceutical companies, combination treatment more often produced blood pressures within the goals of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII) than monotherapy (62% vs 37%; NNT to reach goal=4 [approximately]).^7-8 An ARB plus hydrochlorothiazide lowered blood pressure more effectively than either drug alone but produced more dizziness (8.5% vs 4.7%; P=.002).⁷

In an RCT of 926 patients who had failed monotherapy with an ARB, 74.8% treated with an ARB plus a calcium channel blocker achieved blood pressures <140/90.⁹ Adding a calcium channel blocker decreased blood pressures by about 19 mm Hg systolic and 11 mm Hg diastolic with few adverse drug reactions.

How safe is combination therapy?
Participants in a 6-year RCT of 25,260 patients had more adverse outcomes with an ARB plus ACE-I combination than monotherapy (number needed to harm=100 to cause composite endpoint of death, dialysis, or creatinine doubling).¹⁰ For most other combinations, the safety profile is unknown or similar to monotherapy.

The TABLE summarizes the efficacy and safety profiles of antihypertensive drug combinations.^4-10

TABLE
Efficacy and safety of drug combinations for essential hypertension*

Recommendations

Both the 2003 JNC-VII and the 2008 Canadian Hypertension Education Program recommendations for managing hypertension advise lowering blood pressure to <140/90 mm Hg in all patients and <130/80 mm Hg in patients with diabetes and chronic kidney disease.^11,12 Both guidelines also suggest starting therapy with 2 drugs when blood pressure is more than 20 mm Hg above systolic goal or 10 mm Hg above diastolic goal, but they do not endorse specific combinations.

Evidence summary

A meta-analysis of 147 RCTs with a total of 464,000 patients demonstrated better cardiovascular outcomes for combination therapy vs monotherapy among patients 60 to 69 years of age with diastolic blood pressures 90 mm Hg or higher. Investigators randomized participants with no history of vascular disease, a history of coronary heart disease, or a history of stroke to monotherapy or a combination of 3 drugs from any class at half-standard doses. Combination therapy reduced both coronary heart disease and stroke (number needed to treat [NNT] to prevent 1 new case of coronary heart disease=4, NNT to prevent 1 stroke=3).¹

Another meta-analysis of 61 prospective observational studies with a total of 1 million patients showed that for every coronary event or stroke prevented by doubling the dose of a single drug, 4 events were prevented by using combination therapy.² A 3-point reduction in systolic blood pressure resulted in a 5% to 10% reduction in heart disease and stroke.¹

A meta-analysis of 42 trials with a total of almost 11,000 patients found that combining any 2 drug classes at low doses decreased diastolic blood pressure more than doubling the dose of a single drug (9 mm Hg vs 6 mm Hg).³

ACE-I plus ß-blocker or calcium channnel blocker outperforms thiazide combos
The combination of an ACE-I plus a ß-blocker lowered systolic blood pressure more than ACE-I monotherapy (22.9 mm Hg vs 12.5 mm Hg) in an RCT with 48 patients.⁴ More patients taking an ACE-I plus a calcium channel blocker achieved the primary end point (reductions in systolic blood pressure ≥25 mm Hg) than did patients randomized to monotherapy (74.2% vs 53.9%; NNT=5).⁵

In an RCT of 11,506 patients, benazepril plus amlodipine decreased blood pressure more than benazepril plus hydrochlorothiazide (difference=0.9 mm Hg systolic, 1.1 mm Hg diastolic) and improved the composite outcome of cardiovascular events and deaths (absolute risk reduction=2.2%; NNT=45).⁶ Rates of adverse drug reactions were similar among patients taking ACE-I monotherapy and combinations of benazepril plus amlodipine or benazepril plus hydrochlorothiazide.^4-6

ARB plus a thiazide lowers BP more than monotherapy
Five short-term RCTs comparing ARB-thiazide combinations with monotherapy measured changes in blood pressure rather than morbidity and mortality. In these studies, sponsored by pharmaceutical companies, combination treatment more often produced blood pressures within the goals of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII) than monotherapy (62% vs 37%; NNT to reach goal=4 [approximately]).^7-8 An ARB plus hydrochlorothiazide lowered blood pressure more effectively than either drug alone but produced more dizziness (8.5% vs 4.7%; P=.002).⁷

In an RCT of 926 patients who had failed monotherapy with an ARB, 74.8% treated with an ARB plus a calcium channel blocker achieved blood pressures <140/90.⁹ Adding a calcium channel blocker decreased blood pressures by about 19 mm Hg systolic and 11 mm Hg diastolic with few adverse drug reactions.

