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Urinary tract infection

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Urinary tract infection
Classification and external resources
Multiple white cells seen in the urine of a person with a urinary tract infection using a microscope
ICD-10N39.0
ICD-9599.0
DiseasesDB13657
MedlinePlus000521
eMedicineemerg/625 emerg/626
MeSHD014552

A urinary tract infection (UTI) is an infection caused by bacteria in the urinary tract. The urinary tract is: the kidneys, ureters, the urinary bladder, and urethra. Symptoms of a UTI may be painful peeing, frequent peeing, or wanting to pee (or both). Symptoms of a kidney infection include fever and side and back pain. In older people and young children, the symptoms are not always clear. Often the main cause of a UTI is the bacteria Escherichia coli. Other bacteria, viruses, or fungi may be the cause less often.

Women get urinary tract infections more often than men. Half of women have an infection at some point in their lives. It is common for a person to have many UTI infections in their life. One risk factor for having a UTI is sexual intercourse. Sometimes a person who has a bladder infection will get a kidney infection. Kidney infection may also, but rarely, be caused by bacteria in the blood. Diagnosis in young healthy women can be based on symptoms alone. Sometimes, the urine needs to be tested. A person with frequent infections can take low-dose antibiotics to prevent future infections.

Antibiotics are used to treat simple cases of urinary tract infections. Resistance to antibiotics is increasing. People who have complicated urinary tract infections sometimes have to take antibiotics for a longer time, or might take antibiotics intravenously (through a vein). If symptoms have not improved in two or three days, the person will need further tests. In women, urinary tract infections are the most common form of bacterial infection. 10% of women develop urinary tract infections each year.

Parts of the Urinary System Affects

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Urinary Tract Infections (UTIs) can damage many urinary system components.

  • Urethra: The tube that extends from the bladder to the exterior of the body to excrete pee is known as the urethra. It is possible for bacteria to enter the urethra and grow there, which can result in urethritis, an infection of the urethra.
  • Bladder: Urine is stored in the bladder, a hollow, muscular structure. The illness known as cystitis, which is a bladder infection, can develop as a result of bacteria ascending the urethra and entering the bladder.
  • Ureters: The kidneys and bladder are linked by two tubes called ureters. Urethritis, a disease where UTIs develop in the ureters, is possible but less often than infections of the urethra or bladder.
  • Kidneys: The kidneys are essential organs that filter waste and extra fluid from the circulation to create urine. Pyelonephritis is a more dangerous illness that can develop when bacteria enter the urinary system and go up to the kidneys. Pyelonephritis is a kidney infection.

Signs and symptoms

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Urine can contain pus (a condition known as pyuria) as seen from a person with sepsis due to a urinary tract infection.

Lower urinary tract infection is also known as a bladder infection. The most common symptoms are burning with peeing and having to pee frequently (or wanting to pee) without vaginal discharge or significant pain.[1] These symptoms can vary from mild to severe.[2] In healthy women, the symptoms last an average of six days.[3] Some people will have pain above the pubic bone (lower abdomen) or in the lower back. People who have an upper urinary tract infection, or pyelonephritis (a kidney infection), can have flank pain, fever (a high temperature), or nausea and vomiting. Those symptoms are in addition to the normal symptoms of a lower urinary tract infection.[2] In rare cases the urine looks bloody[4] or contains visible pyuria (pus in the urine).[5]

In children

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In young children, fever can be the only symptom of a urinary tract infection (UTI). Many medical associations recommend a urine culture for females younger than two year old or uncircumcised males who are younger than a year and have a fever. Infants with UTI sometimes eat poorly, vomit, sleep more, or show signs of jaundice ( a yellow coloring of the skin). Older children can have new urinary incontinence (loss of bladder control).[6]

In the elderly

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Urinary tract symptoms are frequently not seen in those who are old.[7] Sometimes, the only symptoms are incontinence (loss of bladder control), a change in mental status (ability to think), or feeling tired.[2] The first symptom for some old people is sepsis, an infection of the blood.[4] Diagnosis can be difficult because many old people are incontinent (cannot hold their pee) or have dementia (poor thinking abilities).[7]

