Bacterial Infections and Pregnancy - Prof. Alaa Mosbah - Professor of Obstetrics and Gynecology

Bacterial Infections and Pregnancy

Fetal and Newborn Infections

-In utero (transplacentally) ,congenital syphilis

-During labor (vertical transmission) , E. coli, group B streptococci, ;conjunctivitis due to chlamydia, gonorrhea or Listeria monocytogenes, and a number of infections due to gram-negative anaerobic bacilli.

-In the neonatal period (i.e., during the first 28 days following birth) , tuberculosis and tetanus

Group B Streptococcus (GBS)

Clinical spectrum

Because only 0.5-1% of mothers who carry GBS develop signs and symptoms of disease, clinical diagnosis of GBS can be problematic.

In pregnant women, GBS is a cause of cystitis, amnionitis, endometritis, and stillbirth. Occasionally, GBS has been a cause of endocarditis and meningitis, while in postpartum women, it has been identified as a cause of urinary tract infections (UTIs) and pelvic abscesses.
Prenatal screening for this condition is now established practice in North America, Australasia and many parts of Europe
The UK and Finland stand out as the only two countries to have consciously resisted this trend, and this is, at least in part, because the incidence of early onset neonatal infection in the UK is less than a third of what it was in America

Group B Streptococcus – background

Streptococcus agalactiae:

Group B Strep, Strep B, beta haemolytic Strep, GBS

Colonisation

Intestinal (up to 30% of adults) & vaginal (up to 25% of women)

Asymptomatic

May be intermittent

90% of adults possess no protective antibodies to GBS

Infection

Infections in adults: the elderly, pregnant women, others with other disease

Most common cause of life-threatening infection in newborn babies

Underlying rate ~ 1/1000 live births overall

GBS infection in babies

Early Onset

Up to 80% of GBS infection in babies

0-6 days (usually less than 24 hours)

Usually septicaemia, also meningitis & pneumonia

11% die


Late onset

Up to 20% of GBS infection in babies
Start 7 or more days after delivery
Usually septicaemia, and meningitis
5% die


Reducing risk of GBS infection in babies

Late onset GBS infection

No medical intervention proven to prevent

Good hygiene

Education / alert

In future – vaccination of women before/during pregnancy

Will prevent EO/LO and adult GBS infection
Reducing risk of GBS infection in babies

Early onset GBS infection

-Intrapartum antibiotic prophylaxis (IAP)

Only proven effective method of prevention available

-Oral antibiotics

No evidence it reduces EOGBS infection

Used to treat GBS in urine

-Intramuscular antibiotics before labour

May eradicate GBS colonisation for up to 6 weeks

-Vaginal flushing with chlorhexidine

No evidence it reduces EOGBS infection

Recognised risk factors for EOGBS infection

Previous baby with GBS infection x 10

GBS bacteriuria during pregnancy x 4

Intrapartum fever x 3

Preterm labour x 3

Prolonged rupture of membranes x 3

Maternal GBS colonisation during pregnancy x 4

But … there’s no way to know a woman is carrying GBS unless we look for it

Testing for GBS carriage

When to swab?

Before 35 weeks of pregnancy

35-37 weeks of pregnancy

Intrapartum
Where to swab? (not speculum)

-High vaginal swab

-Low vaginal swab

-Low vagina & anorectal swab/s (more than 30% more effective than vaginal or cervical alone)


Who to swab?
Pregnant woman

What culture method to use?

Direct agar plate - 24-48 hours to grow culture in lab

Selective Enriched Culture Medium (ECM) - 24-48 hours to grow culture in lab

Polymerase Chain Reaction (PCR) – minutes to hours to grow culture

PCR requires special equipment and special training

Who should be offered intrapartum antibiotic prophylaxis?

-Women with recognised risk factors:

50-60% cases prevented

-GBS carriers this pregnancy:

80-90% cases prevented

-GBS carriers this pregnancy who have risk factors:

less than 50% cases prevented

UK – RCOG guideline summary

Antenatal

Routine screening for GBS not recommended

Antenatal treatment with penicillin is not recommended

Intrapartum

Clinicians should discuss the use of IAP in the presence of known risk factors including incidental carriage.

