Pregnancy, whether normal or complicated, induces change in nearly every system of the body. Because most rheumatologic disorders are multisystemic and often affect young women, it may be difficult to differentiate pregnancy-related change from new onset or exacerbation of rheumatic disease. Familiarity with common manifestations of pregnancy is important in evaluating young women of childbearing age, whether or not they have known rheumatologic disease.
Normal pregnancy induces profound multisystemic changes similar in magnitude to those seen in many well-defined endocrine disorders. However, unlike other endocrine conditions, pregnancy may affect up to half of the normal population. Alterations in the reproductive hormones persist through pregnancy and the initial postpartum period and affect the maternal anatomy, physiology, and metabolism. Familiarity with hormone-induced changes is critical to differentiate between normal and abnormal pregnancy manifestations as well as to differentiate between pregnancy-related symptoms and possible rheumatic disease. Rheumatic diseases disproportionately affect women, often presenting during the childbearing years. Changes of normal and abnormal pregnancy may mimic various symptoms of rheumatologic diseases, including musculoskeletal, dermatologic, hematologic, renal, and neurologic manifestations. The converse may also be true: the initial onset of rheumatologic disorders during pregnancy may present great difficulty in diagnosis because symptoms may be erroneously attributed to normal or complicated pregnancy, delaying appropriate diagnosis and therapy and ultimately affecting prognosis.
Musculoskeletal manifestations of pregnancy
Musculoskeletal complaints are frequent in pregnancy. Normal changes of ligamentous laxity, soft tissue edema, weight gain, and alteration in the center of gravity contribute to the musculoskeletal symptoms associated with pregnancy. Ligamentous laxity is an important physiologic change of pregnancy, allowing remodeling of the pelvic architecture and widening of the symphysis pubis to permit transvaginal passage of the fetus. Soft tissue edema is noted in up to 80% of women, most commonly during the last 8 weeks of pregnancy, and can contribute to tenosynovial or nerve entrapment. Weight gain places additional stress on joints: a 20% increase in weight during pregnancy can increase the force on a joint by as much as 100%. The position of the gravid uterus shifts the center of gravity, causing hyperlordosis, which contributes to the mechanical strain on the back and sacroiliac joints.
It has been suggested that pelvic and low-back pain of pregnancy is related to pregnancy-related hormones in addition to the altered biomechanical forces. Although ligamentous laxity was initially attributed to the production of the pregnancy hormone relaxin, more recent evidence does not support a strict correlation with the relaxin level, that is, relaxin level increases until peaking at 12 weeks, followed by a decline with stabilization at week 17 at 50% of the peak level. Estrogen may be more important for laxity. A small study evaluating 40 knees in 20 pregnant patients showed that high serum estradiol levels during the third trimester correlated with increased anterior tibial translation, measured serially during pregnancy and postpartum. The degree of translation decreased as the serum estradiol returned to nonpregnant levels during the postpartum period.
Low-Back and Pelvic Pain
Up to 72% of pregnant women complain of back pain during the course of pregnancy. Risk of low-back pain increases with an advancing maternal age, a history of previous pregnancy-related low-back pain, multiparity, a higher body mass index, and a history of hypermobility. Exercise before and during pregnancy may be protective. Contributing factors include mechanical strain, pelvic ligamentous laxity, sacroiliac pain, vascular compression, and spondylolisthesis. True lumbar radiculopathy as a cause of pregnancy-associated low-back pain is atypical, occurring in about 1% of pregnant women. Cauda equina syndrome resulting from lumbar disk herniation is rarer but reported and is estimated to occur in 1 in 10,000 pregnant women. Classic symptoms include bilateral radicular leg pain with bladder or bowel dysfunction and saddle anesthesia; if neurologic symptoms progress, surgery may be indicated during pregnancy.
