Vanessa McPherson, MD

Evidence summary

Multiple cohort studies demonstrate that the expected events of normal labor form a bell-shaped curve. The range of labor experiences makes predicting when a particular woman will enter active labor difficult.

When does latent labor become active labor?

The first stage of labor includes latent and active phases. The latent phase is defined as the period between onset of labor and cervical dilatation of 3 to 4 cm or the time between onset of regular contractions and escalation in the rate of cervical dilation. Regular contractions must be intense, last 60 seconds, and occur in a predictable pattern. Escalating cervical dilation is marked by a change in the cervical examination over a short period of time (usually 2 hours).¹

The World Health Organization defines active labor as cervical dilation between 4 and 9 cm, with dilation usually occurring at 1 cm per hour or faster and accompanied by the beginning of fetal descent.²

Latent labor was initially described in a large prospective cohort of 10,293 term gravidas (including 4175 nulliparas and 5599 multiparas) followed from presentation to delivery.¹ Cervical dilation was assessed by examination every 30 to 120 minutes, almost always performed by the same examiner throughout labor. In primigravidas, latent labor averaged 6.4 hours, with 95% of women completing the latent phase in 20.6 hours. In multigravidas, the mean duration of latent labor was 4.8 hours, with 95% of women transitioning to active labor in 13.6 hours.

Shorter intercontraction interval linked to active labor

A recently published cohort study of women presenting to labor and delivery found that a relative decrease in the intercontraction interval was associated with a diagnosis of labor (odds ratio=1.42; 95% confidence interval, 1.06-1.90). The study failed to define either active labor or decrease in the intercontraction interval.³

Earlier admission leads to more interventions and poorer outcomes

Many studies have suggested that admitting women to the hospital during the latent phase of labor is associated with more interventions and poorer outcomes. Two large retrospective cohort studies (N=2697 and 3220) found increased rates of cesarean section in women admitted during the latent phase.^4,5 They also reported increased use of oxytocin, epidural analgesia, intrauterine pressure catheters, and fetal scalp electrodes, and increased rates of chorioamnionitis, postpartum infection, and neonatal intubation.^4,5 See the TABLE for a summary of the effects of latent-phase admission.

TABLE
Consequences of hospital admission during latent vs active labor

Labor assessment program reduced time in the labor ward

Labor assessment programs attempt to delay admission during early active labor. One randomized clinical trial (N=209) among low-risk women with reassuring maternal and fetal assessments in early labor divided the women into 2 groups when they presented for labor and delivery. One group received advice, encouragement, and support along with instructions to walk or return home and come back when labor became more active (defined as regular, painful contractions and dilation of at least 3 cm). The other group was admitted directly to the labor and delivery ward. The study found that early labor assessment decreased use of analgesics and oxytocin and reduced time spent in the labor ward.⁶

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) acknowledges in patient education literature that distinguishing true from false labor is difficult. ACOG lists characteristics of each and recommend that a woman monitor the frequency of contractions for an hour and call the doctor’s office or hospital if she thinks she’s in labor.⁷

Similarly, a patient handout from the American College of Nurse-Midwives recommends calling the health care provider if contractions are ≤5 minutes apart for more than 1 hour, several contractions are so painful that the woman cannot walk or talk, or her water breaks.⁸

A standard textbook describes normal uterine contractions during active labor as occurring every 2 to 5 minutes, and as often as every 2 to 3 minutes.⁹

Evidence summary

Multiple cohort studies demonstrate that the expected events of normal labor form a bell-shaped curve. The range of labor experiences makes predicting when a particular woman will enter active labor difficult.

When does latent labor become active labor?

The first stage of labor includes latent and active phases. The latent phase is defined as the period between onset of labor and cervical dilatation of 3 to 4 cm or the time between onset of regular contractions and escalation in the rate of cervical dilation. Regular contractions must be intense, last 60 seconds, and occur in a predictable pattern. Escalating cervical dilation is marked by a change in the cervical examination over a short period of time (usually 2 hours).¹

The World Health Organization defines active labor as cervical dilation between 4 and 9 cm, with dilation usually occurring at 1 cm per hour or faster and accompanied by the beginning of fetal descent.²

Latent labor was initially described in a large prospective cohort of 10,293 term gravidas (including 4175 nulliparas and 5599 multiparas) followed from presentation to delivery.¹ Cervical dilation was assessed by examination every 30 to 120 minutes, almost always performed by the same examiner throughout labor. In primigravidas, latent labor averaged 6.4 hours, with 95% of women completing the latent phase in 20.6 hours. In multigravidas, the mean duration of latent labor was 4.8 hours, with 95% of women transitioning to active labor in 13.6 hours.

Shorter intercontraction interval linked to active labor

A recently published cohort study of women presenting to labor and delivery found that a relative decrease in the intercontraction interval was associated with a diagnosis of labor (odds ratio=1.42; 95% confidence interval, 1.06-1.90). The study failed to define either active labor or decrease in the intercontraction interval.³

Earlier admission leads to more interventions and poorer outcomes

Many studies have suggested that admitting women to the hospital during the latent phase of labor is associated with more interventions and poorer outcomes. Two large retrospective cohort studies (N=2697 and 3220) found increased rates of cesarean section in women admitted during the latent phase.^4,5 They also reported increased use of oxytocin, epidural analgesia, intrauterine pressure catheters, and fetal scalp electrodes, and increased rates of chorioamnionitis, postpartum infection, and neonatal intubation.^4,5 See the TABLE for a summary of the effects of latent-phase admission.

