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

Ovarian Hyperstimulation Syndrome

 Ovarian hyperstimulation syndrome (OHSS)

Definition:  is an iatrogenic complication of assisted reproduction technology. OHSS usually develops several days after assisted ovulation following gonadotropin therapy. This syndrome is characterized by ovarian enlargement due to multiple ovarian cysts and an acute fluid shift into the extravascular space. Results include ascites, hemoconcentration, hypovolemia, and electrolyte imbalances. OHSS remains a lethal iatrogenic complication of the early luteal phase and/or early pregnancy after ovarian stimulation.
Classification

Mild OHSS Grade 1 - Abdominal distention and discomfort Grade 2 - Grade 1 disease plus nausea, vomiting, and/or diarrhea plus ovarian enlargement from 5-12 cm  
Moderate OHSS Grade 3 - Features of mild OHSS plus ultrasonographic evidence of ascites Severe OHSS Grade 4 - Features of moderate OHSS plus clinical evidence of ascites and/or hydrothorax and breathing difficulties Grade 5 - All of the above plus a change in the blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities, and diminished renal perfusion and function.
There are two clinical forms of OHSS, both hCG related: the early-onset form (occurring in the first eight days after hCG administration) and the late-onset form (occurring nine or more days after hCG administration, related to pregnancy-induced hCG production)
Pathophysiology
The pathogenesis of ovarian hyperstimulation syndrome is unknown, but the process is related to increased vascular permeability in the region surrounding the ovaries and their vasculature. Beta-human chorionic gonadotropin (hCG) and its analogs, estrogen, estradiol, prolactin, histamine, and prostaglandins have all been implicated in the past. Vasoactive substances such as interleukins, tumor necrosis factor (TNF)-alpha, endothelin-1, and vascular endothelial growth factor (VEGF) secreted by the ovaries have been implicated in increasing vascular permeability. Withholding hCG decreases OHSS. Hence, it plays a critical role in enhancing ovarian angiogenesis and triggering the cascade of vascular permeability in ovarian vessels that leads to third spacing and OHSS. Both exogenous and endogenous gonadotropins from molar pregnancy, gonadotroph adenomas, and even pregnancy can aggravate OHSS.These changes in the ovarian vasculature are exaggerated responses to normal luteinizing hormone (LH). The function of hCG is similar to that of LH. As a result, the actions of hCG mimic these changes. Moreover, hCG exerts a follicle stimulating hormone–like action in stimulating the ovaries. In addition, it has a prolonged half-life. All of these properties of hCG lead to ovarian stimulation and changes in periovarian vasculature even after ovulation. These effects lead to poor control of the induction process, initiating and/or aggravating OHSS. Abdominal pain, nausea, and vomiting Enlargement of the ovaries causes abdominal pain, nausea, and vomiting. The enlargement is sometimes as much as 25 cm. Another consequence is discomfort resulting from increased intra-abdominal pressure due to ascites. Ascites and tense distention Ascites and tense distention occur because of the extravasation of protein-rich fluid and increasing leakage from the intravascular space due to an osmolar differential. Leakage of fluid from follicles, increased capillary permeability leading to third spacing (due to the release of vasoactive substances), or frank rupture of follicles can all cause ascites. Localized or generalized peritonitis Localized or generalized peritonitis is caused by peritoneal irritation secondary to blood from ruptured cysts, protein-rich fluid, and inflammatory mediators. Acute abdominal pain Acute abdominal pain may be due to ovarian torsion, intraperitoneal hemorrhage, or rupture of cysts secondary to enlarged ovaries with fragile walls. Hypotension and/or hypovolemia Follicular fluid and perifollicular blood containing large amounts of VEGF, which is thought to increase vascular permeability, escapes into the peritoneal cavity. The fluid is then absorbed into the general vascular bed. Blood vessels both within and outside the ovary become functionally impaired, and the result is the leakage of fluid through those vessels and a massive fluid shift from the intravascular bed to the third compartment. This process results in intravascular hypovolemia with the concomitant development of edema, ascites, hydrothorax, and/or hydropericardium. Hypotension and/or hypovolemia are also caused by compression of the inferior vena cava because of enlarged cysts or ascites. As a result, both venous return and preload decrease. Eventual outcomes are decreased cardiac output and hypotension. Dyspnea Pulmonary function may be compromised as enlarged ovaries and ascites restrict diaphragmatic movement. Other possible causes of dyspnea are the relatively rare manifestations of OHSS, such as pleural effusion, pulmonary edema, atelectasis, pulmonary embolism, acute respiratory distress syndrome (ARDS), and pericardial effusion. Hypercoagulable state A hypercoagulable state is likely due to hemoconcentration and hypovolemia resulting from third spacing and fluid shift. It is also related to increased estrogen levels. Patients have an increased risk of developing deep venous thromboses and pulmonary embolisms. Electrolyte imbalance Electrolyte imbalance occurs due to the extravasation of fluid and resultant renal dysfunction resulting from decreased perfusion. Increased reabsorption of sodium and water occurs in the proximal tubule, leading to oliguria and low urinary sodium excretion. The exchange of hydrogen and potassium for sodium in the distal tubule is reduced. As a result, hydrogen and potassium ions accumulate and cause hyperkalemia and a tendency to develop acidosis. Compensatory and electrolyte-retaining mechanisms fail. Acute renal failure The hypovolemia of OHSS leads to hemoconcentration and creates a hypercoagulable state. Microthrombi form in tubules, leading to decreased renal perfusion. Acute renal failure may result.  

