Pregnancy, Urinary Tract Infections

Pregnancy, Urinary Tract Infections

Background

Urinary tract infections (UTIs) are one of the most common bacterial infections during pregnancy. UTIs are associated with risks to both the fetus and the mother, including pyelonephritis, preterm birth, low birth weight, and increased perinatal mortality. The prevalence rates of bacteriuria in pregnant women and nonpregnant women are essentially the same.¹ UTIs are more common in women when compared with men, primarily because of the anatomic differences of the shorter urethra and its proximity to the vagina and the rectum. However, when pregnant women have a urinary tract infection, they have a higher risk for and increased occurrence of upper tract UTIs when compared with lower tract UTIs.

Several physiologic changes occur during pregnancy that cause otherwise healthy women to be more susceptible to serious sequelae from urinary tract infections.² The infections can be symptomatic or asymptomatic. Asymptomatic bacteriuria, as the name implies, is a positive urine culture without specific symptoms. Asymptomatic bacteriuria increases the risk for an upper tract UTI, also known as pyelonephritis. Treatment of asymptomatic bacteriuria reduces the risk of a symptomatic infection.³

Pathophysiology

Remarkable changes occur in the structure and function of the urinary tract during pregnancy. Blood-volume expansion is accompanied by increases in the glomerular filtration rate (GFR) and urinary output. The ureters undergo tonic relaxation because of the mass production of hormones, particularly progesterone. This loss in tone, along with the increased urinary tract volume, results in urinary stasis, which, in turn, can lead to dilatation of the ureters and the calyceal pelves. Urinary stasis and the presence of vesicoureteral reflux predispose some women to upper tract UTIs and acute pyelonephritis.

Frequency

United States

The frequency of asymptomatic bacteriuria occurs in 2-7% of pregnancies, similar to the nonpregnant population. However, up to 40% of these may progress to symptomatic upper tract UTI or pyelonephritis, significantly more than in nonpregnant women.⁴ Several factors are associated with an increased frequency in various patient populations. Indigent patients have a 5-fold increased incidence of bacteriuria compared with that of nonindigent patients. The risk is doubled in women with sickle cell trait. Other risk factors for bacteriuria include diabetes mellitus, neurogenic bladder retention, and a history of previous urinary tract infections.

Mortality/Morbidity

Untreated upper tract UTIs are associated with low birth weight, prematurity, premature labor, hypertension,preeclampsia, maternal anemia, and amnionitis.⁵ A retrospective population-based study by Mazor-Dray et al showed that urinary tract infection during pregnancy is independently associated with intrauterine growth restriction, preeclampsia, preterm delivery, and cesarean delivery.⁶

Race

When socioeconomic status is controlled, no significance difference among the races seems to exist.

Sex

Urinary tract infections (UTIs) are 14 times more frequent in women than in men. This difference is attributed to several factors: (1) the urethra is shorter in women; (2) in women, the lower third of the urethra is continually contaminated with pathogens from the vagina and the rectum; (3) women tend not to empty their bladders as completely as men; and (4) exposure of the urogenital system to bacteria during intercourse.

Clinical

History

The presentation varies depending on whether the patient has asymptomatic bacteriuria, a lower tract UTI (cystitis), or an upper tract UTI (pyelonephritis).

• Pregnant women with asymptomatic bacteriuria usually are diagnosed incidentally on routine urinalysis and urine culture.
• Burning with urination (dysuria) is the most significant symptom in pregnant women with symptomatic cystitis.
• The usual complaints of increased frequency, nocturia, and suprapubic pressure are not particularly helpful, because most pregnant women experience these as a result of increased pressure from the growing uterus.
• Symptoms of pyelonephritis include the following:
  • Fever (Often, the temperature is very high.)
  • Chills
  • Nausea and vomiting
  • Costovertebral angle (CVA) or flank pain

Physical

A thorough physical examination is recommended, with particular attention to the abdomen.

• CVA tenderness may be present.
• Suprapubic tenderness may be present.
• The fetal heart rate should be noted.
• Pelvic examination is strongly recommended in all patients (with the exception of the third-trimester patient with bleeding) to rule out vaginitis or cervicitis.