Risk factors include:

Prematurity less than  37 weeks

prolonged rupture of membranes more than 18 hours

fever in labour more than 38C

The argument for prophylaxis becomes stronger for mor than 2 risk factors.

IAP should be considered if GBS is detected incidentally in the vagina or the urine in the current pregnancy

IAP offered to women with a previous baby with neonatal GBS disease.

IAP regime is Penicillin G as soon as possible after the onset of labour and at least 2 hours before delivery.

If chorioamnionitis is suspected, broad-spectrum antibiotic therapy including an agent active against GBS should replace GBS-specific antibiotic prophylaxis

Mother should receive antibiotics

mother should receive antibiotics using the following criteria:

Previously delivered infant with invasive GBS infection

GBS bacteriuria during current pregnancy

Delivery at less than 37 weeks' gestation

Duration of ruptured membranes longer than 18 hours

Intrapartum temperature of more than 100.4°F (38°C)

Treatment
During labor, 5 million U of penicillin G should be given as an intravenous loading dose, followed by 12-24 million U/d in 4 divided doses.

An alternative therapy is 2 g of ampicillin as an intravenous loading dose, followed by 1 g every 4 hours until delivery.

In case of penicillin allergy, clindamycin 900 mg IV every 8 hours until delivery or erythromycin 500 mg IV every 6 hours until delivery may be given.

Neonates delivered from a mother who received prophylaxis require careful observation for signs and symptoms of disease.

URINARY TRACT INFECTIONS

Women are predisposed to UTIs compared with men because of :

their anatomically shorter urethra,

the proximity of the urethra to the well-colonized anus and vagina, and

trauma during sexual intercourse.

UTIs are an especially important topic in pregnancy because even asymptomatic bacteruria can lead to complications such as pyelonephritis and premature labor.

Etiology

The most common causative organisms are as follows:

Escherichia coli

Klebsiella species

Enterobacter species

Enterococcus species

Group B Streptococcus

Staphylococcus saprophyticus

Proteus mirabilis

Pseudomonas aeruginosa

Citrobacter diversus

Clinical spectrum

Infection can involve the lower and upper urinary tracts, and patients can present with asymptomatic bacteriuria, cystitis, or pyelonephritis.

Bacteriuria that does not manifest symptoms apparently does not occur more frequently with pregnancy but is more likely to result in acute pyelonephritis in pregnant women.

Approximately 28% of pregnant women with untreated bacteriuria develop pyelonephritis. Some of the complications of bacteriuria observed in pregnancy include maternal anemia, low neonatal birth weight, hypertension, and prematurity.

Cystitis does not occur more frequently in pregnant women. The symptoms of cystitis are often confused with symptoms noted in normal pregnancy. These findings include urgency, frequency, suprapubic discomfort, and dysuria without fever or costovertebral angle tenderness. Urine culture findings are positive, and urinalysis reveals occasional hematuria or pyuria.

Acute pyelonephritis occurs with increased frequency in pregnant women (rate of 1-2%) and is most likely due to stasis of urine and bacteria in the urinary tract because of relative obstruction. This is caused by the dilatation of the ureters secondary to progesterone in early pregnancy and to the mechanical obstruction from the gravid uterus later in pregnancy.

Glycosuria, proteinuria, and aminoaciduria found in pregnancy also facilitate bacterial growth.

Acute pyelonephritis is confirmed by the presence of spiking fever (which sometimes reaches 104°F [40°C]), costovertebral angle tenderness, urinalysis findings with white blood cells and bacteria, and a urine culture result with positive growth of the causative organisms.

The scope of pyelonephritis may encompass many complications, including hyperthermia, anemia, leukocytosis, thrombocytopenia, decreased creatinine clearance, and adult respiratory distress syndrome. Fetal outcomes include low birth weight and prematurity.

Screening and diagnosis

Because asymptomatic bacteriuria is clinically significant in pregnancy, it should be aggressively sought, diagnosed, and treated in all stages. The various screening techniques used to detect bacteriuria include urinalysis, leukocyte esterase activity, a nitrite test, and urine cultures.

