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Should you test or treat pregnant women with a history of pregnancy-related VTE?
YOU PROBABLY SHOULDN’T TEST, although you may want to treat your patient with low-molecular-weight heparin (LMWH).
No high-quality evidence supports testing for thrombophilia in pregnant patients who have experienced venous thromboembolism (VTE) in a previous pregnancy (strength of recommendation [SOR]: C, expert opinion and extrapolation from studies of nonpregnant patients).
Antepartum and postpartum anticoagulation with LMWH produces lower rates of VTE in patients with a prior history of VTE in pregnancy (SOR: B, based on a prospective cohort study and extrapolation from a meta-analysis of treatment in nonpregnant patients). Pregnant women with a prior history of VTE who are not treated with anticoagulation have about a 5% risk of antepartum or postpartum VTE (SOR: B, based on a prospective cohort study).
Expert opinion recommends graduated compression stockings (SOR: C, expert/consensus clinical opinion).
Evidence summary
A population-based cohort study centered in Olmsted County, Minn (N=50,080 births between 1966 and 1995) established a baseline rate of VTE among pregnant patients (105 total events; 0.2% incidence), and found an increased relative risk of VTE among pregnant and postpartum patients (RR=4.29; 95% confidence interval [CI], 3.49-5.22; P<.001) compared with nonpregnant patients. The incidence of VTE was 199.7 per 100,000 woman-years. The postpartum annual incidence of VTE was 5 times higher than antepartum (511.2 vs 95.8 per 100,000).1
Thrombophilia testing typically isn’t useful
There is no evidence of improved outcomes from screening pregnant women with prior VTEs for some of the more common hypercoagulable conditions, including factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, and antiphospholipid syndrome. A recent Clinical Inquiry addressed this question for general medical patients with idiopathic deep venous thrombosis and found no quality evidence to support a thrombophilia work-up in most patients.2 A subsequent review, which addressed pregnant patients specifically, made the same recommendation, that is, no quality evidence supports a thrombophilia work-up in patients at risk for VTE.3
How effective is prophylactic anticoagulation?
A meta-analysis in the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines reviewing data from 1953 orthopedic and medical patients who were mostly postoperative (and not including pregnant women) found that prophylactic anticoagulation with LMWH for patients at risk for VTE produced a relative risk for recurrent VTE of 0.36 (95% CI, 0.20-0.67).4
In a more recent prospective cohort study, prophylactic LMWH was given to 177 of 286 (62% treated) patients according to risk-based scoring for recurrent VTE.5 The treatment protocol called for anticoagulation antepartum, postpartum, or both, depending on risk score (the higher the risk, the longer the period of thromboprophylaxis). Patients with previous pregnancy-associated VTE received both antepartum and postpartum anticoagulation. The study found recurrent VTE rates of 0.35% (95% CI, 0-1.03) antepartum and 0.7% (95% CI, 0-1.67) postpartum among treated patients.5
Data from an earlier report summarized the expected VTE rate in patients not exposed to anticoagulation prophylaxis. This prospective cohort study evaluated 125 pregnant women with a history of prior VTE who had anticoagulation withheld and determined the rate of recurrent antepartum and postpartum VTE. Three women had an antepartum VTE (2.4%; 95% CI, 0.2-6.9). Three additional women developed postpartum VTE, for a total of 6 VTEs (4.8%, no CI reported).6
LMWH is beneficial, but dosing can be tricky
Patients with a history of pregnancy-associated VTE—whether or not they have known thrombophilia—do benefit from routine ante- and postpartum thromboprophylaxis, per expert opinion in practice guidelines.4,7,8 LMWH is the preferred agent because of its safety during pregnancy and ease of dosing.
Precise dosing is nonetheless difficult to determine because clinical studies in pregnant patients are lacking and renal clearance of LMWH increases during pregnancy. Most authors recommend doses between the prophylactic and therapeutic ranges.4 Subcutaneous enoxaparin, for example, can be given at 40 mg every 24 hours (more aggressive, thus higher-risk, dosing is as much as 1 mg/kg every 12 hours); dalteparin can be administered at 5000 units every 24 hours up to as much as 100 units/kg every 12 hours.9
Recommendations
The American College of Obstetricians and Gynecologists (ACOG) 2011 updated Practice Bulletin recommends thrombophilia testing for pregnant patients previously diagnosed with a pregnancy-associated VTE, although they acknowledge the lack of quality evidence to support this recommendation. ACOG also recommends ante- and postpartum thromboprophylaxis for such patients.9
The ACCP expert review recommends that all pregnant women diagnosed with VTE during a previous pregnancy wear graduated elastic compression stockings throughout pregnancy and for at least 6 weeks postpartum.7
The ACCP also recommends LMWH for all pregnant patients with a prior VTE. Additionally, the ACCP says that a thrombophilia work-up, while not routinely recommended, might be appropriate—contingent on additional risk assessment.7
1. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population based study. Ann Intern Med. 2005;143:697-706.