Causes

• Escherichia coli (most common, in as many as 70% of cases)
• Group B Streptococcus (10%)
• Klebsiella or Enterobacter species (3%)
• Proteus species (2%)³

Other Problems to Be Considered

Pyelonephritis

Workup

Laboratory Studies

• In all pregnant patients, a urine specimen should be carefully collected for urinalysis and culturing during the first prenatal visit or at 12-16 weeks' gestation.
  • These tests help to identify patients with asymptomatic bacteriuria as well as those with other specific complaints.
  • For urine collection, a midstream clean catch is adequate, provided the patient is given careful instructions.
  • Catheterization is indicated if the patient is unable to void, too ill, extremely obese, or bedridden.
  • Two consecutive voided specimens with isolation of the same bacterial strain (100,000 CFU/mL) or a single catheterized specimen (100 CFU/mL) is diagnostic.^7,2
  • Counts of less than 100,000 CFU/mL, with 2 or more organisms, usually indicate a contamination rather than an infection.
  • The leukocyte esterase test of the urine can be used as a screening examination for pyuria, although this test may be unreliable in patients with low-level pyuria (5-20 WBCs per high-power field).
• Patients with pyelonephritis often have WBC casts.
• Urine culturing should be performed in cases of suspected acute pyelonephritis, patients requiring hospitalization, and patients with a history of recent instrumentation or repeated infections.
• CBC, electrolyte, blood urea nitrogen (BUN), and creatinine tests should be ordered at the physician's discretion, although the results do not aid in the diagnosis or change treatment unless they are markedly abnormal.

Imaging Studies

• Unless anatomic abnormalities or renal disease is suspected, routine imaging studies are not necessary.
• In cases of persistent symptoms, persistent infection, or suspected urolithiasis, renal ultrasonography may be helpful.

Treatment

Emergency Department Care

Because of the dangers of maternal and fetal complications, care in the ED should be focused on identifying and treating patients with asymptomatic and symptomatic bacteriuria. Treatment of asymptomatic bacteriuria in pregnant patients is important because of the increased risk of urinary tract infection (UTI) and its associated sequelae.⁸ ED care may involve the following:

• Administration of appropriate antibiotics
• Administration of fluid if the patient is dehydrated
• Strongly consider admission if there is any indication of renal involvement

Consultations

An obstetrician may be consulted.

Medication

Antibiotic therapy for urinary tract infection should be initiated after all necessary cultures are obtained. If significant nausea or pain is present, appropriate medication may be indicated. Treatment of all symptomatic and asymptomatic patients with bacteriuria is important.

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Empiric coverage for E coli and Klebsiella, Proteus, and Enterobacter species should be provided.³

Penicillins and cephalosporins are safe for use during pregnancy. Ceftriaxone should be withheld close to parturition due to the possibility of neonatal kernicterus secondary to bilirubin displacement. Trimethoprim is a folic acid antagonist and should be avoided, especially during the first trimester. Fluoroquinolones and tetracyclines are known teratogens and are contraindicated in pregnancy.

Pruritic Urticarial Papules and Plaques of Pregnancy

Background

Pruritic urticarial papules and plaques of pregnancy (PUPPP) is a benign dermatosis that usually arises late in the third trimester of a first pregnancy.¹ The entity previously had been reported as toxemic rash of pregnancy,² toxemic erythema of pregnancy, and late-onset prurigo of pregnancy. The term polymorphic eruption of pregnancy (PEP) is used extensively in Great Britain, while PUPPP typically is used in the United States. Following atopic eruption of pregnancy, which occurs earlier in gestation, PUPPP is the second most common dermatoses of pregnancy.³

Frequency

International

Pruritic urticarial papules and plaques of pregnancy (PUPPP) occur in 1 out of 160-240 initial pregnancies.

Mortality/Morbidity

No mortality is associated with pruritic urticarial papules and plaques of pregnancy (PUPPP). The mere appearance of an unusual skin eruption in pregnancy can provoke anxiety, but the pruritus is the most distressing feature. The latter weeks of pregnancy can be associated with many physical symptoms, and the severe itching of PUPPP may further debilitate and aggravate sleep loss in the weeks prior to delivery. No known systemic complications exist for affected females, and fetal mortality or morbidity do not increase.

Race

Pruritic urticarial papules and plaques of pregnancy (PUPPP) may be less common in blacks.

Sex

Pruritic urticarial papules and plaques of pregnancy (PUPPP) occur in females only.

Age

Pruritic urticarial papules and plaques of pregnancy (PUPPP) occur during childbearing years because it is a dermatosis related to pregnancy.

Clinical

History

Pruritic urticarial papules and plaques of pregnancy (PUPPP) typically begin with intensely pruritic papules arising within striae distensae late in the third trimester of a first pregnancy. Of all cases, 73% are seen in primigravidae pregnancies.³ Additionally, 11.7 % of affected females are multiple-gestation pregnancies.⁴ As many as 15% of PUPPP cases arise in the immediate postpartum period.³ In a few days, the eruption spreads to the trunk and extremities. Patients present for a diagnosis of their unusual skin eruption and seek relief from the intense itching.