How safe is combination therapy?
Participants in a 6-year RCT of 25,260 patients had more adverse outcomes with an ARB plus ACE-I combination than monotherapy (number needed to harm=100 to cause composite endpoint of death, dialysis, or creatinine doubling).¹⁰ For most other combinations, the safety profile is unknown or similar to monotherapy.

The TABLE summarizes the efficacy and safety profiles of antihypertensive drug combinations.^4-10

TABLE
Efficacy and safety of drug combinations for essential hypertension*

Recommendations

Both the 2003 JNC-VII and the 2008 Canadian Hypertension Education Program recommendations for managing hypertension advise lowering blood pressure to <140/90 mm Hg in all patients and <130/80 mm Hg in patients with diabetes and chronic kidney disease.^11,12 Both guidelines also suggest starting therapy with 2 drugs when blood pressure is more than 20 mm Hg above systolic goal or 10 mm Hg above diastolic goal, but they do not endorse specific combinations.

Evidence summary

The total cumulative dose of vitamin D may be more significant than frequency of dosing. An RCT evaluated 38 postmenopausal women (median age 61.5 years) randomized into 3 groups (placebo or daily oral vitamin D₂ in either 5000 or 10,000 IU doses).¹ Only 1 patient had a baseline serum 25(OH)D level greater than 34 ng/mL. After 3 months, 8% of the placebo group, 50% of the 5000 IU daily group, and 75% of the 10,000 IU daily group had levels greater than 34 ng/mL. The cumulative D₂ doses were 0, 450,000, and 900,000 IU, respectively. The number needed to treat (NNT), compared with placebo, was 3 (95% confidence interval [CI], 1-15) for the 5000 IU daily group and 2 (95% CI, 1-3) for the 10,000 IU daily group.

In another RCT that evaluated 48 women (average age 81±8 years) with hip fracture, the same cumulative dose of vitamin D₃ (1500 IU orally per day, 10,500 IU per week, or 45,000 IU per month) approximately doubled serum 25(OH)D levels over the 2-month study period. After a cumulative dose of 90,000 IU, serum 25(OH)D levels rose from 15.7 ng/mL at baseline to 33.2, 29.2, and 37.1 ng/mL, respectively, for the daily, weekly, and monthly dose groups. These levels didn’t differ significantly from each other.²

But frequent dosing also shows effects
On the other hand, an RCT of 338 nursing home patients concluded that dosing frequency makes a difference. Patients (78% female; mean age 84±6.2 years) were randomized to 4 treatment arms: placebo (n=172), daily oral doses of vitamin D₃ of 600 IU (n=55), weekly oral doses of 4200 IU (n=54), or monthly oral doses of 18,000 IU (n=57).

After 4 months, the 600 IU daily dose increased mean serum 25(OH)D levels the most, by 18.9 ng/mL; the 4200 IU weekly dose increased levels by 16.3 ng/mL, and the 18,000 IU monthly dose increased levels the least, by 11 ng/mL (P<.01 between groups). Serum 25(OH)D levels in the placebo group didn’t change. The average patient age of 84 years and high dropout rate (18.3% died or withdrew) limit this study.³

Oral D₃ may be the best bet
The best route and form of vitamin D may be oral D₃. A prospective intervention study randomized 32 female nursing home patients (66-97 years of age) to 4 treatment arms: oral D₃, intramuscular (IM) D₃, oral D₂, or IM D₂ (8 women per arm).⁴ Oral D₃ in a dose of 300,000 IU increased 25(OH)D levels more effectively than the same dose of IM D₃, oral D₂, or IM D₂.