2. Saultz A, Mathews EL, Saultz JW, et al. Clinical inquiries. Does hypercoagulopathy testing benefit patients with DVT? J Fam Pract. 2010;59:291-294.
3. Phillippe HM, Sparkman AY. Venous thrombosis: preventing clots in patients at risk. J Fam Pract. 2010;59:315-321.
4. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S-e736S.
5. Dargaud Y, Rugeri L, Vergnes MC, et al. A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study. Br J Haematol. 2009;145:825-835.
6. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000;343:1439-1444.
7. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest. 2008;133(6 suppl):844S-886S.
8. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost. 2009;101:428-438.
9. James A. Committee on Practice Bulletins—Obstetrics. Practice bulletin No. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118:718-729.
YOU PROBABLY SHOULDN’T TEST, although you may want to treat your patient with low-molecular-weight heparin (LMWH).
No high-quality evidence supports testing for thrombophilia in pregnant patients who have experienced venous thromboembolism (VTE) in a previous pregnancy (strength of recommendation [SOR]: C, expert opinion and extrapolation from studies of nonpregnant patients).
Antepartum and postpartum anticoagulation with LMWH produces lower rates of VTE in patients with a prior history of VTE in pregnancy (SOR: B, based on a prospective cohort study and extrapolation from a meta-analysis of treatment in nonpregnant patients). Pregnant women with a prior history of VTE who are not treated with anticoagulation have about a 5% risk of antepartum or postpartum VTE (SOR: B, based on a prospective cohort study).
Expert opinion recommends graduated compression stockings (SOR: C, expert/consensus clinical opinion).
Evidence summary
A population-based cohort study centered in Olmsted County, Minn (N=50,080 births between 1966 and 1995) established a baseline rate of VTE among pregnant patients (105 total events; 0.2% incidence), and found an increased relative risk of VTE among pregnant and postpartum patients (RR=4.29; 95% confidence interval [CI], 3.49-5.22; P<.001) compared with nonpregnant patients. The incidence of VTE was 199.7 per 100,000 woman-years. The postpartum annual incidence of VTE was 5 times higher than antepartum (511.2 vs 95.8 per 100,000).1
Thrombophilia testing typically isn’t useful
There is no evidence of improved outcomes from screening pregnant women with prior VTEs for some of the more common hypercoagulable conditions, including factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, and antiphospholipid syndrome. A recent Clinical Inquiry addressed this question for general medical patients with idiopathic deep venous thrombosis and found no quality evidence to support a thrombophilia work-up in most patients.2 A subsequent review, which addressed pregnant patients specifically, made the same recommendation, that is, no quality evidence supports a thrombophilia work-up in patients at risk for VTE.3
How effective is prophylactic anticoagulation?
A meta-analysis in the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines reviewing data from 1953 orthopedic and medical patients who were mostly postoperative (and not including pregnant women) found that prophylactic anticoagulation with LMWH for patients at risk for VTE produced a relative risk for recurrent VTE of 0.36 (95% CI, 0.20-0.67).4
In a more recent prospective cohort study, prophylactic LMWH was given to 177 of 286 (62% treated) patients according to risk-based scoring for recurrent VTE.5 The treatment protocol called for anticoagulation antepartum, postpartum, or both, depending on risk score (the higher the risk, the longer the period of thromboprophylaxis). Patients with previous pregnancy-associated VTE received both antepartum and postpartum anticoagulation. The study found recurrent VTE rates of 0.35% (95% CI, 0-1.03) antepartum and 0.7% (95% CI, 0-1.67) postpartum among treated patients.5
Data from an earlier report summarized the expected VTE rate in patients not exposed to anticoagulation prophylaxis. This prospective cohort study evaluated 125 pregnant women with a history of prior VTE who had anticoagulation withheld and determined the rate of recurrent antepartum and postpartum VTE. Three women had an antepartum VTE (2.4%; 95% CI, 0.2-6.9). Three additional women developed postpartum VTE, for a total of 6 VTEs (4.8%, no CI reported).6
LMWH is beneficial, but dosing can be tricky
Patients with a history of pregnancy-associated VTE—whether or not they have known thrombophilia—do benefit from routine ante- and postpartum thromboprophylaxis, per expert opinion in practice guidelines.4,7,8 LMWH is the preferred agent because of its safety during pregnancy and ease of dosing.