Frequency
The rate of ovarian hyperstimulation syndrome depends on definitions, risk factors, stimulation protocols, and conception.  
Rates of OHSS are as follows: Mild, 8-23% Moderate, 1-7% Severe, 0.25-5% The frequency of OHSS may increase if the ovary is overstimulated, as documented by high levels of estradiol and depicted as increased number of follicles on ultrasonography. The incidence is increased when protocols combine luteinizing hormone-releasing hormone (LHRH) agonists and gonadotropins, as compared with gonadotropins alone, to induce ovulation.

Mortality/Morbidity
Morbidity may be clinically significant in cases of severe and critical ovarian hyperstimulation syndrome, and fatalities do occur.  
Race
No racial predisposition is reported in ovarian hyperstimulation syndrome. Sex Ovarian hyperstimulation syndrome affects only women.  
Age
Only women of childbearing age are affected by ovarian hyperstimulation syndrome. The risk is increased in younger women.  
Clinical History
The patient who has ovarian hyperstimulation syndrome (OHSS) is a woman who recently had gonadotropin stimulation to induce ovulation or one who was treated with assisted reproductive technologies such as in vitro fertilization. Early OHSS is usually moderate or severe and manifests 3-7 days after the administration of hCG. Late OHSS is usually severe and occurs 12-17 days after hCG treatment.The former type is due to exogenously administered hormone, and the latter often occurs during an implanting or implanted pregnancy because pregnancy hCG exacerbates the disease. Signs of OHSS Signs of OHSS include the features listed below.(Percentages refer to all classes of OHSS.) -Ascites -Hypercoagulability (6.2%) -Thrombosis -Pleural effusion and pericardial effusion -Hemoconcentration -Leukocytosis (WBC count, >20,000/mm3) -Electrolyte abnormalities (eg, hyponatremia, hyperkalemia) -Elevated transaminase values (26%) -Acute respiratory distress syndrome (2%) -Pulmonary embolism (2%) -Acute renal failure (1%) Symptoms of OHSS Symptoms of OHSS include those listed below.(Percentages refer to cases of severe OHSS.) -Shortness of breath (92%) -Abdominal discomfort (99%) -GI disturbances - Nausea, vomiting, diarrhea (54%) -Oliguria (30%) -Peripheral edema (13%) -Lethargy -Rapid weight gain -Although OHSS usually manifests with a constellation of symptoms, atypical presentations can occur. Rare presentations such as thromboembolism, both venous and arterial, have been observed. Atypical locations of venous thromboembolism include the internal jugular vein, the subclavian vein, the inferior vena cava, the ileofemoral veins, and the intracerebral veins. Other abnormal forms of presentation include isolated hydrothorax and isolated thromboembolism. Additional situations leading to elevated hCG concentrations, such as in molar pregnancy and gonadotroph adenomas may lead to mild forms of OHSS in rare cases. Physical Physical findings of ovarian hyperstimulation syndrome include right or left lower quadrant pain below the umbilicus, as well as edema. Of note, abdominal palpation must be performed gently to avoid the possibility of rupturing a large cyst. Pelvic examination should be deferred in favor of ultrasonography of the pelvis.
Causes No single cause of ovarian hyperstimulation syndrome has been identified. The etiology appears to be multifactorial, though the cardinal events are ovarian enlargement, ascites, and hypovolemia. The hormone hCG and its analogs estrogen, estradiol, histamine, TNF-alpha, endothelin-1, and especially VEGF have all been implicated in OHSS.Increased vascular permeability in periovarian vasculature brought about by the factors described above plays an important role in OHSS.A young age, a decreased body mass index, and a history of OHSS increase the risk. Exogenous induction agents (recombinant hCG) precipitates OHSS more than endogenous agents (gonadotropin-releasing hormone [GnRH] analogs). Other precipitating factors are induction in a hyperestrogenic state and poor timing.  
Differential Diagnoses Acute Respiratory Distress Syndrome Pelvic Inflammatory Disease/Tubo-ovarian Abscess Appendicitis Pericardial Effusion Appendicitis, Acute Peritonitis and Abdominal Sepsis Cholecystitis Pleural Effusion Ectopic Pregnancy Pulmonary Embolism Ovarian Cysts Salpingitis Ovarian Torsion Hemorrhagic cyst