All subjects had serum 25(OH)D levels below 32 ng/mL at baseline. One month after a single 300,000 IU dose, serum 25(OH)D levels increased by 47.8±7.3 ng/mL in the oral D₃ group. Comparable differences (baseline to 1 month after treatment) in serum 25(OH)D levels for the other 3 arms were 15.9±11.3 ng/mL for IM D₃; 17.3±4.7 ng/mL for oral D₂; and 5±4.4 ng/mL for IM D₂; P<.001 comparing 30-day serum 25(OH)D levels in the oral D₃ group with the other 3 groups.⁴

Recommendations

The Institute of Medicine (IOM’s) 2011 report on dietary requirements for calcium and vitamin D doesn’t address the ideal treatment of deficiency, but it states that adequate levels of serum 25(OH)D are 20 ng/mL—not 30 ng/mL. The IOM advises that the upper limit of safe vitamin D intake is 4000 IU per day for people 9 years and older, and is lower for infants and young children.⁵

An online textbook recommends treating vitamin D deficiency (serum 25[OH]D levels below 20 ng/mL) with 50,000 IUs of vitamin D₂ or D₃ orally once a week for 6 to 8 weeks, followed by a maintenance dose (such as 800 to 1000 IUs of vitamin D₃ daily). The same textbook recommends treating nutritional insufficiency (serum 25[OH]D levels between 20 and 30 ng/mL) with 800 to 1000 units of vitamin D₃ daily. The authors recommend vitamin D₃ over vitamin D₂ for supplementation.⁶

Evidence summary

The total cumulative dose of vitamin D may be more significant than frequency of dosing. An RCT evaluated 38 postmenopausal women (median age 61.5 years) randomized into 3 groups (placebo or daily oral vitamin D₂ in either 5000 or 10,000 IU doses).¹ Only 1 patient had a baseline serum 25(OH)D level greater than 34 ng/mL. After 3 months, 8% of the placebo group, 50% of the 5000 IU daily group, and 75% of the 10,000 IU daily group had levels greater than 34 ng/mL. The cumulative D₂ doses were 0, 450,000, and 900,000 IU, respectively. The number needed to treat (NNT), compared with placebo, was 3 (95% confidence interval [CI], 1-15) for the 5000 IU daily group and 2 (95% CI, 1-3) for the 10,000 IU daily group.

In another RCT that evaluated 48 women (average age 81±8 years) with hip fracture, the same cumulative dose of vitamin D₃ (1500 IU orally per day, 10,500 IU per week, or 45,000 IU per month) approximately doubled serum 25(OH)D levels over the 2-month study period. After a cumulative dose of 90,000 IU, serum 25(OH)D levels rose from 15.7 ng/mL at baseline to 33.2, 29.2, and 37.1 ng/mL, respectively, for the daily, weekly, and monthly dose groups. These levels didn’t differ significantly from each other.²

But frequent dosing also shows effects
On the other hand, an RCT of 338 nursing home patients concluded that dosing frequency makes a difference. Patients (78% female; mean age 84±6.2 years) were randomized to 4 treatment arms: placebo (n=172), daily oral doses of vitamin D₃ of 600 IU (n=55), weekly oral doses of 4200 IU (n=54), or monthly oral doses of 18,000 IU (n=57).

After 4 months, the 600 IU daily dose increased mean serum 25(OH)D levels the most, by 18.9 ng/mL; the 4200 IU weekly dose increased levels by 16.3 ng/mL, and the 18,000 IU monthly dose increased levels the least, by 11 ng/mL (P<.01 between groups). Serum 25(OH)D levels in the placebo group didn’t change. The average patient age of 84 years and high dropout rate (18.3% died or withdrew) limit this study.³

Oral D₃ may be the best bet
The best route and form of vitamin D may be oral D₃. A prospective intervention study randomized 32 female nursing home patients (66-97 years of age) to 4 treatment arms: oral D₃, intramuscular (IM) D₃, oral D₂, or IM D₂ (8 women per arm).⁴ Oral D₃ in a dose of 300,000 IU increased 25(OH)D levels more effectively than the same dose of IM D₃, oral D₂, or IM D₂.