TABLE
Consequences of hospital admission during latent vs active labor

Labor assessment program reduced time in the labor ward

Labor assessment programs attempt to delay admission during early active labor. One randomized clinical trial (N=209) among low-risk women with reassuring maternal and fetal assessments in early labor divided the women into 2 groups when they presented for labor and delivery. One group received advice, encouragement, and support along with instructions to walk or return home and come back when labor became more active (defined as regular, painful contractions and dilation of at least 3 cm). The other group was admitted directly to the labor and delivery ward. The study found that early labor assessment decreased use of analgesics and oxytocin and reduced time spent in the labor ward.⁶

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) acknowledges in patient education literature that distinguishing true from false labor is difficult. ACOG lists characteristics of each and recommend that a woman monitor the frequency of contractions for an hour and call the doctor’s office or hospital if she thinks she’s in labor.⁷

Similarly, a patient handout from the American College of Nurse-Midwives recommends calling the health care provider if contractions are ≤5 minutes apart for more than 1 hour, several contractions are so painful that the woman cannot walk or talk, or her water breaks.⁸

A standard textbook describes normal uterine contractions during active labor as occurring every 2 to 5 minutes, and as often as every 2 to 3 minutes.⁹

Evidence summary

Multiple cohort studies demonstrate that the expected events of normal labor form a bell-shaped curve. The range of labor experiences makes predicting when a particular woman will enter active labor difficult.

When does latent labor become active labor?

The first stage of labor includes latent and active phases. The latent phase is defined as the period between onset of labor and cervical dilatation of 3 to 4 cm or the time between onset of regular contractions and escalation in the rate of cervical dilation. Regular contractions must be intense, last 60 seconds, and occur in a predictable pattern. Escalating cervical dilation is marked by a change in the cervical examination over a short period of time (usually 2 hours).¹

The World Health Organization defines active labor as cervical dilation between 4 and 9 cm, with dilation usually occurring at 1 cm per hour or faster and accompanied by the beginning of fetal descent.²

Latent labor was initially described in a large prospective cohort of 10,293 term gravidas (including 4175 nulliparas and 5599 multiparas) followed from presentation to delivery.¹ Cervical dilation was assessed by examination every 30 to 120 minutes, almost always performed by the same examiner throughout labor. In primigravidas, latent labor averaged 6.4 hours, with 95% of women completing the latent phase in 20.6 hours. In multigravidas, the mean duration of latent labor was 4.8 hours, with 95% of women transitioning to active labor in 13.6 hours.

Shorter intercontraction interval linked to active labor

A recently published cohort study of women presenting to labor and delivery found that a relative decrease in the intercontraction interval was associated with a diagnosis of labor (odds ratio=1.42; 95% confidence interval, 1.06-1.90). The study failed to define either active labor or decrease in the intercontraction interval.³

Earlier admission leads to more interventions and poorer outcomes

Many studies have suggested that admitting women to the hospital during the latent phase of labor is associated with more interventions and poorer outcomes. Two large retrospective cohort studies (N=2697 and 3220) found increased rates of cesarean section in women admitted during the latent phase.^4,5 They also reported increased use of oxytocin, epidural analgesia, intrauterine pressure catheters, and fetal scalp electrodes, and increased rates of chorioamnionitis, postpartum infection, and neonatal intubation.^4,5 See the TABLE for a summary of the effects of latent-phase admission.

TABLE
Consequences of hospital admission during latent vs active labor

Labor assessment program reduced time in the labor ward

Labor assessment programs attempt to delay admission during early active labor. One randomized clinical trial (N=209) among low-risk women with reassuring maternal and fetal assessments in early labor divided the women into 2 groups when they presented for labor and delivery. One group received advice, encouragement, and support along with instructions to walk or return home and come back when labor became more active (defined as regular, painful contractions and dilation of at least 3 cm). The other group was admitted directly to the labor and delivery ward. The study found that early labor assessment decreased use of analgesics and oxytocin and reduced time spent in the labor ward.⁶

Recommendations

The American College of Obstetricians and Gynecologists (ACOG) acknowledges in patient education literature that distinguishing true from false labor is difficult. ACOG lists characteristics of each and recommend that a woman monitor the frequency of contractions for an hour and call the doctor’s office or hospital if she thinks she’s in labor.⁷

Similarly, a patient handout from the American College of Nurse-Midwives recommends calling the health care provider if contractions are ≤5 minutes apart for more than 1 hour, several contractions are so painful that the woman cannot walk or talk, or her water breaks.⁸

A standard textbook describes normal uterine contractions during active labor as occurring every 2 to 5 minutes, and as often as every 2 to 3 minutes.⁹

Evidence summary

Urinary tract infections (UTIs) are common in reproductive-aged women. In lactating women, it’s important to select a therapy that is not only effective, but also safe for the breastfeeding infant. No studies in the literature address the safety or efficacy of UTI treatments in lactating women and their infants. Therefore, recommendations are extrapolated from studies of efficacy in the general population, studies of antibiotic penetration into breast milk, and effects of antibiotics given to infants directly.

How the efficacy of UTI treatments stack up

The best evidence for efficacy of UTI treatments comes from a 1999 meta-analysis of uncomplicated UTI in nonpregnant, nonlactating women.¹ They found TMP/SMX to be the most widely studied antibiotic and to have a 93% bacterial eradication rate; it was therefore used as a standard for comparison of other treatments. Nitrofurantoin and quinolones (ofloxacin, ciprofloxacin, and others) had comparable eradication rates to TMP/SMX in the same study; 7-day courses of nitrofurantoin were more efficacious than shorter ones. TMP/SMX is not recommended if the local resistance rate is more than 10% to 20%.²

Three-day therapy for uncomplicated UTI is more effective than single-dose therapy and equal to longer courses for most antibiotics.¹ A longer course (7 days) may be required for nitrofurantoin. Beta-lactams are associated with high levels of resistance and therefore not recommended in empiric treatment of UTI.²

A look at penetration into breast milk

Most of the data regarding antibiotic penetration into breast milk come from case series. One South African series measured breast milk levels of both trimethoprim and sulfamethoxazole among 50 Bantu women treated with TMP/SMX for various infections (including UTI).³ The women received 160 mg TMP and 800 mg SMX 2 or 3 times daily for up to 5 days. The average level of TMP in breast milk was 2 mcg/mL, and the level of SMX was 4.7 mcg/mL. Researchers calculated that the average breastfeeding infant would ingest only 1 mg of TMP and 2.5 mg of SMX per day. TMP/SMX is generally considered safe for infants in the absence of G6PD deficiency.