Cause

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E. coli is the cause of 80–85% of urinary tract infections. Staphylococcus saprophyticus is the cause in 5–10% of cases.[1] In rare cases, viral or fungal infections cause urinary tract infections[8] Other bacterial causes of UTI include:

These bacterial causes are not common and usually happen when the person has an abnormal urinary system or the person has a urinary catheterization (tube inserted into the bladder.[4] Urinary tract infections due toStaphylococcus aureus usually happens after the person has had a blood infection.[2]

Gender

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Sexual intercourse is the cause of 75–90% of bladder infections in young, sexually active women. The risk of infection is related to how often they have sex.[1] With UTIs so frequent when women first get married, the term "honeymoon cystitis" is often used. In post-menopausal women (women who have stopped menstruating), sexual activity does not affect the risk of developing a UTI. Using spermicide (a gel or cream to kill sperm) increases the risk of UTIs.[1]

Women get more UTIs than men because women have a urethra that is much shorter and closer to the anus.[9] As a woman's estrogen (a hormone) levels decrease with menopause, the risk of urinary tract infections increases due to the loss of protective vaginal flora (good bacterial that live in the vagina).[9]

Urinary catheters

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A urinary catheter is a tube that is put into the bladder to drain the urine. Using a catheter increases the risk for urinary tract infections. The risk of bacteriuria (bacteria in the urine) is 3% - 6% every day the catheter is used. Antibiotics do not stop these infections.[9] The risk of an infection can be decreased by:[10][11][12]

  • using a catheter only when necessary
  • making sure everything is very clean (sterile) when putting the catheter in
  • making sure that nothing blocks the catheter.

Others

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Bladder infections are more common in some families. Other risk factors include diabetes,[1] being circumcised, and having a large prostate (a gland around the urethra in males).[2] Complicating factors are not completely clear. These factors may include some anatomic problems (relating to physical narrowing), functional, or metabolic problems. A complicated UTI is more difficult to treat and usually needs more aggressive evaluation, treatment, and follow-up.[13] In children, UTIs are linked to vesicoureteral reflux (an abnormal movement of urine from the bladder into ureters or kidneys) and constipation.[6]

Mechanism

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The bacteria that cause urinary tract infections usually go into the bladder from the uretha. It is believed these bacteria come from the bowel. Females are at greater risk because they have a short urethra that is close to their anus). After entering the bladder, E. Coli are able to stick to the bladder wall. They form a biofilm, which is a coating of microorganisms, that resists the body's immune response.[4] However, infections can also come through the blood or lymph.[4]

Prevention

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The following activities do not cause a UTI or make them happen less frequently:[1][9]

People who often get UTIs and who use spermicide or a diaphragm for birth control should use a different type of birth control.[4] Cranberry (juice or capsules) may decrease the number of infections, but some people cannot use cranberries for long periods of time.[14] Gastrointestinal (stomach) upset occurs in more than 30% of people who regularly drink cranberry juice or take capsules.[15] As of 2011, probiotics used intravaginally (in the vagina) require further study to determine if they are helpful.[4]

Medications

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For people who keep getting infections, taking antibiotics for a long time is helpful.[1] Drugs frequently used include nitrofurantoin and trimethoprim/sulfamethoxazole. If infections are related to sexual intercourse, some women find it useful to take antibiotics after sex.[4] In post-menopausal women, using topical vaginal estrogen (a hormone applied to the skin of the vagina) has been found to reduce getting a UTI. Unlike topical creams, the use of vaginal estrogen from pessaries (medical devices put in the vagina is not as useful as low-dose antibiotics.[16] A number of vaccines were being developed as of 2011.[4]

In children

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There is little evidence that using preventative antibiotics decreases urinary tract infections in children.[17] It is rare for people who have no problems with their kidneys to develop kidney problems from frequent UTIs. Having frequent urinary tract infections as a child causes less than a third of a percent (0.33%) of chronic kidney disease in adults.[18]

Diagnosis

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Many bacilli (rod-shaped bacteria, here shown as black and bean-shaped) shown between white blood cells as seen by looking at urine through a microsope. These changes show a urinary tract infection.