Physical

Classic pruritic urticarial papules and plaques of pregnancy (PUPPP) reveals papules within prominent striae distensae, as shown in the images below.

Courtesy of Jeffrey P. Callen, MD of Louisville, Kentucky.

Courtesy of Jeffrey P. Callen, MD of Louisville, Kentucky.

Erythematous urticarial papules and plaques of the trunk and extremities also are observed, although the periumbilical area is spared. Small vesicles often are noted, but larger bullae, though documented in one case, typically do not occur and would suggest the possibility of herpes gestationis.⁵ Less commonly, target lesions and annular and polycyclic wheals may be present. PUPPP usually does not affect the face, palms, or soles. Although the eruption is intensely pruritic, excoriations rarely are found. One report describes a case of PUPPP that progressed to involve the neck, arms, and legs in a photosensitive distribution as the initial abdominal involvement settled.⁶

Causes

The cause and pathogenesis of PUPPP are not known. A meta-analysis reveals 11.7% of patients with pruritic urticarial papules and plaques of pregnancy (PUPPP) are multiple gestation pregnancies.⁴ Within that group, a higher PUPPP risk for triplet (14%) over twin (2.9%) pregnancies has been published,⁷ suggesting a relationship between skin distension and the development of PUPPP. Most studies reveal increased maternal weight gain in patients with PUPPP when compared with normal pregnancies, further supporting the role of increased skin distension.⁸ 

A study from Israel also found maternal hypertension and induction of labor to be significantly associated with the condition.⁹ One large series¹⁰ of cases revealed a male-to-female infant ratio of 2:1. Investigators have identified fetal DNA in the skin of mothers with PUPPP, suggesting that chimerism might be relevant in the pathogenesis of this disorder.¹¹ Finally, a case-control study from France confirmed previously documented associations with multiple gestations, cesarean deliveries, and male fetuses, although no relationship to maternal or fetal weight gain was noted.¹²

Menopause and Mood Disorders

Menopause and Mood Disorders

Background

Menopause is the permanent cessation of menstruation resulting in the loss of ovarian follicle development. It is considered to occur when 12 menstrual cycles are missed.

Menopausal transition, or perimenopause, is a defined period of time beginning with the onset of irregular menstrual cycles until the last menstrual period, and is marked by fluctuations in reproductive hormones.³ This period is characterized by menstrual irregularities; prolonged and heavy menstruation intermixed with episodes ofamenorrhea, decreased fertility, vasomotor symptoms; and insomnia. Some of these symptoms may emerge 4 years before menses ceases, with a perimenopausal mean age of onset of 47.5 years.⁴ During the menopausal transition, estrogen levels decline and levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increase. Postmenopause is the phase following the last menstrual period.

Depression during menopause

In the United States, 1.3 million women reach menopause annually. Although most women transition tomenopause without experiencing psychiatric problems, an estimated 20% have depression at some point during menopause.⁵

Studies of mood during menopause have generally revealed an increased risk of depression during perimenopause with a decrease in risk during postmenopausal years.

The Penn Ovarian Aging Study, a cohort study, showed depressive symptoms increased during the menopausal transition, and decreased after menopause. The strongest predictors of depressed mood was a prior history of depression, along with fluctuations in reproductive hormone levels associated with depressed mood.⁶

In a cross-sectional population survey from the Netherlands, 2103 women were asked to rate their symptoms of depression before menopause and 3.5 years later, during the menopausal transition. The women experienced most symptoms of depression during the menopausal transition. In the United States, a study of a community sample of women undergoing natural menopause also demonstrated an increase in depressive symptoms during perimenopause.⁷ 

Investigators from the Harvard Study of Moods and Cycles recruited premenopausal women aged 36-44 years with no history of major depression and followed up these women for 9 years to detect new onsets of major depression. Women who entered perimenopause were twice as likely as women who had not yet made the menopausal transition to have clinically significant depressive symptoms.⁸ 

Recent research has shown that reproductive hormones produced during menopause contribute to mood alterations, such as depression. Higher testosterone levels may directly lead to higher depressive symptoms during the menopausal transition. Menopausal status, however, remains an independent predictor of depressive symptoms.⁹

Problems with sleep during menopause

Insomnia occurs in 40-50% of women during the menopausal transition, and problems with sleep may or may not be connected to mood disorders.¹⁰ Women with insomnia are more likely than others to report problems such asanxiety, stress, tension, and depressive symptoms.