Treatment

Any overt UTI or asymptomatic bacteriuria in pregnancy must be treated.
Sulfonamides, amoxicillin, amoxicillin-clavulanate, cephalexin, and nitrofurantoin are all acceptable antibiotics. However, avoid sulfonamides in the last few weeks of gestation in order to prevent kernicterus and hyperbilirubinemia in the newborn.
A 7-day regimen eradicates bacteriuria in 70-80% of patients and is recommended for acute cystitis.
Single-dose therapy is less effective.
A 3-day course of treatment may provide the best balance of achieving adequate therapy and minimizing drug administration in pregnancy and is recommended for asymptomatic bacteriuria.

Cystitis can generally be treated in the same manner as asymptomatic bacteriuria, Women treated for cystitis must be monitored with frequent urine cultures (at monthly intervals) because 25% of women who have cystitis experience another UTI during the course of their pregnancy.

Patients with pyelonephritis in pregnancy: Although mild cases may be treated in an outpatient setting, many of these women need hospitalization and require intravenous antibiotics in addition to parenteral hydration to combat nausea, vomiting, and dehydration.

Initial antibiotic therapy may be empirical, followed by tailoring to the pathogen grown in the urine.

Most patients show symptomatic improvement within 1-2 days of beginning therapy.

If no improvement is observed, consider resistant organisms, nephrolithiasis, abscess formation, and obstruction as causes of therapy failure. Follow-up care in women after an episode of acute pyelonephritis should be frequent with close monitoring of urine cultures.

LISTERIOSIS

Etiology

Listeria monocytogenes is a gram-positive, aerobic, motile bacillus with aerobic and facultative anaerobic characteristics. The organism is found in soil and water and can be carried by animals that do not appear ill, leading to contamination of food of animal origin such as meats and dairy products. Unpasteurized raw milks are also sources of Listeria organisms.

Transmission

Pregnant women are 20 times more likely to contract listeriosis, and approximately one third of all cases of listeriosis occur during pregnancy. Transmission has mainly been by contaminated food, although rare cases of nosocomial transmission and transmission by direct contact with infected animals (which causes a local disease of the skin) have been noted.

The organism is found in soil and water. Vegetables become contaminated from the use of fertilizer, while animals may be asymptomatic carriers transmitting disease to individuals who eat their infected meat.

Outbreaks of listeriosis are still reported. Contaminated turkey meat caused a multistate outbreak in 2002 and led to 46 cases with 7 deaths and 2 stillbirths.

Clinical spectrum
Pregnant patients with listeriosis are often asymptomatic, or, they may have a febrile illness similar to influenza with symptoms of fever, muscle aches, and, sometimes, nausea or diarrhea during the bacteremic phase of the disease. Although the symptoms may be mild during pregnancy, listeriosis can still lead to premature delivery, infection of the newborn, or even stillbirth.
Placental transfer of the organism to the fetus can cause amnionitis, which usually results in either spontaneous septic abortion or premature labor with delivery of an infected baby. Fetal infection may manifest as septicemia, meningoencephalitis, or disseminated granulomatous lesions with microabscesses.

In neonates, the mortality rate is approximately 50%. Mortality is more likely in early-onset neonatal sepsis. Late-onset listeriosis typically manifests as meningitis at age 3-4 weeks

CDC recommendations for prevention

Thoroughly cook raw food from animal sources.

Thoroughly wash raw vegetables before eating.

Keep uncooked meats separate from vegetables, cooked foods, and ready-to-eat foods.

Avoid unpasteurized milk or foods made from raw milk.

Wash hands, knives, and cutting boards after handling uncooked foods.

Avoid soft cheeses.

Cook leftover food or ready-to-eat foods until they are steaming hot.
Diagnosis

Results of blood and cerebrospinal fluid cultures are positive in 60-75% of cases when central nervous system infection is present as indicated by fever or meningeal symptoms. Serological testing is not reliable for confirming a diagnosis, and stool cultures are not sensitive or specific.

Treatment

Ampicillin is the drug of choice for treating listeriosis; a 2-week course is required for bacteremia. A dose of 2 g every 4 hours is recommended.