In a case series, 9 lactating mothers were given nitrofurantoin 100 mg orally every 6 hours for 1 day.⁴ On day 2, after a single 100 to 200 mg dose, drug levels in the breast milk 2 hours post-dose ranged from none (in 6 of the 9 women) to a maximum of 0.5 mcg/mL in one. Since even a very small amount of the drug may trigger a hemolytic reaction among G6PD-deficient individuals, the researchers called for caution when prescribing to mothers from high-risk populations.

A final case seriesadministered ciprofloxacin 750 mg, pefloxacin 400 mg, or ofloxacin 400 mg twice daily to 3 groups of 10 women each.⁵ Milk samples were obtained 6 times over 24 hours following the third dose of antibiotic. Maximum levels in breast milk occurred 2 hours after the dose, and were 3.79, 3.54, and 2.41 mcg/mL for ciprofloxacin, pefloxacin, and ofloxacin respectively. All 3 quinolones achieved higher concentrations in breast milk than in serum.

But are these drugs safe for children?

While TMP/SMX and nitrofurantoin are generally considered safe when given to infants and children (barring G6PD deficiency), data are mixed regarding the safety of quinolones. Ciprofloxacin’s FDA indication for pediatric patients is limited to postexposure anthrax prophylaxis due to evidence of fluoroquinolone-induced joint toxicity in animal studies.⁶ Despite this, they have been prescribed to tens of thousands of children for select scenarios such as chemotherapy-induced immuno-compromise, cystic fibrosis, complicated UTIs, and salmonella infections.⁷

A report was published summarizing safety data from the Bayer database of compassionate use of ciprofloxacin.⁸ The report indicates that 2030 treatment courses of ciprofloxacin were given to 1795 children up to age 17 for a variety of infections; only 3% were under age 5. Most patients received 21 to 40 mg/kg of ciprofloxacin per day; treatment duration was from 1 to 303 days. Arthralgia occurred in 1.5% of patients, most of whom had cystic fibrosis. Of the 31 patients affected, arthralgias resolved in 25, improved in 1, and remained unchanged in 1. (Data regarding resolution were unavailable for 4 patients.)

Recommendations from others

The American Academy of Pediatrics’ Committee on Drugsconsiders the following antibiotics typically used for UTI to be compatible with breastfeeding: ciprofloxacin, ofloxacin, nitrofurantoin (caution for infants with G6PD deficiency), and TMP/SMX.⁹

Drugs in Pregnancy and Lactation considers trimethoprim and sulfamethoxazole to be compatible with breastfeeding but cautions against sulfamethoxazole use in infants with known G6PD deficiency. The authors categorize nitrofurantoin, ciprofloxacin, and ofloxacin as “probably compatible/limited human data,” and advise caution with nitrofurantoin for infants with G6PD deficiency.¹⁰

Evidence summary

Urinary tract infections (UTIs) are common in reproductive-aged women. In lactating women, it’s important to select a therapy that is not only effective, but also safe for the breastfeeding infant. No studies in the literature address the safety or efficacy of UTI treatments in lactating women and their infants. Therefore, recommendations are extrapolated from studies of efficacy in the general population, studies of antibiotic penetration into breast milk, and effects of antibiotics given to infants directly.

How the efficacy of UTI treatments stack up

The best evidence for efficacy of UTI treatments comes from a 1999 meta-analysis of uncomplicated UTI in nonpregnant, nonlactating women.¹ They found TMP/SMX to be the most widely studied antibiotic and to have a 93% bacterial eradication rate; it was therefore used as a standard for comparison of other treatments. Nitrofurantoin and quinolones (ofloxacin, ciprofloxacin, and others) had comparable eradication rates to TMP/SMX in the same study; 7-day courses of nitrofurantoin were more efficacious than shorter ones. TMP/SMX is not recommended if the local resistance rate is more than 10% to 20%.²

Three-day therapy for uncomplicated UTI is more effective than single-dose therapy and equal to longer courses for most antibiotics.¹ A longer course (7 days) may be required for nitrofurantoin. Beta-lactams are associated with high levels of resistance and therefore not recommended in empiric treatment of UTI.²

A look at penetration into breast milk

Most of the data regarding antibiotic penetration into breast milk come from case series. One South African series measured breast milk levels of both trimethoprim and sulfamethoxazole among 50 Bantu women treated with TMP/SMX for various infections (including UTI).³ The women received 160 mg TMP and 800 mg SMX 2 or 3 times daily for up to 5 days. The average level of TMP in breast milk was 2 mcg/mL, and the level of SMX was 4.7 mcg/mL. Researchers calculated that the average breastfeeding infant would ingest only 1 mg of TMP and 2.5 mg of SMX per day. TMP/SMX is generally considered safe for infants in the absence of G6PD deficiency.

In a case series, 9 lactating mothers were given nitrofurantoin 100 mg orally every 6 hours for 1 day.⁴ On day 2, after a single 100 to 200 mg dose, drug levels in the breast milk 2 hours post-dose ranged from none (in 6 of the 9 women) to a maximum of 0.5 mcg/mL in one. Since even a very small amount of the drug may trigger a hemolytic reaction among G6PD-deficient individuals, the researchers called for caution when prescribing to mothers from high-risk populations.