All subjects had serum 25(OH)D levels below 32 ng/mL at baseline. One month after a single 300,000 IU dose, serum 25(OH)D levels increased by 47.8±7.3 ng/mL in the oral D₃ group. Comparable differences (baseline to 1 month after treatment) in serum 25(OH)D levels for the other 3 arms were 15.9±11.3 ng/mL for IM D₃; 17.3±4.7 ng/mL for oral D₂; and 5±4.4 ng/mL for IM D₂; P<.001 comparing 30-day serum 25(OH)D levels in the oral D₃ group with the other 3 groups.⁴

Recommendations

The Institute of Medicine (IOM’s) 2011 report on dietary requirements for calcium and vitamin D doesn’t address the ideal treatment of deficiency, but it states that adequate levels of serum 25(OH)D are 20 ng/mL—not 30 ng/mL. The IOM advises that the upper limit of safe vitamin D intake is 4000 IU per day for people 9 years and older, and is lower for infants and young children.⁵

An online textbook recommends treating vitamin D deficiency (serum 25[OH]D levels below 20 ng/mL) with 50,000 IUs of vitamin D₂ or D₃ orally once a week for 6 to 8 weeks, followed by a maintenance dose (such as 800 to 1000 IUs of vitamin D₃ daily). The same textbook recommends treating nutritional insufficiency (serum 25[OH]D levels between 20 and 30 ng/mL) with 800 to 1000 units of vitamin D₃ daily. The authors recommend vitamin D₃ over vitamin D₂ for supplementation.⁶

Evidence summary

The total cumulative dose of vitamin D may be more significant than frequency of dosing. An RCT evaluated 38 postmenopausal women (median age 61.5 years) randomized into 3 groups (placebo or daily oral vitamin D₂ in either 5000 or 10,000 IU doses).¹ Only 1 patient had a baseline serum 25(OH)D level greater than 34 ng/mL. After 3 months, 8% of the placebo group, 50% of the 5000 IU daily group, and 75% of the 10,000 IU daily group had levels greater than 34 ng/mL. The cumulative D₂ doses were 0, 450,000, and 900,000 IU, respectively. The number needed to treat (NNT), compared with placebo, was 3 (95% confidence interval [CI], 1-15) for the 5000 IU daily group and 2 (95% CI, 1-3) for the 10,000 IU daily group.

In another RCT that evaluated 48 women (average age 81±8 years) with hip fracture, the same cumulative dose of vitamin D₃ (1500 IU orally per day, 10,500 IU per week, or 45,000 IU per month) approximately doubled serum 25(OH)D levels over the 2-month study period. After a cumulative dose of 90,000 IU, serum 25(OH)D levels rose from 15.7 ng/mL at baseline to 33.2, 29.2, and 37.1 ng/mL, respectively, for the daily, weekly, and monthly dose groups. These levels didn’t differ significantly from each other.²

But frequent dosing also shows effects
On the other hand, an RCT of 338 nursing home patients concluded that dosing frequency makes a difference. Patients (78% female; mean age 84±6.2 years) were randomized to 4 treatment arms: placebo (n=172), daily oral doses of vitamin D₃ of 600 IU (n=55), weekly oral doses of 4200 IU (n=54), or monthly oral doses of 18,000 IU (n=57).

After 4 months, the 600 IU daily dose increased mean serum 25(OH)D levels the most, by 18.9 ng/mL; the 4200 IU weekly dose increased levels by 16.3 ng/mL, and the 18,000 IU monthly dose increased levels the least, by 11 ng/mL (P<.01 between groups). Serum 25(OH)D levels in the placebo group didn’t change. The average patient age of 84 years and high dropout rate (18.3% died or withdrew) limit this study.³

Oral D₃ may be the best bet
The best route and form of vitamin D may be oral D₃. A prospective intervention study randomized 32 female nursing home patients (66-97 years of age) to 4 treatment arms: oral D₃, intramuscular (IM) D₃, oral D₂, or IM D₂ (8 women per arm).⁴ Oral D₃ in a dose of 300,000 IU increased 25(OH)D levels more effectively than the same dose of IM D₃, oral D₂, or IM D₂.