Trimethoprim/sulfamethoxazole, the usual alternative for penicillin-allergic patients, has not been approved for use in pregnancy.

Syphilis

Caused by Treponema pallidum a helical, tightly coiled, motile spirochete..

Treponemes appear able to cross the placenta at any time during pregnancy, thereby infecting the fetus.

Early diagnosis and treatment are extremely important for preventing the effects syphilis may have on pregnant women and their infants. Untreated primary or secondary syphilis in pregnant women can lead to congenital syphilis in 40-50% of cases.
Lack of prenatal care and failure to properly diagnose and treat syphilis in the mother are the most important factors leading to congenital syphilis, and these areas should be the focus of preventive efforts.

Clinical spectrum

The stage of maternal disease during which the fetus is exposed to infection determines the morbidity; the earlier the disease stage, the higher the morbidity. Untreated primary or secondary syphilis in pregnancy causes almost a 100% rate of infection in the fetus. The disease can cause stillbirth, neonatal death, or congenital syphilis.

The stages of disease mirror the stages in nonpregnant women. In the first stage, primary syphilis, a hard, painless red ulcer forms on the vulva, cervix, or vagina. Secondary syphilis predominantly manifests as a nonpruritic rash that may involve the palms and soles. Fever and joint pain are less common manifestations of secondary syphilis. The latent phase causes no symptoms, and, although the disease may not be transmitted to sexual partners, it is still transmissible to the fetus. One third of patients may progress to tertiary syphilis, during which the organism can damage the heart, eyes, brain, nervous system, bones, or joints.


Screening

Even when syphilis is considered unlikely, routine antenatal screening is warranted for prevention and surveillance. The earlier in pregnancy the treatment, the more efficacious it is. Therefore, serologic tests should be performed at the initial prenatal visit. If the patient is considered to be at high risk, tests should be repeated at 28 weeks' gestation and at delivery.
The nontreponemal antibody tests are generally used for screening. These tests are highly sensitive but are nonspecific. They include the rapid plasmin reagin and VDRL tests. Pregnancy often causes false-positive nontreponemal antibody test results; therefore, positive findings should be confirmed with specific antitreponemal antibody tests such as the microhemagglutination assay-T pallidum and the fluorescent treponemal antibody absorption test.
Diagnosis

The diagnosis can be made in the same manner as for a nonpregnant woman. In primary syphilis, the diagnosis can be confirmed by identifying T pallidum in dark-field examination of material taken from a lesion. Because most pregnant women do not have visible lesions, serologic screening as mentioned previously is the primary means of establishing the diagnosis.

Treatment

Once a diagnosis is made, consider other sexually transmitted diseases before starting treatment. Treatment is the same as for nonpregnant women, with a single dose of 2.4 million U of benzathine penicillin for primary and secondary syphilis, but some experts recommend a second dose of benzathine penicillin G 1 week after the initial dose, especially in the third trimester or in the case of secondary syphilis.

In latent syphilis, treatment consists of 3 doses of benzathine penicillin (as for nonpregnant women). If results of the monthly quantitative VDRL or equivalent test show a 4-fold increase, re-treat the patient and perform a lumbar puncture to rule out neurosyphilis.

Penicillin-allergic women must be desensitized and then treated with penicillin because the accepted alternatives to treatment are erythromycin and tetracycline. Erythromycin may not prevent congenital syphilis, and tetracycline and doxycycline are not recommended for pregnant women.
Using penicillin therapy in pregnant women with early syphilis can cause a Jarisch-Herxheimer reaction. Pregnant women, apart from the usual manifestations, can present with uterine contractions, preterm labor, and premature delivery.

Chlamydia

Chlamydia trachomatis - obligate, intracellular bacterium with 15 immunotypes:

A-C - trachoma

D-K - genital tract infections

L1-L3 - lymphogranuloma venereum

One of the leading causes of infertility in women.

Etiology

Chlamydia trachomatis is an obligate intracellular organism. Initially considered a virus, it is now classified as a bacterium based on its sensitivity to antibiotics and its reproduction cycle.