A final case seriesadministered ciprofloxacin 750 mg, pefloxacin 400 mg, or ofloxacin 400 mg twice daily to 3 groups of 10 women each.⁵ Milk samples were obtained 6 times over 24 hours following the third dose of antibiotic. Maximum levels in breast milk occurred 2 hours after the dose, and were 3.79, 3.54, and 2.41 mcg/mL for ciprofloxacin, pefloxacin, and ofloxacin respectively. All 3 quinolones achieved higher concentrations in breast milk than in serum.

But are these drugs safe for children?

While TMP/SMX and nitrofurantoin are generally considered safe when given to infants and children (barring G6PD deficiency), data are mixed regarding the safety of quinolones. Ciprofloxacin’s FDA indication for pediatric patients is limited to postexposure anthrax prophylaxis due to evidence of fluoroquinolone-induced joint toxicity in animal studies.⁶ Despite this, they have been prescribed to tens of thousands of children for select scenarios such as chemotherapy-induced immuno-compromise, cystic fibrosis, complicated UTIs, and salmonella infections.⁷

A report was published summarizing safety data from the Bayer database of compassionate use of ciprofloxacin.⁸ The report indicates that 2030 treatment courses of ciprofloxacin were given to 1795 children up to age 17 for a variety of infections; only 3% were under age 5. Most patients received 21 to 40 mg/kg of ciprofloxacin per day; treatment duration was from 1 to 303 days. Arthralgia occurred in 1.5% of patients, most of whom had cystic fibrosis. Of the 31 patients affected, arthralgias resolved in 25, improved in 1, and remained unchanged in 1. (Data regarding resolution were unavailable for 4 patients.)

Recommendations from others

The American Academy of Pediatrics’ Committee on Drugsconsiders the following antibiotics typically used for UTI to be compatible with breastfeeding: ciprofloxacin, ofloxacin, nitrofurantoin (caution for infants with G6PD deficiency), and TMP/SMX.⁹

Drugs in Pregnancy and Lactation considers trimethoprim and sulfamethoxazole to be compatible with breastfeeding but cautions against sulfamethoxazole use in infants with known G6PD deficiency. The authors categorize nitrofurantoin, ciprofloxacin, and ofloxacin as “probably compatible/limited human data,” and advise caution with nitrofurantoin for infants with G6PD deficiency.¹⁰

Evidence summary

Urinary tract infections (UTIs) are common in reproductive-aged women. In lactating women, it’s important to select a therapy that is not only effective, but also safe for the breastfeeding infant. No studies in the literature address the safety or efficacy of UTI treatments in lactating women and their infants. Therefore, recommendations are extrapolated from studies of efficacy in the general population, studies of antibiotic penetration into breast milk, and effects of antibiotics given to infants directly.

How the efficacy of UTI treatments stack up

The best evidence for efficacy of UTI treatments comes from a 1999 meta-analysis of uncomplicated UTI in nonpregnant, nonlactating women.¹ They found TMP/SMX to be the most widely studied antibiotic and to have a 93% bacterial eradication rate; it was therefore used as a standard for comparison of other treatments. Nitrofurantoin and quinolones (ofloxacin, ciprofloxacin, and others) had comparable eradication rates to TMP/SMX in the same study; 7-day courses of nitrofurantoin were more efficacious than shorter ones. TMP/SMX is not recommended if the local resistance rate is more than 10% to 20%.²

Three-day therapy for uncomplicated UTI is more effective than single-dose therapy and equal to longer courses for most antibiotics.¹ A longer course (7 days) may be required for nitrofurantoin. Beta-lactams are associated with high levels of resistance and therefore not recommended in empiric treatment of UTI.²

A look at penetration into breast milk

Most of the data regarding antibiotic penetration into breast milk come from case series. One South African series measured breast milk levels of both trimethoprim and sulfamethoxazole among 50 Bantu women treated with TMP/SMX for various infections (including UTI).³ The women received 160 mg TMP and 800 mg SMX 2 or 3 times daily for up to 5 days. The average level of TMP in breast milk was 2 mcg/mL, and the level of SMX was 4.7 mcg/mL. Researchers calculated that the average breastfeeding infant would ingest only 1 mg of TMP and 2.5 mg of SMX per day. TMP/SMX is generally considered safe for infants in the absence of G6PD deficiency.

In a case series, 9 lactating mothers were given nitrofurantoin 100 mg orally every 6 hours for 1 day.⁴ On day 2, after a single 100 to 200 mg dose, drug levels in the breast milk 2 hours post-dose ranged from none (in 6 of the 9 women) to a maximum of 0.5 mcg/mL in one. Since even a very small amount of the drug may trigger a hemolytic reaction among G6PD-deficient individuals, the researchers called for caution when prescribing to mothers from high-risk populations.

A final case seriesadministered ciprofloxacin 750 mg, pefloxacin 400 mg, or ofloxacin 400 mg twice daily to 3 groups of 10 women each.⁵ Milk samples were obtained 6 times over 24 hours following the third dose of antibiotic. Maximum levels in breast milk occurred 2 hours after the dose, and were 3.79, 3.54, and 2.41 mcg/mL for ciprofloxacin, pefloxacin, and ofloxacin respectively. All 3 quinolones achieved higher concentrations in breast milk than in serum.

But are these drugs safe for children?