Pelvic girdle pain of pregnancy is common and may affect the anterior or posterior pelvis. Pain in the pubic symphysis usually occurs because of increased motion as a result of ligamentous laxity. The syndrome of osteitis pubis is characterized by a gradual onset of pubic symphysis pain followed by rapid progression over several days to severe pain radiating down the inner thighs; although painful, recovery generally occurs within several days to weeks. The syndrome is also characterized by bony resorption about the symphysis followed by spontaneous reossification and may occur during pregnancy or in the postpartum period. Spontaneous rupture of the pubic symphysis, with complete tear of the ligaments, is rare and occurs most commonly during parturition. This rupture is believed to be caused by the forceful descent of the fetal head against the pelvic ring. Treatment is usually conservative with bed rest, pelvic support, and pain control, although surgical fixation is occasionally required. True pelvic dislocation because of the rupture of the symphysis pubis as well as the sacroiliac joint ligaments is extremely rare and is best managed with a surgical approach.
Osteitis condensans ilii is a radiologic diagnosis identified on radiograph in the postpartum period during workup for back or pelvic pain, which can be confused with inflammatory sacroiliitis. It is a benign, but sometimes painful condition, characterized by bilateral and symmetric sclerosis (triangular) on the iliac side of the sacroiliac joints; unlike sacroiliitis associated with ankylosing spondylitis and other inflammatory conditions, articular margins are intact and the joint space is preserved. The condition is most common in multiparous women and may result from mechanical stress across the sacroiliac joints in association with other pregnancy changes. Most affected women note the onset of pain during pregnancy or the postpartum period. Therapy is conservative with physical therapy and analgesics; radiographic results often return to normal over time.
Hip Pain
True hip pain, as distinct from hip area pain radiating from the back or pelvis, is an uncommon but concerning symptom during pregnancy. The differential diagnosis includes transient osteoporosis and avascular necrosis of the hip. Transient osteoporosis of the hip usually presents during the third trimester. This osteoporosis is a self-limiting demineralization of the femoral head and neck, which spontaneously resolves over 6 months. The typical presentation is the onset of acute hip pain worsened by weight bearing and relieved with rest. Prognosis is good if recognized; if not diagnosed, continued weight bearing may lead to fracture. Although usually unilateral, bilateral involvement leading to bilateral femoral neck and acetabular fractures has been reported. Treatment with antiresorptive bone agents such as calcitonin and bisphosphonates may shorten symptom duration in pregnant and postpartum patients, although use of bisphosphonates during pregnancy is controversial and is generally discouraged.
Avascular necrosis of the hip has been reported in pregnant patients who do not have other predisposing factors. The clinical presentation may be similar to that of transient osteoporosis of the hip, with pain exacerbated by weight bearing, often during the third trimester. Prognosis is variable, and postpartum core decompression or hip replacement may be necessary. Magnetic resonance imaging can effectively distinguish between transient osteoporosis and avascular necrosis and is considered safe in pregnancy.
Tenosynovitis
de Quervain tenosynovitis is the inflammation of the abductor pollicis longus and extensor pollicis brevis tendons in the first dorsal compartment of the wrist. Although often related to repetitive movement, this condition is also common in pregnant and lactating women. Patients develop pain with thumb movement, which radiates to the radial aspect of the wrist. Finkelstein test is diagnostic, with pain provoked by ulnar flexion of the closed fist with the thumb inside. Occurrence during pregnancy and lactation is attributed to fluid retention associated with hormonal changes. During the postpartum period, it may also be because of child care. Pregnancy- and postpartum-related disease is self-limited and usually resolves with cessation of pregnancy or lactation. Treatment during pregnancy or lactation includes splinting and/or corticosteroid injection. In one small study, corticosteroid injection was more effective than splinting and so may be the preferred temporizing therapy.