All subjects had serum 25(OH)D levels below 32 ng/mL at baseline. One month after a single 300,000 IU dose, serum 25(OH)D levels increased by 47.8±7.3 ng/mL in the oral D₃ group. Comparable differences (baseline to 1 month after treatment) in serum 25(OH)D levels for the other 3 arms were 15.9±11.3 ng/mL for IM D₃; 17.3±4.7 ng/mL for oral D₂; and 5±4.4 ng/mL for IM D₂; P<.001 comparing 30-day serum 25(OH)D levels in the oral D₃ group with the other 3 groups.⁴

Recommendations

The Institute of Medicine (IOM’s) 2011 report on dietary requirements for calcium and vitamin D doesn’t address the ideal treatment of deficiency, but it states that adequate levels of serum 25(OH)D are 20 ng/mL—not 30 ng/mL. The IOM advises that the upper limit of safe vitamin D intake is 4000 IU per day for people 9 years and older, and is lower for infants and young children.⁵

An online textbook recommends treating vitamin D deficiency (serum 25[OH]D levels below 20 ng/mL) with 50,000 IUs of vitamin D₂ or D₃ orally once a week for 6 to 8 weeks, followed by a maintenance dose (such as 800 to 1000 IUs of vitamin D₃ daily). The same textbook recommends treating nutritional insufficiency (serum 25[OH]D levels between 20 and 30 ng/mL) with 800 to 1000 units of vitamin D₃ daily. The authors recommend vitamin D₃ over vitamin D₂ for supplementation.⁶

Evidence summary

Standard management for croup has included glucocorticoids, nebulized racemic epinephrine, humidified air, and, for patients with severe respiratory distress and impending respiratory failure, helium-oxygen mixtures.

Glucocorticoids have significant benefits
A 2011 Cochrane review of glucocorticoids in children with croup identified 38 RCTs with 4299 patients.¹ Effective treatments included dexamethasone (oral, subcutaneous, intramuscular, nebulized), budesonide (inhaled), and prednisolone (oral). Meta-analysis revealed a significant decrease in the rate of return visits and (re)admissions for patients treated with glucocorticoids compared with placebo (relative risk=0.5; 95% confidence interval [CI], 0.3-0.7). Glucocorticoid-treated children spent less time in the ED or hospital (weighted mean difference=-12 hours; 95% CI, -5 to -19) and were less likely to need epinephrine (risk difference=10%; 95% CI, 1%-20%).

The standardized improvement in the Westley score (TABLE) for all glucocorticoid treatments compared with placebo was -1.2 (95% CI, -1.6 to -0.8) at 6 hours and -1.9 (95% CI, -2.4 to -1.3) at 12 hours. No statistically significant difference was found at 24 hours (-1.3; 95% CI, -2.7 to 0.2). The combined studies favored glucocorticoids over placebo with a number needed to treat of 5. Meta-regression analysis didn’t demonstrate superiority for any single glucocorticoid.

A single 0.15 mg/kg dose of oral dexamethasone proved as effective as higher doses of 0.3 to 0.6 mg/kg in 3 RCTs (N=100, 120, and 99).^2-4

TABLE
Westley Croup Score⁵

Nebulized epinephrine improves moderate to severe croup
Three RCTs (N=54, 20, and 13) found that in moderate to severe croup, treatment with nebulized racemic epinephrine improved croup score within 10 to 30 minutes.⁵

A small RCT (31 children, 6 months to 6 years of age) demonstrated L-epinephrine [1:1000] to be as effective and well tolerated as racemic epinephrine in moderate to severe croup. Improvement in croup score and respiratory rate peaked at 30 minutes. The effect of epinephrine (racemic or L-form) didn’t last beyond 120 minutes.⁶

In a retrospective study of 50 children with croup who were given aerosolized racemic epinephrine and observed in the ED for 2 hours after treatment, 58% received steroids during observation and 34% were prescribed prednisolone at discharge. Only 1 child required a return visit within 48 hours.⁷

Effect of helium-oxygen mixtures isn’t clear
A 2010 Cochrane review identified 2 RCTs of heliox in acute croup. No significant differences in croup score changes were found when heliox was compared with 30% oxygen (n=15, mild to moderate croup) and 100% oxygen with prn nebulized racemic epinephrine (n=29, moderate to severe croup).⁸ Both studies were underpowered and had significant methodological limitations.