While TMP/SMX and nitrofurantoin are generally considered safe when given to infants and children (barring G6PD deficiency), data are mixed regarding the safety of quinolones. Ciprofloxacin’s FDA indication for pediatric patients is limited to postexposure anthrax prophylaxis due to evidence of fluoroquinolone-induced joint toxicity in animal studies.⁶ Despite this, they have been prescribed to tens of thousands of children for select scenarios such as chemotherapy-induced immuno-compromise, cystic fibrosis, complicated UTIs, and salmonella infections.⁷

A report was published summarizing safety data from the Bayer database of compassionate use of ciprofloxacin.⁸ The report indicates that 2030 treatment courses of ciprofloxacin were given to 1795 children up to age 17 for a variety of infections; only 3% were under age 5. Most patients received 21 to 40 mg/kg of ciprofloxacin per day; treatment duration was from 1 to 303 days. Arthralgia occurred in 1.5% of patients, most of whom had cystic fibrosis. Of the 31 patients affected, arthralgias resolved in 25, improved in 1, and remained unchanged in 1. (Data regarding resolution were unavailable for 4 patients.)

Recommendations from others

The American Academy of Pediatrics’ Committee on Drugsconsiders the following antibiotics typically used for UTI to be compatible with breastfeeding: ciprofloxacin, ofloxacin, nitrofurantoin (caution for infants with G6PD deficiency), and TMP/SMX.⁹

Drugs in Pregnancy and Lactation considers trimethoprim and sulfamethoxazole to be compatible with breastfeeding but cautions against sulfamethoxazole use in infants with known G6PD deficiency. The authors categorize nitrofurantoin, ciprofloxacin, and ofloxacin as “probably compatible/limited human data,” and advise caution with nitrofurantoin for infants with G6PD deficiency.¹⁰

TABLE 1
Interventions that affect vomiting or regurgitation

TABLE 2
Interventions that affect pH probe/measured reflux

Evidence summary

Regurgitation (“spitting up”) and gastroesophageal reflux are common in infants. In a cross-sectional survey of 948 parents of healthy infants aged 0 to 13 months, regurgitation occurred daily in half of infants from birth to 3 months old, peaked to 67% at age 4 months, and was absent in 95% by age 12 months.¹ Gastroesophageal disease (GERD) is characterized by refractory symptoms or complications (pain, irritability, vomiting, failure to thrive, dysphagia, respiratory symptoms, or esophagitis) and occurs in the minority of infants with reflux.² This distinguishes the “happy spitter,” whose parents may simply require reassurance, from infants who require treatment.

Unfortunately, most of the available studies do not make this distinction in their subjects. Also, available data primarily regard formula-fed infants, and are insufficient to make recommendations for breastfed infants. Esophageal pH probe monitoring is the gold standard for measuring reflux in research; however, its correlation with symptoms is questionable and it is infrequently used in clinical practice.³ Therefore, recommendations are focused primarily on treating only clinically-evident reflux (emesis and regurgitation).

Five small RCTs studied the practice of using formula thickeners (TABLES 1 AND 2). In 1 study, formula thickened with rice cereal decreased emesis episodes.⁴ Two studies of carob bean gum–thickened formula vs plain formula yielded conflicting results.^5,6 In the study showing improvement with carob bean gum, the parents were not blinded to the treatment, which may have led to bias favoring the treatment.⁵ An uncontrolled, comparative trial of carob bean gum vs rice cereal suggested superiority of carob bean gum as a thickener, although both treatments yielded improvement.⁷ Carob bean gum is available in the UK as a powder (Instant Carobel) but is not widely available in the US.

Three trials studied the effects of other conservative therapies such as positional changes and pacifiers on reflux measured by pH probe; unfortunately, none assessed clinical outcomes such as emesis or regurgitation.³ Reflux by pH probe was worsened in a trial studying the infant seat for positioning. In the trial studying elevating the head of the bed to 30° in the prone position, reflux measured by pH probe was also unchanged; prone positioning is no longer recommended due to the risk of Sudden Infant Death Syndrome (SIDS).⁸ The trial of pacifier use showed improvement of reflux by pH probe when used in the seated position, but worsening in the prone position. Since pH probe does not necessarily reflect clinical symptoms, the utility of the information from these studies is limited.

Only 1 trial of drugs used to treat infant reflux measured clinical symptoms. This large manufacturer-sponsored RCT found that sodium alginate⁹ significantly reduced emesis episodes in treated infants. Sodium alginate is marketed in the UK as Gaviscon Infant. While this trial included breastfed infants, it did not report the numbers of breastfed infants in the 2 treatment groups or present data separately for breastfed infants. Small RCTs of metoclopramide¹⁰ and omeprazole¹¹ show significant improvement in reflux index measured by pH probe. However, metoclopramide yielded no improvement in symptom counts, and the omeprazole study resulted in no differences in “cry-fuss time” between treatment groups.

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends thickening agents or a trial of hypoallergenic formula for vomiting infants.² They caution against prone positioning and favor proton pump inhibitors over H2 blockers for symptomatic relief and healing of esophagitis. They found insufficient evidence to recommend surgery over medication.

TABLE 1
Interventions that affect vomiting or regurgitation

TABLE 2
Interventions that affect pH probe/measured reflux

Evidence summary

Regurgitation (“spitting up”) and gastroesophageal reflux are common in infants. In a cross-sectional survey of 948 parents of healthy infants aged 0 to 13 months, regurgitation occurred daily in half of infants from birth to 3 months old, peaked to 67% at age 4 months, and was absent in 95% by age 12 months.¹ Gastroesophageal disease (GERD) is characterized by refractory symptoms or complications (pain, irritability, vomiting, failure to thrive, dysphagia, respiratory symptoms, or esophagitis) and occurs in the minority of infants with reflux.² This distinguishes the “happy spitter,” whose parents may simply require reassurance, from infants who require treatment.

Unfortunately, most of the available studies do not make this distinction in their subjects. Also, available data primarily regard formula-fed infants, and are insufficient to make recommendations for breastfed infants. Esophageal pH probe monitoring is the gold standard for measuring reflux in research; however, its correlation with symptoms is questionable and it is infrequently used in clinical practice.³ Therefore, recommendations are focused primarily on treating only clinically-evident reflux (emesis and regurgitation).