In most cases, UTIs can be diagnosed just from the symptoms and there is no need for laboratory testing. Urinalysis (testing the urine) can be used to confirm the diagnosis in complicated cases. The urine is tested for urinary nitrites, white blood cells (leukocytes), or leukocyte esterase. Another test, urine microscopy, looks for red blood cells, white blood cells, or bacteria. Urine culture is considered positive if it shows a bacterial colony count of greater than or equal to 103 colony-forming units per mL of a typical bacteria that causes infections of the urinary tract. Cultures can also be used to test which antibiotic will work. However, women with negative cultures can still improve with antibiotic treatment.[1] UTI symptoms in old people can be vague, and diagnosis can be difficult as there is no really reliable test.[7]

Classification

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A urinary tract infection in the lower urinary tract is known as a bladder infection. A UTI in the upper urinary tract is known as pyelonephritis or kidney infection. If the urine has significant bacteria, but there are no symptoms, the condition is known as asymptomatic bacteriuria.[2]

A urinary tract infection is said to be complicated if:[3][4]

Otherwise if a person (can be either male or female) is healthy, the infection is said to be uncomplicated.[3] When children also have a fever, the urinary tract infection is considered to be an upper urinary tract infection.[6]

In children

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To diagnose a urinary tract infection in children, a positive urinary culture is required. Contamination poses a frequent challenge so a cutoff of 105 CFU/mL is used for a "clean-catch" mid-stream sample, 104 CFU/mL is used for catheter-obtained specimens, and 102 CFU/mL is used for suprapubic aspirations (a sample drawn directly from the bladder through the stomach wall with a needle). The World Health Organization does not like the use of “urine bags” to collect samples because there is a high rate of contamination when that urine is cultured. Catheterization is preferred if an individual is unable to use a toilet. Some medical groups, such as the American Academy of Pediatrics, recommend renal ultrasound and voiding cystourethrogram (watching a person's urethra and urinary bladder with real time X-rays while they urinate) in all children who are younger than 2 years old and have had a urinary tract infection.Other medical groups such as the National Institute for Clinical Excellence recommend routine imaging only in babies younger than 6 months old or who have unusual findings.[6]

Differential diagnosis

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In women with cervicitis (inflammation of the cervix) or vaginitis (inflammation of the vagina) and in young men with UTI symptoms, a Chlamydia trachomatis or Neisseria gonorrheae infection may be the cause.[2][19] Vaginitis may also be due to a yeast infection.[20] Interstitial cystitis (chronic pain in the bladder) can be the cause for people who have UTI symptoms many times, but whose urine cultures remain negative and do not improved with antibiotics.[21] Prostatitis (inflammation of the prostate) may also be considered in the differential diagnosis.[22]

Treatment

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Phenazopyridine can be used in addition to antibiotics to help ease the burning pain of a bladder infection.[23] However, phenazopyridine is no longer commonly recommended due to safety concerns. It can cause methemoglobinemia, which means there is higher than normal level of methemoglobin in the blood.[24] Acetaminophen can be used for fevers.[25]

Women who keep getting simple UTIs can benefit from self-treatment; these women should get medical treatment medical only if the initial treatment fails. Health care providers may also prescribe the antibiotics by phone.[1]

Uncomplicated

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Simple infections can be diagnosed and treated based on symptoms alone.[1] Oral antibiotics such as trimethoprim/sulfamethoxazole (TMP/SMX), cephalosporins, nitrofurantoin, or a fluoroquinolone will shorten the time to recovery. All these drugs are equally effective.[26] A three-day treatment with trimethoprim, TMP/SMX, or a fluoroquinolone is usually enough. Nitrofurantoin needs 5–7 days.[1][27] With treatment, symptoms should improve within 36 hours.[3] About 50% of people will get better without treatment within a few days or weeks.[1] The Infectious Diseases Society of America does not recommend fluoroquinolones as first treatment because of concerns that overuse will lead to resistance to this class of drugs, making these drugs less effective for more serious infections.[27] Despite this precaution, some resistance has developed to all of these drugs because to their widespread use.[1] In some countries, trimethoprim alone is deemed to be equivalent to TMP/SMX.[27] Children with simple UTIs are often helped by a three-day course of antibiotics.[28]