Precise dosing is nonetheless difficult to determine because clinical studies in pregnant patients are lacking and renal clearance of LMWH increases during pregnancy. Most authors recommend doses between the prophylactic and therapeutic ranges.4 Subcutaneous enoxaparin, for example, can be given at 40 mg every 24 hours (more aggressive, thus higher-risk, dosing is as much as 1 mg/kg every 12 hours); dalteparin can be administered at 5000 units every 24 hours up to as much as 100 units/kg every 12 hours.9
Recommendations
The American College of Obstetricians and Gynecologists (ACOG) 2011 updated Practice Bulletin recommends thrombophilia testing for pregnant patients previously diagnosed with a pregnancy-associated VTE, although they acknowledge the lack of quality evidence to support this recommendation. ACOG also recommends ante- and postpartum thromboprophylaxis for such patients.9
The ACCP expert review recommends that all pregnant women diagnosed with VTE during a previous pregnancy wear graduated elastic compression stockings throughout pregnancy and for at least 6 weeks postpartum.7
The ACCP also recommends LMWH for all pregnant patients with a prior VTE. Additionally, the ACCP says that a thrombophilia work-up, while not routinely recommended, might be appropriate—contingent on additional risk assessment.7
YOU PROBABLY SHOULDN’T TEST, although you may want to treat your patient with low-molecular-weight heparin (LMWH).
No high-quality evidence supports testing for thrombophilia in pregnant patients who have experienced venous thromboembolism (VTE) in a previous pregnancy (strength of recommendation [SOR]: C, expert opinion and extrapolation from studies of nonpregnant patients).
Antepartum and postpartum anticoagulation with LMWH produces lower rates of VTE in patients with a prior history of VTE in pregnancy (SOR: B, based on a prospective cohort study and extrapolation from a meta-analysis of treatment in nonpregnant patients). Pregnant women with a prior history of VTE who are not treated with anticoagulation have about a 5% risk of antepartum or postpartum VTE (SOR: B, based on a prospective cohort study).
Expert opinion recommends graduated compression stockings (SOR: C, expert/consensus clinical opinion).
Evidence summary
A population-based cohort study centered in Olmsted County, Minn (N=50,080 births between 1966 and 1995) established a baseline rate of VTE among pregnant patients (105 total events; 0.2% incidence), and found an increased relative risk of VTE among pregnant and postpartum patients (RR=4.29; 95% confidence interval [CI], 3.49-5.22; P<.001) compared with nonpregnant patients. The incidence of VTE was 199.7 per 100,000 woman-years. The postpartum annual incidence of VTE was 5 times higher than antepartum (511.2 vs 95.8 per 100,000).1
Thrombophilia testing typically isn’t useful
There is no evidence of improved outcomes from screening pregnant women with prior VTEs for some of the more common hypercoagulable conditions, including factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, and antiphospholipid syndrome. A recent Clinical Inquiry addressed this question for general medical patients with idiopathic deep venous thrombosis and found no quality evidence to support a thrombophilia work-up in most patients.2 A subsequent review, which addressed pregnant patients specifically, made the same recommendation, that is, no quality evidence supports a thrombophilia work-up in patients at risk for VTE.3
How effective is prophylactic anticoagulation?
A meta-analysis in the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines reviewing data from 1953 orthopedic and medical patients who were mostly postoperative (and not including pregnant women) found that prophylactic anticoagulation with LMWH for patients at risk for VTE produced a relative risk for recurrent VTE of 0.36 (95% CI, 0.20-0.67).4
In a more recent prospective cohort study, prophylactic LMWH was given to 177 of 286 (62% treated) patients according to risk-based scoring for recurrent VTE.5 The treatment protocol called for anticoagulation antepartum, postpartum, or both, depending on risk score (the higher the risk, the longer the period of thromboprophylaxis). Patients with previous pregnancy-associated VTE received both antepartum and postpartum anticoagulation. The study found recurrent VTE rates of 0.35% (95% CI, 0-1.03) antepartum and 0.7% (95% CI, 0-1.67) postpartum among treated patients.5
Data from an earlier report summarized the expected VTE rate in patients not exposed to anticoagulation prophylaxis. This prospective cohort study evaluated 125 pregnant women with a history of prior VTE who had anticoagulation withheld and determined the rate of recurrent antepartum and postpartum VTE. Three women had an antepartum VTE (2.4%; 95% CI, 0.2-6.9). Three additional women developed postpartum VTE, for a total of 6 VTEs (4.8%, no CI reported).6
LMWH is beneficial, but dosing can be tricky
Patients with a history of pregnancy-associated VTE—whether or not they have known thrombophilia—do benefit from routine ante- and postpartum thromboprophylaxis, per expert opinion in practice guidelines.4,7,8 LMWH is the preferred agent because of its safety during pregnancy and ease of dosing.