Humidified air shows no benefit
A Cochrane review of 3 RCTs comparing humidified air with room air in emergency settings (n=135) found no evidence of benefit in croup score, oxygen saturation, or pulse rate.⁹

Recommendations

The 2008 Alberta Medical Association guideline recommends that all children with croup be treated with 0.6 mg/kg oral dexamethasone.¹⁰ Children with mild croup can be discharged home without further observation. Children with moderate croup should be observed for at least 4 hours. Hospitalization should be considered for children who fail to show adequate improvement. The guideline advises giving both steroids and nebulized epinephrine to children with severe croup.

The Advanced Pediatric Life Support (APLS) course of the American Academy of Pediatrics and the American College of Emergency Physicians recommends treatment with corticosteroids.¹¹ For severe croup, the APLS advocates racemic or L-epinephrine, followed by observation for 3 or 4 hours and hospital admission in the event of inadequate response or recurrence of severe distress.

Evidence summary

Standard management for croup has included glucocorticoids, nebulized racemic epinephrine, humidified air, and, for patients with severe respiratory distress and impending respiratory failure, helium-oxygen mixtures.

Glucocorticoids have significant benefits
A 2011 Cochrane review of glucocorticoids in children with croup identified 38 RCTs with 4299 patients.¹ Effective treatments included dexamethasone (oral, subcutaneous, intramuscular, nebulized), budesonide (inhaled), and prednisolone (oral). Meta-analysis revealed a significant decrease in the rate of return visits and (re)admissions for patients treated with glucocorticoids compared with placebo (relative risk=0.5; 95% confidence interval [CI], 0.3-0.7). Glucocorticoid-treated children spent less time in the ED or hospital (weighted mean difference=-12 hours; 95% CI, -5 to -19) and were less likely to need epinephrine (risk difference=10%; 95% CI, 1%-20%).

The standardized improvement in the Westley score (TABLE) for all glucocorticoid treatments compared with placebo was -1.2 (95% CI, -1.6 to -0.8) at 6 hours and -1.9 (95% CI, -2.4 to -1.3) at 12 hours. No statistically significant difference was found at 24 hours (-1.3; 95% CI, -2.7 to 0.2). The combined studies favored glucocorticoids over placebo with a number needed to treat of 5. Meta-regression analysis didn’t demonstrate superiority for any single glucocorticoid.

A single 0.15 mg/kg dose of oral dexamethasone proved as effective as higher doses of 0.3 to 0.6 mg/kg in 3 RCTs (N=100, 120, and 99).^2-4

TABLE
Westley Croup Score⁵

Nebulized epinephrine improves moderate to severe croup
Three RCTs (N=54, 20, and 13) found that in moderate to severe croup, treatment with nebulized racemic epinephrine improved croup score within 10 to 30 minutes.⁵

A small RCT (31 children, 6 months to 6 years of age) demonstrated L-epinephrine [1:1000] to be as effective and well tolerated as racemic epinephrine in moderate to severe croup. Improvement in croup score and respiratory rate peaked at 30 minutes. The effect of epinephrine (racemic or L-form) didn’t last beyond 120 minutes.⁶

In a retrospective study of 50 children with croup who were given aerosolized racemic epinephrine and observed in the ED for 2 hours after treatment, 58% received steroids during observation and 34% were prescribed prednisolone at discharge. Only 1 child required a return visit within 48 hours.⁷

Effect of helium-oxygen mixtures isn’t clear
A 2010 Cochrane review identified 2 RCTs of heliox in acute croup. No significant differences in croup score changes were found when heliox was compared with 30% oxygen (n=15, mild to moderate croup) and 100% oxygen with prn nebulized racemic epinephrine (n=29, moderate to severe croup).⁸ Both studies were underpowered and had significant methodological limitations.

Humidified air shows no benefit
A Cochrane review of 3 RCTs comparing humidified air with room air in emergency settings (n=135) found no evidence of benefit in croup score, oxygen saturation, or pulse rate.⁹

Recommendations

The 2008 Alberta Medical Association guideline recommends that all children with croup be treated with 0.6 mg/kg oral dexamethasone.¹⁰ Children with mild croup can be discharged home without further observation. Children with moderate croup should be observed for at least 4 hours. Hospitalization should be considered for children who fail to show adequate improvement. The guideline advises giving both steroids and nebulized epinephrine to children with severe croup.