Pyelonephritis

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Pyelonephritis (kidney infection) is treated more aggressively than a simple bladder infection using either a longer course of oral antibiotics or intravenous antibiotics.[29] Seven days of the oral fluoroquinolone ciprofloxacin is typically used in geographic areas where the resistance rate is less than 10%. If the local resistance rates are greater than 10%, a dose of intravenous ceftriaxone often is prescribed. People with more severe symptoms are sometimes admitted a hospital for ongoing antibiotics.[29] If symptoms do not improve following two or three days of treatment, it can mean that the urinary tract is blocked by a kidney stone.[2][29]

Likelihood

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Urinary tract infections are the most frequent bacterial infection in women.[3] They occur most frequently between the ages of 16 and 35 years. 10% of women get an infection yearly; 60% have an infection at some point in their lives.[1][4] Nearly half of people get a second infection within a year. Urinary tract infections occur four times more frequently in females than males.[4] Pyelonephritis occurs between 20–30 times less frequently than bladder infections.[1] Pyelonephritis is the most common cause of hospital acquired infections, accounting for approximately 40% of hospital-acquired infections.[30] Rates of asymptomatic bacteria in the urine increase with age from 2% to 7% in women of childbearing age to as high as 50% in elderly women in care homes.[9] Rates of aysmtomatic bacteria in the urine among men over 75 are 7-10%.[7]

Urinary tract infections can affect 10% of people during childhood.[4] Urinary tract infections in children are the most common in uncircumcised males younger than 3 months of age, followed by females younger than one year.[6] Estimates of frequency among children, however, vary widely. In a group of children with a fever, ranging in age between birth and 2 years, 2- 20% were diagnosed with a UTI.[6]

Society and culture

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In the United States, urinary tract infections lead to nearly seven million office visits, a million emergency department visits, and 100,000 hospitalizations every year.[4] The cost of these infections is high due to both lost time at work and costs of medical care. The direct cost of treatment is estimated at 1.6 billion USD yearly in the United States.[30]

History

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Urinary tract infections have been described since ancient times. The first written description, found in the Ebers Papyrus, dates to around 1550 BC.[31] The Egyptians described a urinary tract infection as "sending forth heat from the bladder."[32] Herbs, bloodletting, and rest were the common treatments until the 1930s, when antibiotics became available.[31] Sulphonamides became available around 1935.

In pregnancy

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Pregnant women with UTIs have a higher risk of kidney infections. During pregnancy, high progesterone (a hormone) levels decreased muscle tone of the ureters and bladder. Decreased muscle tone leads to a greater likelihood of reflux, where urine flows back up the ureters and toward the kidneys. If bacteria are present, pregnant women have a 25-40% risk of a kidney infection.[9] Thus treatment is recommended if urine testing shows signs of an infection—even in the absence of symptoms. Cephalexin or nitrofurantoin are typically used because those medications are generally considered safe in pregnancy.[33] A kidney infection during pregnancy may result in premature birth or pre-eclampsia (a state of high blood pressure, kidney dysfunction, or seizures).[9]