Precise dosing is nonetheless difficult to determine because clinical studies in pregnant patients are lacking and renal clearance of LMWH increases during pregnancy. Most authors recommend doses between the prophylactic and therapeutic ranges.4 Subcutaneous enoxaparin, for example, can be given at 40 mg every 24 hours (more aggressive, thus higher-risk, dosing is as much as 1 mg/kg every 12 hours); dalteparin can be administered at 5000 units every 24 hours up to as much as 100 units/kg every 12 hours.9
Recommendations
The American College of Obstetricians and Gynecologists (ACOG) 2011 updated Practice Bulletin recommends thrombophilia testing for pregnant patients previously diagnosed with a pregnancy-associated VTE, although they acknowledge the lack of quality evidence to support this recommendation. ACOG also recommends ante- and postpartum thromboprophylaxis for such patients.9
The ACCP expert review recommends that all pregnant women diagnosed with VTE during a previous pregnancy wear graduated elastic compression stockings throughout pregnancy and for at least 6 weeks postpartum.7
The ACCP also recommends LMWH for all pregnant patients with a prior VTE. Additionally, the ACCP says that a thrombophilia work-up, while not routinely recommended, might be appropriate—contingent on additional risk assessment.7
1. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population based study. Ann Intern Med. 2005;143:697-706.
2. Saultz A, Mathews EL, Saultz JW, et al. Clinical inquiries. Does hypercoagulopathy testing benefit patients with DVT? J Fam Pract. 2010;59:291-294.
3. Phillippe HM, Sparkman AY. Venous thrombosis: preventing clots in patients at risk. J Fam Pract. 2010;59:315-321.
4. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S-e736S.
5. Dargaud Y, Rugeri L, Vergnes MC, et al. A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study. Br J Haematol. 2009;145:825-835.
6. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000;343:1439-1444.
7. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest. 2008;133(6 suppl):844S-886S.
8. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost. 2009;101:428-438.
9. James A. Committee on Practice Bulletins—Obstetrics. Practice bulletin No. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118:718-729.
1. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population based study. Ann Intern Med. 2005;143:697-706.
2. Saultz A, Mathews EL, Saultz JW, et al. Clinical inquiries. Does hypercoagulopathy testing benefit patients with DVT? J Fam Pract. 2010;59:291-294.
3. Phillippe HM, Sparkman AY. Venous thrombosis: preventing clots in patients at risk. J Fam Pract. 2010;59:315-321.
4. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S-e736S.
5. Dargaud Y, Rugeri L, Vergnes MC, et al. A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study. Br J Haematol. 2009;145:825-835.
6. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med. 2000;343:1439-1444.
7. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest. 2008;133(6 suppl):844S-886S.
8. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost. 2009;101:428-438.
9. James A. Committee on Practice Bulletins—Obstetrics. Practice bulletin No. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118:718-729.
Evidence-based answers from the Family Physicians Inquiries Network
What is the best treatment for infants with colic?
Infantile colic, defined as excessive crying in an otherwise healthy baby, is a distressing phenomenon, but there is little evidence to support the many treatments offered. Several small studies report some benefit from use of a hypoallergenic (protein hydrolysate) formula, maternal diet adjustment (focusing on a low-allergen diet), and reduced stimulation of the infant. While dicyclomine has been shown to be effective for colic, there are significant concerns about its safety, and the manufacturer has contraindicated its use in this population. An herbal tea containing chamomile, vervain, licorice, fennel, and balm-mint was also effective in a small RCT, but the volume necessary for treatment limits its usefulness (strength of recommendation: B, inconsistent or limited-quality patientoriented evidence). The one proven treatment is time, as this behavior tends to dissipate by 6 months of age.
For pure colic, only time will help
Anne Eglash, MD
Department of Family Medicine, University of Wisconsin Medical School, Madison
A broad definition for colic may capture infants who cry for a variety of reasons. I consider pure colic to be a patterned daily behavior of crying that a parent can predict will occur and stop at certain times, and the baby is fine at other times of day. For these babies, I wouldn’t expect a change in formula or maternal diet to help; they greatly improve by about age 3 months.
However, for babies who are fussy and difficult to console throughout day and night, further evaluation and dietary changes are worth trying. For breastfeeding mothers, I usually start with dairy avoidance and test the baby’s stools for microscopic blood to be sure there is no colitis related to maternal diet. Only if there is evidence of infant colitis or allergy should a more restrictive maternal diet be prescribed. For formula-fed infants, a change to a proteinhydrolysate formula is worth a try, the main risk being the cost of the formula.
Evidence summary
Colic has been described using the “rule of 3”: crying for at least 3 hours per day on at least 3 days per week for at least 3 weeks.1 The distinction can be subtle; a normal infant can cry more than 2 hours per day. This syndrome has its onset typically in the first few weeks of life. It spontaneously resolves by age 4 to 6 months. Prevalence depends on the definition used for colic; approximately 5% to 25% of infants meet some reasonable definition of colic.2 The cause of infantile colic is poorly understood. Although clinicians tend to focus on a likely gastrointestinal cause, neuropsychological issues, food allergy, and parenting misadventures are also potential contributing factors.