Pulmonary edema

Ruptured ovarian cyst
Workup Laboratory Studies
 In ovarian hyperstimulation syndrome (OHSS), the hematocrit is the most important measure in deciding if a patient should be hospitalized. If the patient's hematocrit level is greater than 60% and if she has ascites, hospitalize her immediately. Laboratory monitoring may involve the following parameters: -CBC with differential: This is helpful because decreased intravascular volume leads to hemoconcentration and an increased hematocrit. -Complete metabolic panel -Liver function: Liver function is decreased, as indicated by increased concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. -Kidney function: Renal function is reduced, BUN and creatinine values are increased, whereas albumin and protein levels are decreased. Electrolyte imbalances, hyperkalemia, and acidosis may be present. -Coagulation profile, including the prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR): These findings aid in detecting a hypercoagulable state and in monitoring anticoagulation. -Leukocyte count: This count is related to the seriousness of OHSS and to the risk of thromboembolism. -Beta-hCG concentration: A beta-hCG measurement is especially useful at more than 12 days after an injection of hCG. A positive result at this stage indicates pregnancy, an endogenous source of hCG for OHSS. hCG upregulates vascular endothelial growth factor (VEGF) receptors, and this upregulation increases third spacing.Mild OHSS may deteriorate to severe OHSS because of the increased availability of hCG. -Estradiol levels: Values are increased. -Laboratory findings of a serum estradiol concentration greater than 2000 pg/mL and a progesterone concentration greater than 30 ng/mL in the early part of the luteal phase are warning signs of developing OHSS. Signs that may indicate a progression in severity are increases in hCG level, hematocrit, hypoproteinemia, and hypoalbuminemia (third spacing). Additional signs are decreasing renal and liver function. OHSS is critical when the signs and symptoms of severe OHSS are present with any of the following findings: renal failure, ARDS, thromboembolism, or a hematocrit level greater than 60%.

Imaging Studies :

-Ultrasonography may be needed to measure the size of the ovaries, to assess the follicles, and to evaluate ascites

-Chest radiography may be indicated if dyspnea is present.

Treatment :