Transmission

The usual mode of transmission to the fetus is vertical during the second stage of labor. The major routes of entry are the eye and the nasopharynx.

Clinical spectrum
Approximately 75% of women with chlamydia are asymptomatic.
The disease can cause endometritis, cervicitis, acute PID, and acute urethral syndrome in all women and chorioamnionitis, postpartum endometritis, and gestational bleeding in pregnant women.

Diagnosis

Chlamydial cervicitis should be considered in the presence of a yellow or green vaginal discharge, greater than 10 polymorphonuclear leukocytes per high-power field, and bleeding or edema of the cervix.

The following are the accepted screening methods according to the CDC:

A nucleic acid amplification test performed on an endocervical swab specimen or on urine

An unamplified nucleic acid hybridization test, an enzyme immunoassay, or direct fluorescent antibody test performed on an endocervical swab specimen

Culture performed on an endocervical swab specimen

Monoclonal antibodies labeled with fluorescein to detect elementary bodies of Chlamydia species (MicroTrak) or enzyme-linked immunosorbent assay is used for screening.

Treatment

In asymptomatic women with positive culture findings and in symptomatic women,

500 mg of erythromycin 4 times daily for 7 days is the treatment of choice.

Single-dose therapy with 1 g of azithromycin is an alternative.

Tetracycline, the drug of choice for treating chlamydia in other situations, is contraindicated in pregnancy. Retest treated women after 3-4 weeks, and evaluate and treat sexual contacts.

GONORRHEA

Gonorrhea is caused by Neisseria gonorrhoeae, a gram-negative diplococcus.

Gonorrhea is transmitted vertically during the birth process. No evidence suggests placental transmission

Gonococcal infections cause no symptoms in approximately 50% of patients and thus warrant screening in pregnancy.

Clinical spectrum

Gonorrhea can infect the uterus, cervix, and fallopian tubes, leading to ectopic pregnancy and infertility.

During pregnancy, women with gonorrhea may be asymptomatic, although reports have been received of endocervicitis, premature rupture of membranes, chorioamnionitis, septic abortion, intrauterine growth retardation, prematurity, and postpartum sepsis.

Newborns exposed to gonorrhea during vaginal delivery can develop an acute conjunctivitis known as ophthalmia neonatorum.
Pregnancy is a predisposing factor in the development of disseminated gonococcal infection. The classic presentation of disseminated disease is the triad of arthritis, skin lesions, and fever. The rash is vesicular and pustular, usually over the distal joints.

Diagnosis

A Gram stain of the endocervical secretions should be performed when an immediate diagnosis is necessary. Gram-negative diplococci in polymorphonuclear leukocytes are diagnostic.

A culture specimen should be taken directly from the endocervix onto Thayer-Martin media. Other sites, such as the pharynx, rectum, and urethra, should also be cultured as indicated.
Enzyme immunoassay is another rapid means of diagnosis.

Treatment

The treatment of choice for uncomplicated cervicitis is a single dose of 250 mg of ceftriaxone intramuscularly. Penicillin-allergic pregnant women can be treated with spectinomycin. Although ciprofloxacin is one of the standard drugs of choice, it is contraindicated in pregnancy.

All patients treated for gonococcal infection should also be empirically treated for chlamydial infection.

BACTERIAL VAGINOSIS
Bacterial vaginosis is an infection caused by excessive growth of bacteria that may normally be present in the vagina.
In the United States, the rate of bacterial vaginosis in pregnancy is approximately 16%
Infection can be transmitted via the placenta to the fetus and cause intrauterine fetal death.

Etiology

The etiology is polymicrobial in nature and is associated with G vaginalis, Bacteroides species, Mobiluncus species, Peptococcus species, and Mycoplasma hominis.

Clinical spectrum

Abnormal vaginal discharge with an unpleasant, fishlike odor, especially after sexual intercourse. The discharge is generally white or gray, and women may have dysuria or itching around the vagina.

The bacteria can ascend and colonize the amniotic membranes, decreasing the tensile strength of the membranes and causing the weakened membranes to rupture. G vaginalis can also cause prostaglandin production and lead to premature labor unresponsive to tocolytic therapy.