There are myriad strategies—ranging from craniosacral osteopathic manipulation to car ride simulation—offered for dealing with infantile colic. Although none of these treatments has been validated in rigorous studies, the available evidence offers tentative support for 3 strategies: (1) a trial of a hypoallergenic (protein hydrolysate) formula (for formula fed infants), (2) a low-allergen maternal diet (for breastfeeding mothers), and (3) reduced stimulation of the infant.
A systematic review analyzed controlled clinical trials lasting at least 3 days involving infants less than 6 months of age who cried excessively.3 Twenty-seven studies were included; the outcome measure was colic symptoms, typically reported as duration of crying. Two reports studying hypoallergenic (protein hydrolysate) formula in nearly 130 infants found an effect size of 0.22 (95% confidence interval [CI], 0.10–0.34) for the hypoallergenic formula. Additionally, 3 behavioral trials (involving nearly 200 infants) revealed the benefits of reduced stimulation of the colicky infant (effect size of 0.48; 95% CI, 0.23–0.74).
A more recent systematic review4 followed a similar high-quality search strategy and identified 22 articles, and reported a number needed to treat (NNT) of 6 for the 2 hypoallergenic formula studies identified in the previous review.4 Because of concern regarding the quality of the behavioral studies involving infants with colic, the authors of this second review only included 1 small (42 patients) trial of decreased stimulation, which resulted in a relative risk (RR) of 1.87 (95% CI, 1.04–3.34) and a NNT of 2. There was some inconclusive evidence to suggest benefit to dietary adjustment for breastfeeding mothers (specifically, the avoidance of cow’s milk and other potential allergens like nuts, eggs, and wheat).
A recent randomized controlled trial confirmed the value of this approach by showing significant improvement in distress scores of infants whose mothers followed a low-allergen diet (excluding dairy, soy, wheat, eggs, peanuts, tree nuts, and fish) for 7 days.5 This well-designed study included 107 patients (a relatively large sample in the published research about colic), and showed an absolute risk reduction of 37% (NNT=3) for those mothers following the challenge.
A small RCT (43 patients) suggested efficacy in the substitution of a whey hydrolysate formula in place of cow’s milkbased formula for infants with colic (casein hydrolysate formula has been more widely studied), but there continues to be controversy regarding the preferred protein hydrolysate formula (whey vs casein) in the treatment of colic.3
Several medications have been tested in RCTs; only dicyclomine has shown an effect in a few small RCTs.3,4 However, there have been reports of apnea and other serious, although infrequent, adverse effects. For that reason, the manufacturer has contraindicated the use of this medication in infants aged <6 months.
A small (n=68) study of an herbal tea showed reduced symptoms (RR=0.57 favoring the active tea), although the mean volume of tea consumption (32 mL/kg/d) is a nutritional concern in this age group.6 No adverse events were noted, but the small sample size limits the ability to detect any but the most common events.
Recommendations from others
The American Gastroenterological Association recommends a hypoallergenic, protein hydrolysate formula for formula fed infants or a maternal low-allergen diet as an initial strategy for infant struggling with colic symptoms if the clinician is considering a diagnosis of (cow’s milk) allergy.7
The American Academy of Family Physicians on their familydoctor.org web site makes no specific formula or diet adjustment recommendations.8 The web site does list some techniques (eg, massage or warm compress of abdomen, swing or car rides) not supported by the available evidence. The National Library of Medicine and the National Institutes of Health web site Medline Plus presents similar information.9 The American Academy of Pediatrics does not address the topic on its public web site.
1. Wessel MA, Cobb JC, Jackson EB, Harris GS, Jr, Detwiler AC. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 1954;14:421-435.
2. Kilgour T, Wade S. Infantile colic. Clin Evid 2005;13:362-372.
3. Lucassen PL, Assendelft WJ, Gubbels JW, van Eijk JT, van Geldrop WJ, Neven AK. Effectiveness of treatments for infantile colic: systematic review. BMJ 1998;316:1563-1569.
4. Garrison MM, Christakis DA. A systematic review of treatments for infant colic. Pediatrics 2000;106:184-190.
5. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics 2005;116:e709-e715.
6. Lucassen PLBJ, Assendelft WJJ, Gubbels JW, van Eijk JT, Douwes AC. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomized, placebo-controlled trial. Pediatrics 2000;106:1349-1354.
7. Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the evaluation of food allergy in gastrointestinal disorders. Gastroenterology 2001;120:1026-1040.
8. Familydoctor.org [web site]. Colic: Learning how to deal with your baby’s crying. Last updated April 2005. Available at: familydoctor.org/036.xml. Accessed on June 12, 2006.