Five small RCTs studied the practice of using formula thickeners (TABLES 1 AND 2). In 1 study, formula thickened with rice cereal decreased emesis episodes.⁴ Two studies of carob bean gum–thickened formula vs plain formula yielded conflicting results.^5,6 In the study showing improvement with carob bean gum, the parents were not blinded to the treatment, which may have led to bias favoring the treatment.⁵ An uncontrolled, comparative trial of carob bean gum vs rice cereal suggested superiority of carob bean gum as a thickener, although both treatments yielded improvement.⁷ Carob bean gum is available in the UK as a powder (Instant Carobel) but is not widely available in the US.

Three trials studied the effects of other conservative therapies such as positional changes and pacifiers on reflux measured by pH probe; unfortunately, none assessed clinical outcomes such as emesis or regurgitation.³ Reflux by pH probe was worsened in a trial studying the infant seat for positioning. In the trial studying elevating the head of the bed to 30° in the prone position, reflux measured by pH probe was also unchanged; prone positioning is no longer recommended due to the risk of Sudden Infant Death Syndrome (SIDS).⁸ The trial of pacifier use showed improvement of reflux by pH probe when used in the seated position, but worsening in the prone position. Since pH probe does not necessarily reflect clinical symptoms, the utility of the information from these studies is limited.

Only 1 trial of drugs used to treat infant reflux measured clinical symptoms. This large manufacturer-sponsored RCT found that sodium alginate⁹ significantly reduced emesis episodes in treated infants. Sodium alginate is marketed in the UK as Gaviscon Infant. While this trial included breastfed infants, it did not report the numbers of breastfed infants in the 2 treatment groups or present data separately for breastfed infants. Small RCTs of metoclopramide¹⁰ and omeprazole¹¹ show significant improvement in reflux index measured by pH probe. However, metoclopramide yielded no improvement in symptom counts, and the omeprazole study resulted in no differences in “cry-fuss time” between treatment groups.

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends thickening agents or a trial of hypoallergenic formula for vomiting infants.² They caution against prone positioning and favor proton pump inhibitors over H2 blockers for symptomatic relief and healing of esophagitis. They found insufficient evidence to recommend surgery over medication.

TABLE 1
Interventions that affect vomiting or regurgitation

TABLE 2
Interventions that affect pH probe/measured reflux

Evidence summary

Regurgitation (“spitting up”) and gastroesophageal reflux are common in infants. In a cross-sectional survey of 948 parents of healthy infants aged 0 to 13 months, regurgitation occurred daily in half of infants from birth to 3 months old, peaked to 67% at age 4 months, and was absent in 95% by age 12 months.¹ Gastroesophageal disease (GERD) is characterized by refractory symptoms or complications (pain, irritability, vomiting, failure to thrive, dysphagia, respiratory symptoms, or esophagitis) and occurs in the minority of infants with reflux.² This distinguishes the “happy spitter,” whose parents may simply require reassurance, from infants who require treatment.

Unfortunately, most of the available studies do not make this distinction in their subjects. Also, available data primarily regard formula-fed infants, and are insufficient to make recommendations for breastfed infants. Esophageal pH probe monitoring is the gold standard for measuring reflux in research; however, its correlation with symptoms is questionable and it is infrequently used in clinical practice.³ Therefore, recommendations are focused primarily on treating only clinically-evident reflux (emesis and regurgitation).

Five small RCTs studied the practice of using formula thickeners (TABLES 1 AND 2). In 1 study, formula thickened with rice cereal decreased emesis episodes.⁴ Two studies of carob bean gum–thickened formula vs plain formula yielded conflicting results.^5,6 In the study showing improvement with carob bean gum, the parents were not blinded to the treatment, which may have led to bias favoring the treatment.⁵ An uncontrolled, comparative trial of carob bean gum vs rice cereal suggested superiority of carob bean gum as a thickener, although both treatments yielded improvement.⁷ Carob bean gum is available in the UK as a powder (Instant Carobel) but is not widely available in the US.

Three trials studied the effects of other conservative therapies such as positional changes and pacifiers on reflux measured by pH probe; unfortunately, none assessed clinical outcomes such as emesis or regurgitation.³ Reflux by pH probe was worsened in a trial studying the infant seat for positioning. In the trial studying elevating the head of the bed to 30° in the prone position, reflux measured by pH probe was also unchanged; prone positioning is no longer recommended due to the risk of Sudden Infant Death Syndrome (SIDS).⁸ The trial of pacifier use showed improvement of reflux by pH probe when used in the seated position, but worsening in the prone position. Since pH probe does not necessarily reflect clinical symptoms, the utility of the information from these studies is limited.

Only 1 trial of drugs used to treat infant reflux measured clinical symptoms. This large manufacturer-sponsored RCT found that sodium alginate⁹ significantly reduced emesis episodes in treated infants. Sodium alginate is marketed in the UK as Gaviscon Infant. While this trial included breastfed infants, it did not report the numbers of breastfed infants in the 2 treatment groups or present data separately for breastfed infants. Small RCTs of metoclopramide¹⁰ and omeprazole¹¹ show significant improvement in reflux index measured by pH probe. However, metoclopramide yielded no improvement in symptom counts, and the omeprazole study resulted in no differences in “cry-fuss time” between treatment groups.

Recommendations from others

The North American Society for Pediatric Gastroenterology and Nutrition recommends thickening agents or a trial of hypoallergenic formula for vomiting infants.² They caution against prone positioning and favor proton pump inhibitors over H2 blockers for symptomatic relief and healing of esophagitis. They found insufficient evidence to recommend surgery over medication.