The Advanced Pediatric Life Support (APLS) course of the American Academy of Pediatrics and the American College of Emergency Physicians recommends treatment with corticosteroids.¹¹ For severe croup, the APLS advocates racemic or L-epinephrine, followed by observation for 3 or 4 hours and hospital admission in the event of inadequate response or recurrence of severe distress.

Evidence summary

Standard management for croup has included glucocorticoids, nebulized racemic epinephrine, humidified air, and, for patients with severe respiratory distress and impending respiratory failure, helium-oxygen mixtures.

Glucocorticoids have significant benefits
A 2011 Cochrane review of glucocorticoids in children with croup identified 38 RCTs with 4299 patients.¹ Effective treatments included dexamethasone (oral, subcutaneous, intramuscular, nebulized), budesonide (inhaled), and prednisolone (oral). Meta-analysis revealed a significant decrease in the rate of return visits and (re)admissions for patients treated with glucocorticoids compared with placebo (relative risk=0.5; 95% confidence interval [CI], 0.3-0.7). Glucocorticoid-treated children spent less time in the ED or hospital (weighted mean difference=-12 hours; 95% CI, -5 to -19) and were less likely to need epinephrine (risk difference=10%; 95% CI, 1%-20%).

The standardized improvement in the Westley score (TABLE) for all glucocorticoid treatments compared with placebo was -1.2 (95% CI, -1.6 to -0.8) at 6 hours and -1.9 (95% CI, -2.4 to -1.3) at 12 hours. No statistically significant difference was found at 24 hours (-1.3; 95% CI, -2.7 to 0.2). The combined studies favored glucocorticoids over placebo with a number needed to treat of 5. Meta-regression analysis didn’t demonstrate superiority for any single glucocorticoid.

A single 0.15 mg/kg dose of oral dexamethasone proved as effective as higher doses of 0.3 to 0.6 mg/kg in 3 RCTs (N=100, 120, and 99).^2-4

TABLE
Westley Croup Score⁵

Nebulized epinephrine improves moderate to severe croup
Three RCTs (N=54, 20, and 13) found that in moderate to severe croup, treatment with nebulized racemic epinephrine improved croup score within 10 to 30 minutes.⁵

A small RCT (31 children, 6 months to 6 years of age) demonstrated L-epinephrine [1:1000] to be as effective and well tolerated as racemic epinephrine in moderate to severe croup. Improvement in croup score and respiratory rate peaked at 30 minutes. The effect of epinephrine (racemic or L-form) didn’t last beyond 120 minutes.⁶

In a retrospective study of 50 children with croup who were given aerosolized racemic epinephrine and observed in the ED for 2 hours after treatment, 58% received steroids during observation and 34% were prescribed prednisolone at discharge. Only 1 child required a return visit within 48 hours.⁷

Effect of helium-oxygen mixtures isn’t clear
A 2010 Cochrane review identified 2 RCTs of heliox in acute croup. No significant differences in croup score changes were found when heliox was compared with 30% oxygen (n=15, mild to moderate croup) and 100% oxygen with prn nebulized racemic epinephrine (n=29, moderate to severe croup).⁸ Both studies were underpowered and had significant methodological limitations.

Humidified air shows no benefit
A Cochrane review of 3 RCTs comparing humidified air with room air in emergency settings (n=135) found no evidence of benefit in croup score, oxygen saturation, or pulse rate.⁹

Recommendations

The 2008 Alberta Medical Association guideline recommends that all children with croup be treated with 0.6 mg/kg oral dexamethasone.¹⁰ Children with mild croup can be discharged home without further observation. Children with moderate croup should be observed for at least 4 hours. Hospitalization should be considered for children who fail to show adequate improvement. The guideline advises giving both steroids and nebulized epinephrine to children with severe croup.

The Advanced Pediatric Life Support (APLS) course of the American Academy of Pediatrics and the American College of Emergency Physicians recommends treatment with corticosteroids.¹¹ For severe croup, the APLS advocates racemic or L-epinephrine, followed by observation for 3 or 4 hours and hospital admission in the event of inadequate response or recurrence of severe distress.