9. Colic and crying. Medline Plus, last updated August 23, 2005. Available at: www.nlm.nih.gov/medlineplus/ency/article/000978.htm#Treatment. Accessed on June 12, 2006.
Infantile colic, defined as excessive crying in an otherwise healthy baby, is a distressing phenomenon, but there is little evidence to support the many treatments offered. Several small studies report some benefit from use of a hypoallergenic (protein hydrolysate) formula, maternal diet adjustment (focusing on a low-allergen diet), and reduced stimulation of the infant. While dicyclomine has been shown to be effective for colic, there are significant concerns about its safety, and the manufacturer has contraindicated its use in this population. An herbal tea containing chamomile, vervain, licorice, fennel, and balm-mint was also effective in a small RCT, but the volume necessary for treatment limits its usefulness (strength of recommendation: B, inconsistent or limited-quality patientoriented evidence). The one proven treatment is time, as this behavior tends to dissipate by 6 months of age.
For pure colic, only time will help
Anne Eglash, MD
Department of Family Medicine, University of Wisconsin Medical School, Madison
A broad definition for colic may capture infants who cry for a variety of reasons. I consider pure colic to be a patterned daily behavior of crying that a parent can predict will occur and stop at certain times, and the baby is fine at other times of day. For these babies, I wouldn’t expect a change in formula or maternal diet to help; they greatly improve by about age 3 months.
However, for babies who are fussy and difficult to console throughout day and night, further evaluation and dietary changes are worth trying. For breastfeeding mothers, I usually start with dairy avoidance and test the baby’s stools for microscopic blood to be sure there is no colitis related to maternal diet. Only if there is evidence of infant colitis or allergy should a more restrictive maternal diet be prescribed. For formula-fed infants, a change to a proteinhydrolysate formula is worth a try, the main risk being the cost of the formula.
Evidence summary
Colic has been described using the “rule of 3”: crying for at least 3 hours per day on at least 3 days per week for at least 3 weeks.1 The distinction can be subtle; a normal infant can cry more than 2 hours per day. This syndrome has its onset typically in the first few weeks of life. It spontaneously resolves by age 4 to 6 months. Prevalence depends on the definition used for colic; approximately 5% to 25% of infants meet some reasonable definition of colic.2 The cause of infantile colic is poorly understood. Although clinicians tend to focus on a likely gastrointestinal cause, neuropsychological issues, food allergy, and parenting misadventures are also potential contributing factors.
There are myriad strategies—ranging from craniosacral osteopathic manipulation to car ride simulation—offered for dealing with infantile colic. Although none of these treatments has been validated in rigorous studies, the available evidence offers tentative support for 3 strategies: (1) a trial of a hypoallergenic (protein hydrolysate) formula (for formula fed infants), (2) a low-allergen maternal diet (for breastfeeding mothers), and (3) reduced stimulation of the infant.
A systematic review analyzed controlled clinical trials lasting at least 3 days involving infants less than 6 months of age who cried excessively.3 Twenty-seven studies were included; the outcome measure was colic symptoms, typically reported as duration of crying. Two reports studying hypoallergenic (protein hydrolysate) formula in nearly 130 infants found an effect size of 0.22 (95% confidence interval [CI], 0.10–0.34) for the hypoallergenic formula. Additionally, 3 behavioral trials (involving nearly 200 infants) revealed the benefits of reduced stimulation of the colicky infant (effect size of 0.48; 95% CI, 0.23–0.74).
A more recent systematic review4 followed a similar high-quality search strategy and identified 22 articles, and reported a number needed to treat (NNT) of 6 for the 2 hypoallergenic formula studies identified in the previous review.4 Because of concern regarding the quality of the behavioral studies involving infants with colic, the authors of this second review only included 1 small (42 patients) trial of decreased stimulation, which resulted in a relative risk (RR) of 1.87 (95% CI, 1.04–3.34) and a NNT of 2. There was some inconclusive evidence to suggest benefit to dietary adjustment for breastfeeding mothers (specifically, the avoidance of cow’s milk and other potential allergens like nuts, eggs, and wheat).
A recent randomized controlled trial confirmed the value of this approach by showing significant improvement in distress scores of infants whose mothers followed a low-allergen diet (excluding dairy, soy, wheat, eggs, peanuts, tree nuts, and fish) for 7 days.5 This well-designed study included 107 patients (a relatively large sample in the published research about colic), and showed an absolute risk reduction of 37% (NNT=3) for those mothers following the challenge.
A small RCT (43 patients) suggested efficacy in the substitution of a whey hydrolysate formula in place of cow’s milkbased formula for infants with colic (casein hydrolysate formula has been more widely studied), but there continues to be controversy regarding the preferred protein hydrolysate formula (whey vs casein) in the treatment of colic.3
Several medications have been tested in RCTs; only dicyclomine has shown an effect in a few small RCTs.3,4 However, there have been reports of apnea and other serious, although infrequent, adverse effects. For that reason, the manufacturer has contraindicated the use of this medication in infants aged <6 months.