Sleep disturbances during menopause have been associated with estrogen deficiency, as exogenous estrogen has been shown to improve both subjective and objective sleep, attributed to a decrease in hot flashes. A recent study proposed elevated LH levels during late menopause produce poor sleep quality through a thermoregulatory mechanism, resulting in high core body temperatures.¹¹ Whether the sleep problems are associated with age-related changes in sleep architecture, hormonal status, or other symptoms of menopause (eg, vasomotor symptoms) is unclear. However, in the Medical Research Council National Survey of Health, women who were transitioning into menopause were more likely to report severe sleep difficulty compared with women who were premenopausal.¹² 

Rates of sleep apnea increase with age, rising from 6.5% in women aged 30-39 years to 16% in women aged 50-60 years. The pathophysiology is not known, but theories include a relationship to postmenopausal weight gain or to decreased progesterone levels because progesterone stimulates respiration.^13,14 In addition to undergoing changes in estrogen and progesterone levels, postmenopausal women experience a decline in melatonin andgrowth hormone levels, both of which have effects on sleep.¹⁵

Schizophrenia during menopause

In most cases, schizophrenia first manifests in young adulthood, with the rate of new cases declining in both male and female individuals after early adulthood. A second peak in the incidence of schizophrenia is noted among women aged 45-50 years; this second peak is not observed in men.¹⁶

Some researchers have observed a worsening of the course of schizophrenia in women during the menopausal transition. These observations may suggest that estrogen plays a modulatory role in the pathophysiology of schizophrenia.¹⁷

Panic disorder during menopause

Panic disorder is common during perimenopause. New-onset panic disorder may occur during menopause, or preexisting panic disorder may worsen. Panic disorder may be most common in women with many physical symptoms of menopause.¹⁸ 

In a cross-sectional survey of 3,369 postmenopausal women aged 50-79 years, panic attacks were most prevalent among women in the menopausal transition. Panic attacks were associated with negative life events, functional impairment, and medical comorbidity.¹⁹ 

Obsessive-compulsive disorder during menopause

New-onset obsessive-compulsive disorder (OCD), a relapse of OCD, or a change in OCD symptoms may occur during menopause. Fluctuations in OCD have been correlated with the menstrual cycle and with pregnancy, suggesting that hormone levels may contribute to the disorder.²⁰

Bipolar disorder during menopause

Exacerbation of mood symptoms during menopause has been noted in women with preexisting bipolar disorder. Research has suggested that women with bipolar disorder have higher rates of depressive episodes during the menopausal transition. The frequency of depressive episodes in this population appears to be higher than during premenopausal years.²¹ Earlier studies suggested an increase in rapid cycling during the menopausal transition; however, this finding has not been reproduced.²²

Pathophysiology

Depression during perimenopause is likely due to fluctuating and declining estrogen levels in part. Steroid hormones, such as estrogen, act in the CNS by means of various mechanisms. For instance, they stimulate the synthesis of neurotransmitters, the expression of receptors, and influence membrane permeability.²³

Estrogen increases the effects of serotonin and norepinephrine, which are thought to be the neurotransmitters most related to the physiologic cause of depression. Among other mechanisms, estrogen decreases monoamine oxidase (MAO) activity in the CNS, hindering the break down of serotonin and norepinephrine.² In addition, estrogen increases serotonin synthesis, upregulates 5-hydroxytryptamine (5-HT)-1 (5-HT1) receptors, and downregulates 5-HT2 receptors. Estrogen also increases norepinephrine activity in the brain, perhaps by decreasing reuptake and degradation due to inhibition of the enzymes MAO and catechol O-methyltransferase.²⁴

Although the precise mechanisms are yet unknown, regulation of serotonin and norepinephrine may change as estrogen levels fluctuate and thus contribute to depression. Because estrogen facilitates the actions of serotonin and norepinephrine, a decline in estrogen concentrations may, in turn, decrease levels of these hormones.^2,23,24Changes in estrogen levels, perhaps due to mechanisms involving these neurotransmitters, may be related to depressive symptoms in the menopausal transition of some women.

Frequency

United States

Each year, 1.3 million women reach menopause. An estimated 20% of these women experience depression.⁵

Mortality/Morbidity

Although morbidity and mortality secondary to perimenopausal depression has not been studied, depression is known to be a significant health problem in women. According to the World Health Organization's Global Burden of Disease Study, unipolar depression is the leading cause of disease-related disability in women.²⁵ In the Global Burden of Disease Study, unipolar major depression was second to only ischemic heart disease in terms of associated morbidity and mortality.²⁶

Race

The racial distribution of perimenopausal depression is not known. However, in countries where older women are highly valued, women experience fewer symptoms overall during menopause.