Evidence summary

Analgesic rebound headaches are seen in 1% of the population, mostly middle-aged women with underlying migraines.^1,2 Also termed analgesic-overuse headaches, they are defined by the International Headache Society guidelines as headaches occurring more than 15 days per month, mild to moderate in intensity, developing or worsening with analgesic overuse, and resolving or reverting to the prior underlying headache pattern within 2 months of discontinuing the analgesic(s).³

A case series studied 50 patients with rebound headaches for 5 or more days a week at baseline.⁴ Patients were educated regarding analgesic overuse headaches, after which their analgesics were abruptly discontinued, and they were followed up to a year. Subcutaneous DHE was used as needed for symptomatic relief of excruciating headaches. At study completion, 78% of patients had adequately stopped analgesics. The goal of greater than 6 consecutive headache-free days was achieved in 74% patients in an average of 84 days.

A 9-week double-blind, placebo-controlled trial randomized 20 nondepressed patients with analgesic overuse headache to receive amitriptyline or active placebo (trihexyphenidyl).⁵ Patients were admitted to the hospital for 1 week and withdrawn from all analgesics. The 2 groups had similar baseline characteristics. During the hospitalization, the amitriptyline treatment group received intravenous amitriptyline escalating from 25 to 75 mg. During the following month, oral study medications were continued, and patients took low doses of aspirin or acetaminophen, as needed. There was no significant difference between the 2 groups with regard to analgesic use. At completion of this low-powered study, no difference was found between the 2 groups in headache frequency or analgesic use, although certain components of a quality-of-life scale were better in the amitriptyline group.

An open-label trial of patients with chronic migraine and analgesic overuse in a headache sub-specialty center abruptly withdrew 150 participants from analgesics and quasi-randomized them to 3 groups: prednisone (tapering from 60 to 20 mg over 6 days), naratriptan (Amerge) (2.5 mg twice daily for 6 days), or no prophylactic treatment.⁶ Patients given the active substances were told it would reduce withdrawal symptoms; patients given placebo were not given this advice. All patients received education about the pathophysiology of rebound headaches, kept a headache diary, and were phoned weekly to ensure compliance. In addition, they all received capsules containing gradually increasing doses of atenolol, nortriptyline, and flunarazine (a calcium channel blocker not FDA-approved.) Indo-methacin and chlorpromazine were used as needed. Results from the first 6 days showed no difference in headaches between the 3 groups; however, significantly more patients used chlorpromazine in the “no pharmacologic treatment” group

By the end of 5 weeks, headache frequency was significantly reduced in all groups from baseline; however, there were no differences between groups in headache frequency or intensity in this small study. Of note, there were statistically fewer withdrawal symptoms and less use of rescue medications among patients who received the initial prophylactic treatments. The indomethacin rescue use was 24%, 18%, and 14% of patients for the no prophylactic treatment, prednisone, and naratriptan groups respectively, while chlorpromazine rescue use was 14%, 0%, and 0%, respectively. The number of patients needed to treat to prevent any withdrawal symptoms (nausea, vomiting, nervousness, dizziness, etc.) was 1 for every 3.5 for naratriptan, and 6.4 for prednisone.

Recommendations from others

The American Council for Headache Education recommends discontinuing all analgesics.⁷ It notes some patients may need prophylactic medication (although no specific agent is recommended), and hospitalization may be indicated for withdrawal for patients who have abused narcotics. A headache textbook recommends 1 of 2 approaches for patients undergoing outpatient treatment: (1) gradual tapering of the offending medication with substitution of a long-acting nonsteroidal anti-inflammatory drug (NSAID) and initiation of preventive therapy, or (2) abrupt discontinuation of the offending medication and initiation followed by gradual tapering of a “transitional” medication such as NSAIDs, DHE, corticosteroids, or triptans. The authors recommend an intravenous DHE protocol for treatment failures and patients requiring inpatient treatment.⁸

Evidence summary

Analgesic rebound headaches are seen in 1% of the population, mostly middle-aged women with underlying migraines.^1,2 Also termed analgesic-overuse headaches, they are defined by the International Headache Society guidelines as headaches occurring more than 15 days per month, mild to moderate in intensity, developing or worsening with analgesic overuse, and resolving or reverting to the prior underlying headache pattern within 2 months of discontinuing the analgesic(s).³

A case series studied 50 patients with rebound headaches for 5 or more days a week at baseline.⁴ Patients were educated regarding analgesic overuse headaches, after which their analgesics were abruptly discontinued, and they were followed up to a year. Subcutaneous DHE was used as needed for symptomatic relief of excruciating headaches. At study completion, 78% of patients had adequately stopped analgesics. The goal of greater than 6 consecutive headache-free days was achieved in 74% patients in an average of 84 days.

A 9-week double-blind, placebo-controlled trial randomized 20 nondepressed patients with analgesic overuse headache to receive amitriptyline or active placebo (trihexyphenidyl).⁵ Patients were admitted to the hospital for 1 week and withdrawn from all analgesics. The 2 groups had similar baseline characteristics. During the hospitalization, the amitriptyline treatment group received intravenous amitriptyline escalating from 25 to 75 mg. During the following month, oral study medications were continued, and patients took low doses of aspirin or acetaminophen, as needed. There was no significant difference between the 2 groups with regard to analgesic use. At completion of this low-powered study, no difference was found between the 2 groups in headache frequency or analgesic use, although certain components of a quality-of-life scale were better in the amitriptyline group.