References

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  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 Nicolle LE (2008). "Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis". Urol Clin North Am. 35 (1): 1–12, v. doi:10.1016/j.ucl.2007.09.004. PMID 18061019.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Lane, DR; Takhar, SS (Aug 2011). "Diagnosis and management of urinary tract infection and pyelonephritis". Emergency Medicine Clinics of North America. 29 (3): 539–52. doi:10.1016/j.emc.2011.04.001. PMID 21782073.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Colgan, R; Williams, M (Oct 1, 2011). "Diagnosis and treatment of acute uncomplicated cystitis". American Family Physician. 84 (7): 771–6. PMID 22010614.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 Salvatore, Stefano; Salvatore, Silvia; Cattoni, Elena; Siesto, Gabriele; Serati, Maurizio; Sorice, Paola; Torella, Marco (Jun 2011). "Urinary tract infections in women". European Journal of Obstetrics, Gynecology, and Reproductive Biology. 156 (2): 131–6. doi:10.1016/j.ejogrb.2011.01.028. PMID 21349630.
  5. ↑ Arellano, Ronald S. (19 January 2011). Non-vascular interventional radiology of the abdomen. New York: Springer. p. 67. ISBN 9781441977311.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Bhat, Rahul G.; Katy, Tamara A.; Place, Frederick C. (Aug 2011). "Pediatric urinary tract infections". Emergency Medicine Clinics of North America. 29 (3): 637–53. doi:10.1016/j.emc.2011.04.004. PMID 21782079.
  7. ↑ 7.0 7.1 7.2 7.3 Woodford, HJ; George, J (Feb 2011). "Diagnosis and management of urinary infections in older people". Clinical Medicine (London, England). 11 (1): 80–3. doi:10.7861/clinmedicine.11-1-80. PMC 5873814. PMID 21404794.
  8. ↑ Amdekar, Sarika; Singh, Vinod; Singh, Desh Deepak (Nov 2011). "Probiotic therapy: immunomodulating approach toward urinary tract infection". Current Microbiology. 63 (5): 484–90. doi:10.1007/s00284-011-0006-2. PMID 21901556. S2CID 24123416.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Dielubanza, EJ; Schaeffer, AJ (Jan 2011). "Urinary tract infections in women". The Medical Clinics of North America. 95 (1): 27–41. doi:10.1016/j.mcna.2010.08.023. PMID 21095409.
  10. ↑ Nicolle LE (2001). "The chronic indwelling catheter and urinary infection in long-term-care facility residents". Infect Control Hosp Epidemiol. 22 (5): 316–21. doi:10.1086/501908. PMID 11428445. S2CID 40832193.
  11. ↑ Phipps, Simon; Lim, Yik N; McClinton, Samuel; Barry, Chris; Rane, Ajay; N'Dow, James MO (2006-04-19). Cochrane Incontinence Group (ed.). "Short term urinary catheter policies following urogenital surgery in adults". Cochrane Database of Systematic Reviews (2): CD004374. doi:10.1002/14651858.CD004374.pub2. PMID 16625600.
  12. ↑ Phipps, Simon; Lim, Yik N; McClinton, Samuel; Barry, Chris; Rane, Ajay; N'Dow, James MO (2006-04-19). Cochrane Incontinence Group (ed.). "Short term urinary catheter policies following urogenital surgery in adults". Cochrane Database of Systematic Reviews (2): CD004374. doi:10.1002/14651858.CD004374.pub2. PMID 16625600.
  13. ↑ Infectious Disease, Chapter Seven, Urinary Tract Infections from Infectious Disease Section of Microbiology and Immunology On-line. By Charles Bryan MD. University of South Carolina. This page last changed on Wednesday, April 27, 2011
  14. ↑ Jepson RG, Craig JC (2008). "Cranberries for preventing urinary tract infections". In Jepson, Ruth G (ed.). Cochrane Database of Systematic Reviews. pp. CD001321. doi:10.1002/14651858.CD001321.pub4. PMID 18253990. {{cite book}}: |journal= ignored (help)
  15. ↑ Rossi, Ruggero; Porta, Silvia; Canovi, Brenno (Sep 2010). "Overview on cranberry and urinary tract infections in females". Journal of Clinical Gastroenterology. 44 (Suppl 1): S61-2. doi:10.1097/MCG.0b013e3181d2dc8e. PMID 20495471.