Diagnosis

When using the clinical criteria, 3 of the following 4 should be present:

A homogenous, white, noninflammatory discharge that smoothly coats the vaginal wall

Clue cells, ie, vaginal epithelial cells that have a stippled appearance due to aggregates of coccobacilli

Vaginal fluid pH of more than 4.5

A positive whiff test result, ie, a fishy odor to the vaginal discharge before or after the addition of 10% potassium hydroxide solution
When using Gram stain to make a diagnosis, determine the relative concentration of the bacterial morphotypes characteristic of the altered flora of bacterial vaginosis.
Treatment

Metronidazole at 500 mg twice a day for 7 days or metronidazole gel 0.75% intravaginally twice a day for 5 days is the treatment of choice. Avoid the gel in the first trimester of pregnancy.

Clindamycin 300 mg twice a day for 7 days

Antibiotic Use During Pregnancy And Birth Defects: Study Examines Associations

Crider and her colleagues (2009) analyzed data on more than 13,000 women whose babies had one of more than 30 birth defects. They compared the women's rates of antibiotic usage, from the month leading up to pregnancy through the end of the first trimester, with that of almost 5,000 women whose children did not have a birth defect.

November 2009, Archives of Pediatrics & Adolescent Medicine
Although penicillin and several other antibacterial medications commonly taken by pregnant women do not appear to be associated with many birth defects, other antibiotics, such as sulfonamides and nitrofurantoins, may be associated with several severe birth defects and require additional scrutiny, a new study has found

November 2009, Archives of Pediatrics  and Adolescent Medicine

Antibiotics (anti-microbials)
Commonly used antibiotics

Penicillins (category B):
 These are the most widely used antibiotics in pregnancy because of their wide margin of safety and lack of known toxicity. In the collaborative perinatal project, 3546 women used penicillin during the first trimester and no adverse effects were demonstrated. Ticarcillin, however, has shown some toxicity in animals and may not be safe in pregnancy.

Cephalosporins (category B):
 This group has not been well studied in the first trimester and should therefore not be considered the first line of treatment in the first trimester of pregnancy. Generally, these drugs are considered safe and have shown no teratogenicity

Sulfonamides (category C):
Avoid sulfonamides in the third trimester of pregnancy and during breastfeeding. Although these agents cause no known damage in utero, they can cause hyperbilirubinemia and kernicterus if the drug is still present in the neonate after birth. In mothers with G-6-PD deficiency, sulfonamide use has been associated with hemolysis. The combination of sulfonamides with trimethoprim in the first trimester has been associated with cardiovascular birth defects.

Sulfonamides were also tied to an increased risk for hypoplastic left heart syndrome and coarctation of the aorta, choanal atresia (a blockage of the nasal passage), transverse limb deficiency , diaphragmatic hernia and anencephaly

November 2009, Archives of Pediatrics & Adolescent Medicine

Tetracyclines (category D):

-Pregnant women are susceptible to acute fatty necrosis of the liver, pancreatitis, and renal damage.

-In the fetus, these agents can cause stunting of growth, discoloration of teeth, and hypoplasia of dental enamel.


Nitrofurantoin (category B):
The collaborative perinatal project showed no increased risk of anomalies in 590 women who were exposed to the drug. In mothers with G-6-PD deficiency, it has caused hemolysis in both the mother and the fetus and should therefore be avoided near delivery.

Nitrofurantoins were also associated with multiple birth defects, including anophthalmia and microphthalmos , a cleft lip or cleft palate and several congenital heart defects

November 2009, Archives of Pediatrics & Adolescent Medicine

Quinolones (category C):
Although animal studies have shown arthropathies, no human studies have been conducted and no cases of teratogenicity have been reported. These agents have a high affinity for bone and cartilage.

Metronidazole (category B):
Metronidazole should not be used in the first trimester or during lactation. When used in the second or third trimester, large single-dose treatments should be avoided.

Macrolides (category B):
These agents have not been associated with birth defects and are considered safe for use in pregnancy.

Clindamycin (category B):
This drug has not been associated with birth defects