An open-label trial of patients with chronic migraine and analgesic overuse in a headache sub-specialty center abruptly withdrew 150 participants from analgesics and quasi-randomized them to 3 groups: prednisone (tapering from 60 to 20 mg over 6 days), naratriptan (Amerge) (2.5 mg twice daily for 6 days), or no prophylactic treatment.⁶ Patients given the active substances were told it would reduce withdrawal symptoms; patients given placebo were not given this advice. All patients received education about the pathophysiology of rebound headaches, kept a headache diary, and were phoned weekly to ensure compliance. In addition, they all received capsules containing gradually increasing doses of atenolol, nortriptyline, and flunarazine (a calcium channel blocker not FDA-approved.) Indo-methacin and chlorpromazine were used as needed. Results from the first 6 days showed no difference in headaches between the 3 groups; however, significantly more patients used chlorpromazine in the “no pharmacologic treatment” group

By the end of 5 weeks, headache frequency was significantly reduced in all groups from baseline; however, there were no differences between groups in headache frequency or intensity in this small study. Of note, there were statistically fewer withdrawal symptoms and less use of rescue medications among patients who received the initial prophylactic treatments. The indomethacin rescue use was 24%, 18%, and 14% of patients for the no prophylactic treatment, prednisone, and naratriptan groups respectively, while chlorpromazine rescue use was 14%, 0%, and 0%, respectively. The number of patients needed to treat to prevent any withdrawal symptoms (nausea, vomiting, nervousness, dizziness, etc.) was 1 for every 3.5 for naratriptan, and 6.4 for prednisone.

Recommendations from others

The American Council for Headache Education recommends discontinuing all analgesics.⁷ It notes some patients may need prophylactic medication (although no specific agent is recommended), and hospitalization may be indicated for withdrawal for patients who have abused narcotics. A headache textbook recommends 1 of 2 approaches for patients undergoing outpatient treatment: (1) gradual tapering of the offending medication with substitution of a long-acting nonsteroidal anti-inflammatory drug (NSAID) and initiation of preventive therapy, or (2) abrupt discontinuation of the offending medication and initiation followed by gradual tapering of a “transitional” medication such as NSAIDs, DHE, corticosteroids, or triptans. The authors recommend an intravenous DHE protocol for treatment failures and patients requiring inpatient treatment.⁸

Evidence summary

Analgesic rebound headaches are seen in 1% of the population, mostly middle-aged women with underlying migraines.^1,2 Also termed analgesic-overuse headaches, they are defined by the International Headache Society guidelines as headaches occurring more than 15 days per month, mild to moderate in intensity, developing or worsening with analgesic overuse, and resolving or reverting to the prior underlying headache pattern within 2 months of discontinuing the analgesic(s).³

A case series studied 50 patients with rebound headaches for 5 or more days a week at baseline.⁴ Patients were educated regarding analgesic overuse headaches, after which their analgesics were abruptly discontinued, and they were followed up to a year. Subcutaneous DHE was used as needed for symptomatic relief of excruciating headaches. At study completion, 78% of patients had adequately stopped analgesics. The goal of greater than 6 consecutive headache-free days was achieved in 74% patients in an average of 84 days.

A 9-week double-blind, placebo-controlled trial randomized 20 nondepressed patients with analgesic overuse headache to receive amitriptyline or active placebo (trihexyphenidyl).⁵ Patients were admitted to the hospital for 1 week and withdrawn from all analgesics. The 2 groups had similar baseline characteristics. During the hospitalization, the amitriptyline treatment group received intravenous amitriptyline escalating from 25 to 75 mg. During the following month, oral study medications were continued, and patients took low doses of aspirin or acetaminophen, as needed. There was no significant difference between the 2 groups with regard to analgesic use. At completion of this low-powered study, no difference was found between the 2 groups in headache frequency or analgesic use, although certain components of a quality-of-life scale were better in the amitriptyline group.

An open-label trial of patients with chronic migraine and analgesic overuse in a headache sub-specialty center abruptly withdrew 150 participants from analgesics and quasi-randomized them to 3 groups: prednisone (tapering from 60 to 20 mg over 6 days), naratriptan (Amerge) (2.5 mg twice daily for 6 days), or no prophylactic treatment.⁶ Patients given the active substances were told it would reduce withdrawal symptoms; patients given placebo were not given this advice. All patients received education about the pathophysiology of rebound headaches, kept a headache diary, and were phoned weekly to ensure compliance. In addition, they all received capsules containing gradually increasing doses of atenolol, nortriptyline, and flunarazine (a calcium channel blocker not FDA-approved.) Indo-methacin and chlorpromazine were used as needed. Results from the first 6 days showed no difference in headaches between the 3 groups; however, significantly more patients used chlorpromazine in the “no pharmacologic treatment” group

By the end of 5 weeks, headache frequency was significantly reduced in all groups from baseline; however, there were no differences between groups in headache frequency or intensity in this small study. Of note, there were statistically fewer withdrawal symptoms and less use of rescue medications among patients who received the initial prophylactic treatments. The indomethacin rescue use was 24%, 18%, and 14% of patients for the no prophylactic treatment, prednisone, and naratriptan groups respectively, while chlorpromazine rescue use was 14%, 0%, and 0%, respectively. The number of patients needed to treat to prevent any withdrawal symptoms (nausea, vomiting, nervousness, dizziness, etc.) was 1 for every 3.5 for naratriptan, and 6.4 for prednisone.

Recommendations from others

The American Council for Headache Education recommends discontinuing all analgesics.⁷ It notes some patients may need prophylactic medication (although no specific agent is recommended), and hospitalization may be indicated for withdrawal for patients who have abused narcotics. A headache textbook recommends 1 of 2 approaches for patients undergoing outpatient treatment: (1) gradual tapering of the offending medication with substitution of a long-acting nonsteroidal anti-inflammatory drug (NSAID) and initiation of preventive therapy, or (2) abrupt discontinuation of the offending medication and initiation followed by gradual tapering of a “transitional” medication such as NSAIDs, DHE, corticosteroids, or triptans. The authors recommend an intravenous DHE protocol for treatment failures and patients requiring inpatient treatment.⁸