  16. ↑ Perrotta, Carla; Aznar, Mireya; Mejia, Raul; Albert, Xavier; Ng, Cheen Werne (2008-04-16). "Oestrogens for preventing recurrent urinary tract infection in postmenopausal women". Cochrane Database of Systematic Reviews (Online) (2): CD005131. doi:10.1002/14651858.CD005131.pub2. PMID 18425910.
  17. ↑ Dai, B; Liu, Y; Jia, J; Mei, C (2010). "Long-term antibiotics for the prevention of recurrent urinary tract infection in children: a systematic review and meta-analysis". Archives of Disease in Childhood. 95 (7): 499–508. doi:10.1136/adc.2009.173112. PMID 20457696. S2CID 6714180.
  18. ↑ Salo, Jarmo; Ikäheimo, Risto; Tapiainen, Terhi; Uhari, Matti (Nov 2011). "Childhood urinary tract infections as a cause of chronic kidney disease". Pediatrics. 128 (5): 840–7. doi:10.1542/peds.2010-3520. PMID 21987701. S2CID 41304559.
  19. ↑ Raynor, Mathew C.; Carson, Culley C. (Jan 2011). "Urinary infections in men". The Medical Clinics of North America. 95 (1): 43–54. doi:10.1016/j.mcna.2010.08.015. PMID 21095410.
  20. ↑ Hui, David (2011). Approach to internal medicine : a resource book for clinical practice. Alexander K. C. Leung, Raj Padwal (3rd ed.). New York: Springer. ISBN 978-1-4419-6505-9. OCLC 704395504.
  21. ↑ Office urology : the clinician's guide. Totowa, N.J.: Humana Press. 2001. ISBN 978-1-59259-010-0. OCLC 606422147.
  22. ↑ Mick, Nathan W. (2006). Blueprints emergency medicine. Jessica Radin Peters, Daniel, MD Egan, Eric S. Nadel, Nathan W. Mick (2nd ed.). Malden, Mass.: Blackwell Pub. ISBN 1-4051-0461-9. OCLC 58534274.
  23. ↑ Gaines, KK (Jun 2004). "Phenazopyridine hydrochloride: the use and abuse of an old standby for UTI". Urologic Nursing. 24 (3): 207–9. PMID 15311491.
  24. ↑ Aronson, Jeffrey K., ed. (2008). Meyler's side effects of analgesics and anti-inflammatory drugs. Amsterdam: Elsevier Science. p. 219. ISBN 9780444532732.
  25. ↑ Family practice guidelines (2nd ed.). New York: Springer. 2011. ISBN 978-0-8261-1813-4. OCLC 695990370.
  26. ↑ Zalmanovici Trestioreanu, Anca; Green, Hefziba; Paul, Mical; Yaphe, John; Leibovici, Leonard (2010-10-06). Cochrane Kidney and Transplant Group (ed.). "Antimicrobial agents for treating uncomplicated urinary tract infection in women". Cochrane Database of Systematic Reviews (10): CD007182. doi:10.1002/14651858.CD007182.pub2. PMID 20927755.
  27. ↑ 27.0 27.1 27.2 Gupta, Kalpana; Hooton, Thomas M.; Naber, Kurt G.; Wullt, Björn; Colgan, Richard; Miller, Loren G.; Moran, Gregory J.; Nicolle, Lindsay E.; Raz, Raul; Schaeffer, Anthony J.; Soper, David E.; Infectious Diseases Society of America; European Society for Microbiology Infectious Diseases (Mar 1, 2011). "International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases". Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 52 (5): e103-20. doi:10.1093/cid/ciq257. PMID 21292654.
  28. ↑ "BestBets: Is a short course of antibiotics better than a long course in the treatment of UTI in children".
  29. ↑ 29.0 29.1 29.2 Colgan, R.; Williams, M.; Johnson, J. R. (Sep 1, 2011). "Diagnosis and treatment of acute pyelonephritis in women". American Family Physician. 84 (5): 519–26. PMID 21888302.
  30. ↑ 30.0 30.1 Brunner & Suddarth's textbook of medical-surgical nursing (12th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2010. p. 1359. ISBN 9780781785891.
  31. ↑ 31.0 31.1 Al-Achi, Antoine (2008). An introduction to botanical medicines : history, science, uses, and dangers. Westport, Conn.: Praeger Publishers. p. 126. ISBN 9780313350092.
  32. ↑ Wilson...], general ed.: Graham (1990). Topley and Wilson's Principles of bacteriology, virology and immunity : in 4 volumes (8. ed.). London: Arnold. p. 198. ISBN 0713145919.
  33. ↑ Guinto, Valerie T; De Guia, Blanca; Festin, Mario R; Dowswell, Therese (2010-09-08). Cochrane Pregnancy and Childbirth Group (ed.). "Different antibiotic regimens for treating asymptomatic bacteriuria in pregnancy". Cochrane Database of Systematic Reviews (9): CD007855. doi:10.1002/14651858.CD007855.pub2. PMC 4033758. PMID 20824868.
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