Mild hyperstimulation Treatment for ovarian hyperstimulation syndrome (OHSS) is supportive, as needed. Mild ovarian hyperstimulation can develop into moderate or severe disease, especially if conception ensues. Therefore, women with mild disease should be observed for enlarging abdominal girth, acute weight gain, and abdominal discomfort on an ambulatory basis for at least 2 weeks or until menstrual bleeding occurs.
Moderate hyperstimulation Treatment of moderate OHSS consists of observation, bed rest, provision of adequate fluids, and sonographic monitoring of the size of cysts. Serum electrolyte concentrations, hematocrits, and creatinine levels should also be evaluated. Some physicians have their outpatients keep track of their fluid intake and output. Intake or output less than 1000 mL/d or a discrepancy in fluid balance greater than 1000 mL/d is a cause for concern. The beginning of the resolution of OHSS is apparent when the cysts shrink, as seen on 2 consecutive ultrasonographic examinations, and when clinical symptoms recede. In contrast, early detection of progression to the severe form of the syndrome is marked by continuous weight gain (>2 lb/d), increased severity of existing symptoms, or appearance of new symptoms (eg, vomiting, diarrhea, or dyspnea).  
Severe hyperstimulation -Experience with severe OHSS is mandatory for appropriate treatment. One should transfer the patient to a different center if no one who is experienced in managing severe OHSS is available at the present location. -Severe OHSS is not common, but it is dangerous. Severe and critical forms of OHSS are potentially lethal disorders, and history taking and physical examination are paramount at the time of admission. In most clinical situations, patients require bed rest. Daily physical examination should consist of measuring the patient's weight and abdominal girth. Fluid balance must be assessed every 4 hours. -Medical treatment of severe hyperstimulation is directed at maintaining intravascular blood volume. Simultaneous goals are correcting the disturbed fluid and electrolyte balance, relieving secondary complications of ascites and hydrothorax, and preventing thromboembolic phenomena. -The main interventions are fluid management and correction of hypovolemia. These measures consists of initial fast intravenous administration of normal saline. Dextrose 5% in normal saline or normal saline is infused at a rate of 125-150 mL/h with 4-hour tabulations of urine production. If urine production is restored or improved, a maintenance protocol is started. The patient should be closely monitored for clinical signs of overhydration. If urine output is unsatisfactory, hyperosmolar intravenous therapy is indicated with an infusion of 200 mL of 25% human albumin. The use of diuretics in patients with low urine production and hypovolemia is counterproductive and dangerous. -Close surveillance of fluid management is necessary. Intravenous fluid administration is stopped when urine production, appetite, or interest in drinking increases and when an overall clinical improvement is observed. In the resolution phase of severe OHSS, the patient's fluid intake should be restricted to avoid renewed hemodilution. -To prevent thrombosis, subcutaneous heparin 5000-7500 U/d is begun on the first day of admission. It is stopped after adequate mobilization is achieved. -To manage ascites, ultrasonographic-guided vaginal paracentesis is indicated if the patient has severe discomfort or pain or if she has pulmonary or renal compromise.The procedure entails the same setup as that used for transvaginal follicular puncture. Whelan and Vlahos advise that an anesthesiologist be present. Paracentesis may be repeated if required. Critical hyperstimulation Critical OHSS may include renal failure, hepatic damage, thromboembolic phenomena, ARDS, and multiorgan failure.Its management and treatment requires intensive care in a critical care unit. Intensive care should include invasive monitoring of circulatory indicators, including venous pressure and wedge pressure. The patient may need extra oxygenation (assisted ventilation). If renal failure is present, an intravenous dopamine regimen should be started. To treat thromboembolism, therapeutic doses of anticoagulants should be administered. Thoracocentesis should be performed in the case of severe hydrothorax. Finally, if a pregnancy is maintaining a life-threatening OHSS, therapeutic abortion must be considered. Clinical Pearls What not to do Aggressive palpation of the abdomen: This can precipitate follicular rupture. Early surgical intervention: Early surgery may cause extensive bleeding from ovarian cysts. However, surgery is mandated if torsion or rupture has occurred. Neglect of deterioration in organs and systems: Remember that OHSS is a syndrome of multiorgan dysfunction. What to do Maintain a high degree of clinical suspicion and a low threshold for admission. Implement early surgical intervention in cases of ovarian torsion or hemorrhage. Perform paracentesis to address ascites. This decreases pressure on inferior vena cava and diaphragm. Place a transthoracic tube to manage pleural effusions. Resolution After several days, third-space fluid begins to re-enter the intravascular space, hemoconcentration reverses, and natural diuresis ensues. Intravenous fluids may be tapered as the patient's oral intake increases. Complete resolution typically takes 10-14 days from the onset of initial symptoms. Careful maintenance of blood volume, correction of electrolyte imbalances, and relief of secondary complications of ascites and hydrothorax are generally sufficient to support the patient during the severe phase of ovarian hyperstimulation. Anticoagulant therapy is usually unnecessary if these therapies are promptly administered. Blood coagulation may be monitored because of the danger of disseminated intravascular clotting. Surgical Care Ovarian hyperstimulation syndrome is a self-limiting disease. Therefore, treatment should be conservative and directed at symptoms. Medical therapy suffices for most patients. Women with severe symptoms often require intensive medical care. Surgery is necessary only in extreme cases, such as in the case of a ruptured cyst, ovarian torsion, or internal hemorrhage. Surgical management further aggravates electrolyte imbalances and increases morbidity. Ascites can be tapped by means of paracentesis. Harvesting of eggs in women with OHSS can lead to hemorrhage and peritonitis. However, tapping follicles when they are of moderate size may prevent OHSS. Laparotomy during torsion and intraperitoneal hemorrhage is life saving and recommended. Consultations In severe cases of OHSS, consultation with a physician specializing in fluid and electrolyte imbalances is warranted. For some cases, aggressive treatment in the surgical intensive care unit may be required. Diet Ensure that patient receives plenty of hydration. Activity Activity should be minimal. Physical examination should be performed gently because of the tendency of follicles to rupture.