A small (n=68) study of an herbal tea showed reduced symptoms (RR=0.57 favoring the active tea), although the mean volume of tea consumption (32 mL/kg/d) is a nutritional concern in this age group.6 No adverse events were noted, but the small sample size limits the ability to detect any but the most common events.
Recommendations from others
The American Gastroenterological Association recommends a hypoallergenic, protein hydrolysate formula for formula fed infants or a maternal low-allergen diet as an initial strategy for infant struggling with colic symptoms if the clinician is considering a diagnosis of (cow’s milk) allergy.7
The American Academy of Family Physicians on their familydoctor.org web site makes no specific formula or diet adjustment recommendations.8 The web site does list some techniques (eg, massage or warm compress of abdomen, swing or car rides) not supported by the available evidence. The National Library of Medicine and the National Institutes of Health web site Medline Plus presents similar information.9 The American Academy of Pediatrics does not address the topic on its public web site.
Infantile colic, defined as excessive crying in an otherwise healthy baby, is a distressing phenomenon, but there is little evidence to support the many treatments offered. Several small studies report some benefit from use of a hypoallergenic (protein hydrolysate) formula, maternal diet adjustment (focusing on a low-allergen diet), and reduced stimulation of the infant. While dicyclomine has been shown to be effective for colic, there are significant concerns about its safety, and the manufacturer has contraindicated its use in this population. An herbal tea containing chamomile, vervain, licorice, fennel, and balm-mint was also effective in a small RCT, but the volume necessary for treatment limits its usefulness (strength of recommendation: B, inconsistent or limited-quality patientoriented evidence). The one proven treatment is time, as this behavior tends to dissipate by 6 months of age.
For pure colic, only time will help
Anne Eglash, MD
Department of Family Medicine, University of Wisconsin Medical School, Madison
A broad definition for colic may capture infants who cry for a variety of reasons. I consider pure colic to be a patterned daily behavior of crying that a parent can predict will occur and stop at certain times, and the baby is fine at other times of day. For these babies, I wouldn’t expect a change in formula or maternal diet to help; they greatly improve by about age 3 months.
However, for babies who are fussy and difficult to console throughout day and night, further evaluation and dietary changes are worth trying. For breastfeeding mothers, I usually start with dairy avoidance and test the baby’s stools for microscopic blood to be sure there is no colitis related to maternal diet. Only if there is evidence of infant colitis or allergy should a more restrictive maternal diet be prescribed. For formula-fed infants, a change to a proteinhydrolysate formula is worth a try, the main risk being the cost of the formula.
Evidence summary
Colic has been described using the “rule of 3”: crying for at least 3 hours per day on at least 3 days per week for at least 3 weeks.1 The distinction can be subtle; a normal infant can cry more than 2 hours per day. This syndrome has its onset typically in the first few weeks of life. It spontaneously resolves by age 4 to 6 months. Prevalence depends on the definition used for colic; approximately 5% to 25% of infants meet some reasonable definition of colic.2 The cause of infantile colic is poorly understood. Although clinicians tend to focus on a likely gastrointestinal cause, neuropsychological issues, food allergy, and parenting misadventures are also potential contributing factors.
There are myriad strategies—ranging from craniosacral osteopathic manipulation to car ride simulation—offered for dealing with infantile colic. Although none of these treatments has been validated in rigorous studies, the available evidence offers tentative support for 3 strategies: (1) a trial of a hypoallergenic (protein hydrolysate) formula (for formula fed infants), (2) a low-allergen maternal diet (for breastfeeding mothers), and (3) reduced stimulation of the infant.
A systematic review analyzed controlled clinical trials lasting at least 3 days involving infants less than 6 months of age who cried excessively.3 Twenty-seven studies were included; the outcome measure was colic symptoms, typically reported as duration of crying. Two reports studying hypoallergenic (protein hydrolysate) formula in nearly 130 infants found an effect size of 0.22 (95% confidence interval [CI], 0.10–0.34) for the hypoallergenic formula. Additionally, 3 behavioral trials (involving nearly 200 infants) revealed the benefits of reduced stimulation of the colicky infant (effect size of 0.48; 95% CI, 0.23–0.74).
A more recent systematic review4 followed a similar high-quality search strategy and identified 22 articles, and reported a number needed to treat (NNT) of 6 for the 2 hypoallergenic formula studies identified in the previous review.4 Because of concern regarding the quality of the behavioral studies involving infants with colic, the authors of this second review only included 1 small (42 patients) trial of decreased stimulation, which resulted in a relative risk (RR) of 1.87 (95% CI, 1.04–3.34) and a NNT of 2. There was some inconclusive evidence to suggest benefit to dietary adjustment for breastfeeding mothers (specifically, the avoidance of cow’s milk and other potential allergens like nuts, eggs, and wheat).