Sex

Depression is approximately twice as common in women as in men (21% vs 12.7%). Moreover, depressive are more recurrent, longer, worse, and more impairing for women and for men.^27,28 In addition, the prevalence of dysthymia and minor depression is increases among women. These differences have not been noted for mania. Sex-related differences emerge at the age of 11-15 years.²⁵

Age

The mean age of onset for the menopausal transition is 47.5 years.⁴

Clinical

History

Perimenopause

• Hot flashes
• Cold sweats
• Irregular menstrual bleeding
• Urogenital atrophy and dryness with resultant dyspareunia (see gynecologic pain), itching, and urinary urge incontinence
• Cognitive and affective disturbance

Major depression
Essential criteria include the following:

• Depressed mood and/or
• Decreased interest or pleasure in activities

Additional criteria include the following:

• Increased or decreased appetite
• Weight change
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Feelings of worthlessness or guilt
• Decreased concentration
• Indecisiveness
• Suicidal ideation and plans
• Homicidal thoughts and plans

Overlapping symptoms of depression and perimenopause

• Low energy
• Impaired concentration
• Sleep disturbances
• Weight changes
• Libido changes

Depression (with the following suggestive features from a Mental Status Examination)

• Motor retardation or agitation
• Latency of response to questions
• Slowed thought process
• Diminished prosody of speech
• Poor eye contact
• Poor grooming or hygiene (may indicate advanced depression)

Physical

Findings of perimenopause include urogenital atrophy, as well as flushing and diaphoresis during hot flashes.

Causes

Causes of menopause-related mood disorders may include hormonal changes, life stressors, psychological or social conditions, and/or a preexisting tendency to develop depression.

Hormonal changes

Depression seems to be significantly linked to times of hormonal change in women. Several observations and study data support this theory. For example, the disparity between rates of depression in women and men begins at puberty. Also, hormonal changes are thought to be major contributors to premenstrual dysphoric disorder, as well as mood changes experienced in the postpartum period and at the menopausal transition.^27,28 Furthermore, estrogen affects both serotonin and norepinephrine, the 2 neurotransmitters thought to be most directly associated with depression.

Of note, absolute levels of gonadal hormones are not correlated with depression. Estrogen and progesterone levels do not distinguish a woman with depression from one without depression. When hormone concentrations were measured in perimenopausal or postmenopausal women with depression, no abnormal levels were found.²⁹ Rather, a certain subset of women seem to be predisposed to have mood disturbances triggered by hormonal fluctuations. This subset includes women with a history of mood disorders or of premenstrual and postpartum mood-related symptoms. The risk of depression appears to be higher during perimenopause, when hormone levels are changing, than during postmenopause, when estrogen and progesterone levels are low but stable.^23,30,6

Life stressors

Societal roles and expectations may contribute to the heightened rate of depression in women. Women with particular types of stressors seem to be at increased risk for perimenopausal depression. Such stressors include the following^5,28 :

• Lack of social support
• Unemployment
• Surgical menopause
• Poor overall health status

Dysphoric mood during the early perimenopausal transition is most common in women with relatively low educational status. Therefore, low levels of education may be a marker for other stressors, such as ongoing low socioeconomic status.³¹

An Australian study of women transitioning to menopause revealed more depression in women with the following states³² :

• Negative mood before menopause
• Negative attitude toward menopause and aging
• Smoking
• Little or no exercise
• No partner
• A number of bothersome symptoms
• Poor self-perceived health
• Negative feelings toward partner
• A number of perceived problems
• Interpersonal stress

Other stressors that tend to correspond with perimenopause and that are postulated to relate to depression include the following:

• Onset of illness in self or others
• Care of aging parents
• Changes in employment

Psychological or social conditions

Numerous psychological and social theories have been proffered to explain why women may become depressed during perimenopause. Some of these are related to the following factors:

• Change in the childbearing role
• Loss of fertility, which may be associated with a loss of an essential meaning of life
• Empty-nest syndrome (However, surveys have indicated that women whose children have moved out of the house tend to report more happiness and enjoyment in life than do others.)
• Societal value of youth (In societies where age is valued, women tend to report having fewer symptoms at the menopause transition.)

Preexisting tendency to develop depression

A personal or family history of major depression, postpartum depression, or premenstrual dysphoric disorder seem to be a major risk factor for depression in the perimenopausal period.⁵ However, perimenopausal depressive syndrome is a risk even in women without a history of depression.