Medication :

Medical therapy is aimed at the correction of fluid and electrolyte balance. Thrombosis can occur in the arteries (25%) and veins (75%). Therefore, use of heparin, low molecular weight heparin (enoxaparin sodium [Lovenox]), antiembolism stockings, and sequential compression devices (boots) are all recommended as prophylaxis against thrombosis. Heparin prophylaxis is usually started in patients with a history of thrombosis, factor V Leiden deficiency, or other thrombophilic states before the induction of ovulation. Anticoagulant These agents inhibit key factors involved in thrombogenesis.

Heparin Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but can inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Dosing Adult 5000-7500 U SC qd Interactions Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity Contraindications Documented hypersensitivity; subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Electrolyte supplement, parenteral Used to replenish intravascular and extravascular volume.

Normal saline Used to restore interstitial and intravascular volume. Dosing Adult 1-2 L IV initially, given as fast bolus; assess hemodynamic response, then 125-150 mL/h until urine production improves; followed by maintenance dose Interactions May decrease lithium levels when administered concurrently Contraindications Edema in brain or lungs (pulmonary edema may contribute to ARDS); hypernatremia Precautions Pregnancy A - Fetal risk not revealed in controlled studies in humans Precautions Exercise caution to prevent fluid overload; monitor cardiovascular and pulmonary function; stop fluids when desired hemodynamic response observed or pulmonary edema develops; interstitial edema may occur; caution in congestive heart failure, hypertension, edema, liver cirrhosis, or renal insufficiency Blood product derivatives These agents are used to expand plasma volume. Albumin (Albuminar, Albumisol, Albunex, Albutein, Buminate) Major plasma protein responsible for colloid oncotic pressure of blood. Pooled from blood, serum, plasma, or placenta from healthy donors. Given in certain types of shock or impending shock. Use 5% solution to expand plasma volume and maintain cardiac output. Use 25% solution to raise oncotic pressure. Dosing Adult 200 mL of 25% solution IV over 20-30 min, then assess hemodynamic and renal response Interactions None reported Contraindications Documented hypersensitivity; pulmonary edema; severe congestive heart failure or anemia; protein load of 5% albumin (tends to exacerbate renal insufficiency, a potential complication of septic shock) Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Caution in renal or hepatic failure, may cause protein overload; rapid infusion may cause vascular overload or hypotension; monitor for volume overload; caution in sodium-restricted patients; common adverse effects include congestive heart failure, hypotension, tachycardia, fever, chills, and pulmonary edema; do not dilute albumin 25% with sterile water for injection (produces hypotonic solution and, if administered, may result in life-threatening hemolysis and acute renal failure) Adrenergic agonist agent These agents increase blood pressure. Dopamine (Intropin) Naturally occurring endogenous catecholamine that stimulates beta1-adrenergic, alpha1-adrenergic, and dopaminergic receptors in dose-dependent fashion; stimulates release of norepinephrine.At low dosages (2-5 mcg/kg/min), acts on dopaminergic receptors in renal and splanchnic vascular beds, causing vasodilation-selective dilation of renal vasculature, enhancing renal perfusion. Also reduces sodium absorption, decreasing energy requirement of damaged tubules. This enhances urine flow, which, in turn, helps prevent tubular cast obstruction. Most clinical studies have failed to establish this beneficial role of renal-dose dopamine infusion.At midrange dosages (5-15 mcg/kg/min), acts on beta-adrenergic receptors to increase heart rate and contractility.At high dosages (15-20 mcg/kg/min), acts on alpha-adrenergic receptors to increase systemic vascular resistance and raise blood pressure. Dosing Adult 1-5 mcg/kg/min IV Interactions Monoamine oxidase inhibitors (MAOIs) may prolong effects; beta-blockers may antagonize peripheral vasoconstriction caused by high doses; butyrophenones (eg, haloperidol) and phenothiazines can suppress dopaminergic renal and mesenteric vasodilation induced with low-dose infusion; low doses concurrently administered with diuretics may produce additive effects on urine flow; hypotension and bradycardia may occur with phenytoin; may decrease effects of phenytoin Contraindications Documented hypersensitivity; pheochromocytoma or ventricular fibrillation Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Closely monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure during infusion; before infusion, correct hypovolemia with whole blood or plasma, as indicated; monitoring of central venous pressure or left ventricular filling pressure may help in detecting and treating hypovolemia; in patients who have received MAOIs the last 2-3 weeks, doses should not exceed 1/10th the initial dose of dopamine; ventricular arrhythmias and hypertension may occur in patients receiving cyclopropane or halogenated hydrocarbon anesthetics