A recent randomized controlled trial confirmed the value of this approach by showing significant improvement in distress scores of infants whose mothers followed a low-allergen diet (excluding dairy, soy, wheat, eggs, peanuts, tree nuts, and fish) for 7 days.5 This well-designed study included 107 patients (a relatively large sample in the published research about colic), and showed an absolute risk reduction of 37% (NNT=3) for those mothers following the challenge.
A small RCT (43 patients) suggested efficacy in the substitution of a whey hydrolysate formula in place of cow’s milkbased formula for infants with colic (casein hydrolysate formula has been more widely studied), but there continues to be controversy regarding the preferred protein hydrolysate formula (whey vs casein) in the treatment of colic.3
Several medications have been tested in RCTs; only dicyclomine has shown an effect in a few small RCTs.3,4 However, there have been reports of apnea and other serious, although infrequent, adverse effects. For that reason, the manufacturer has contraindicated the use of this medication in infants aged <6 months.
A small (n=68) study of an herbal tea showed reduced symptoms (RR=0.57 favoring the active tea), although the mean volume of tea consumption (32 mL/kg/d) is a nutritional concern in this age group.6 No adverse events were noted, but the small sample size limits the ability to detect any but the most common events.
Recommendations from others
The American Gastroenterological Association recommends a hypoallergenic, protein hydrolysate formula for formula fed infants or a maternal low-allergen diet as an initial strategy for infant struggling with colic symptoms if the clinician is considering a diagnosis of (cow’s milk) allergy.7
The American Academy of Family Physicians on their familydoctor.org web site makes no specific formula or diet adjustment recommendations.8 The web site does list some techniques (eg, massage or warm compress of abdomen, swing or car rides) not supported by the available evidence. The National Library of Medicine and the National Institutes of Health web site Medline Plus presents similar information.9 The American Academy of Pediatrics does not address the topic on its public web site.
1. Wessel MA, Cobb JC, Jackson EB, Harris GS, Jr, Detwiler AC. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 1954;14:421-435.
2. Kilgour T, Wade S. Infantile colic. Clin Evid 2005;13:362-372.
3. Lucassen PL, Assendelft WJ, Gubbels JW, van Eijk JT, van Geldrop WJ, Neven AK. Effectiveness of treatments for infantile colic: systematic review. BMJ 1998;316:1563-1569.
4. Garrison MM, Christakis DA. A systematic review of treatments for infant colic. Pediatrics 2000;106:184-190.
5. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics 2005;116:e709-e715.
6. Lucassen PLBJ, Assendelft WJJ, Gubbels JW, van Eijk JT, Douwes AC. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomized, placebo-controlled trial. Pediatrics 2000;106:1349-1354.
7. Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the evaluation of food allergy in gastrointestinal disorders. Gastroenterology 2001;120:1026-1040.
8. Familydoctor.org [web site]. Colic: Learning how to deal with your baby’s crying. Last updated April 2005. Available at: familydoctor.org/036.xml. Accessed on June 12, 2006.
9. Colic and crying. Medline Plus, last updated August 23, 2005. Available at: www.nlm.nih.gov/medlineplus/ency/article/000978.htm#Treatment. Accessed on June 12, 2006.
1. Wessel MA, Cobb JC, Jackson EB, Harris GS, Jr, Detwiler AC. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 1954;14:421-435.
2. Kilgour T, Wade S. Infantile colic. Clin Evid 2005;13:362-372.
3. Lucassen PL, Assendelft WJ, Gubbels JW, van Eijk JT, van Geldrop WJ, Neven AK. Effectiveness of treatments for infantile colic: systematic review. BMJ 1998;316:1563-1569.
4. Garrison MM, Christakis DA. A systematic review of treatments for infant colic. Pediatrics 2000;106:184-190.
5. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics 2005;116:e709-e715.
6. Lucassen PLBJ, Assendelft WJJ, Gubbels JW, van Eijk JT, Douwes AC. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomized, placebo-controlled trial. Pediatrics 2000;106:1349-1354.
7. Sampson HA, Sicherer SH, Birnbaum AH. AGA technical review on the evaluation of food allergy in gastrointestinal disorders. Gastroenterology 2001;120:1026-1040.
8. Familydoctor.org [web site]. Colic: Learning how to deal with your baby’s crying. Last updated April 2005. Available at: familydoctor.org/036.xml. Accessed on June 12, 2006.
9. Colic and crying. Medline Plus, last updated August 23, 2005. Available at: www.nlm.nih.gov/medlineplus/ency/article/000978.htm#Treatment. Accessed on June 12, 2006.
Evidence-based answers from the Family Physicians Inquiries Network