Deterrence/Prevention -Ovarian hyperstimulation syndrome (OHSS) is a self-limiting disease of the luteal phase. Without luteinizing hormone (LH) or its imitator hCG, ovulation or the luteal phase does not occur. Avoidance of hCG during ovarian stimulation offers an opportunity to prevent OHSS in high-risk patients. However, those patients do not conceive. Other options are delaying hCG (coasting) for 1-3 days until estradiol levels plateau or decline.
<2500 -laboratory="" -the="" -vaginal="" 2000="" 30="" a="" activities="" adapt="" agonist="" also="" and="" any="" are="" as="" assumed="" at="" avoid="" be="" because="" best="" closely="" concentration="" cyst.="" developing="" doses="" early="" estradiol="" estrogen="" exertion.="" findings="" follicles="" gnrh="" grade="" greater="" hcg.="" high="" impact-type="" in="" induce="" intercourse="" is="" levels="" lowering="" luteal="" many="" method="" ml="" monitor="" monitored="" ng="" of="" ohss.="" ohss="" or="" ovarian="" ovulation.="" ovulation="" part="" patients="" pg="" phase="" polycystic="" preventive="" progesterone="" remember="" restricted="" risk.="" risk="" rupturing="" serum="" should="" signs="" strenuous="" strong="" syndrome="" than="" that="" the="" those="" time="" to="" treatment="" using="" warning="" well.="" with="" women="">

The prognosis is excellent if ovarian hyperstimulation syndrome is mild or moderate. In severe OHSS, the prognosis is optimistic if good treatment is given. Hypercoagulability may endanger the patient. Death from OHSS is largely due to hypovolemic shock and electrolyte imbalance, hemorrhage, and thromboemboli. Estimated fatality rates are 1 per 400,000-500,000 stimulated cycles.  
Patient Education
Patients are instructed to record their weight on a daily basis, to avoid exercise and intercourse, and to maintain adequate hydration after in vitro fertilization. They should measure their abdominal girth, intake, and output, and they should report urinary output of less than 1000 mL in any 24-hour period. Patients are educated to report progressive bloating, abdominal discomfort, decreases or increases in urination, cramping, dizziness, shortness of breath, and weight gain of more than 5 lb/wk.
Women should notify their doctor when they have: 

• Difficulty breathing
• Continued vomiting or nausea
• Difficulty tolerating fluids
• Abdominal swelling
• Decreased urination
• Weight gain of over 3 pounds in 2 days
• Sudden onset of abdominal pain
• Other symptoms such as facial numbness, weakness, lower extremity swelling, or redness