Arthralgia and Arthritis
In addition to the common musculoskeletal manifestations of pregnancy, otherwise healthy women may also complain of small joint pain during pregnancy, raising the question of inflammatory disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. Choi and colleagues recently evaluated the incidence of arthritis and arthralgia in a series of 155 healthy pregnant women followed up at Seoul National University Hospital between January and May 2004. Patients with other musculoskeletal diagnoses were excluded, including those with low-back pain, pelvic girdle pain, symphysis pubis pain, hip pain, carpal tunnel syndrome, rheumatic disease, trauma, or infection. Patients were evaluated by rheumatologists serially throughout pregnancy and for 6 weeks postpartum. The frequency of arthralgia was 16.7% and that of arthritis was 9.6%. Arthralgia and arthritis usually developed in the third trimester, and the proximal interphalangeal joints were most commonly involved. In most cases, symptoms improved spontaneously. Although one patient later developed spondyloarthropathy, no patient developed rheumatoid arthritis or SLE during the follow-up period. Symptoms were attributed to the characteristic changes in edema, joint laxity, hormone levels, and cytokines seen in pregnancy.
Onset of new rheumatoid arthritis during pregnancy is unusual, and studies suggest that pregnancy is protective against new-onset rheumatoid disease. However, an increased risk of disease onset is noted in the postpartum period. As a result, new onset of polyarthralgia or polyarthritis in the postpartum period should raise concerns about a new diagnosis of rheumatoid arthritis.
Cutaneous manifestations of pregnancy
Physiologic skin changes induced by pregnancy are primarily of cosmetic concern. However, these changes may mimic those suggesting flare of existing rheumatic disease or prompt concern about a new rheumatic disease diagnosis. Changes are seen in pigmentation, hair growth, nails, glandular function, connective tissues of the skin, and vascular structures.
Pigment Changes
Hyperpigmentation occurs in up to 90% of pregnant women. Melasma (chloasma or mask of pregnancy) is a diffuse macular facial hyperpigmentation found in up to 70% of pregnant women. A malar distribution, mimicking a lupus rash, is most common, followed by a more generalized facial distribution (centrofacial pattern). Like rash associated with lupus, symptoms are often exacerbated by exposure to visible and ultraviolet light. Melasma is more common in those with darker baseline skin tone. Although the change usually resolves postpartum, it may persist in darker-skinned individuals and often recurs in subsequent pregnancies or with the use of oral contraceptives. Despite the malar distribution and sun sensitivity, true inflammatory changes, such as those associated with lupus rash, are not seen.
Vascular Changes
Blood flow to the skin increases significantly by the end of the second month of pregnancy because of elevated estrogen levels and increased blood volume. Spider angiomas and telangiectasias develop in up to two-thirds of White women, usually resolving in the postpartum period. Nonpitting edema is frequent and may occur early owing to hormonal factors. These changes may suggest skin abnormalities associated with the systemic sclerosis spectrum of disease. Palmar erythema is seen in 30% to 70% of women, and when prominent, it may mimic cutaneous vasculitis seen in SLE or other connective tissue diseases.
Other Changes
A common pregnancy-induced dermatologic change suggestive of connective tissue disease is postpartum hair loss (telogen effluvium), which can be noticeable and distressing even when expected. Although usually limited to a period of several months, the hair loss may take up to 15 months to resolve, prompting concern about an underlying process. Before delivery, some women note a less-typical frontoparietal hair recession and diffuse hair thinning in the later months of pregnancy. Nail changes may occur, including onycholysis, grooving, and subungual hyperkeratosis. These changes may suggest psoriatic arthritis, especially in the setting of the common pregnancy complaint of low-back pain. Pruritis and urticaria also occur in pregnancy, which are nonspecific symptoms that may also present in connective tissue and other systemic diseases.
Pregnancy-Associated Rashes
Uncommon dermatoses specific to pregnancy may be confused with new-onset autoimmune rashes. Uncommon dermatoses include autoimmune progesterone dermatitis, pruritic urticarial papules and plaques of pregnancy, impetigo herpetiformis (a form of pustular psoriasis), and herpes gestationis (which shares many features with bullous pemphigoid but is limited to pregnant women). It is especially important to appropriately identify impetigo herpetiformis and herpes gestationis because they may be associated with the risk of maternal or fetal adverse effects.
Erythema Nodosum
Erythema nodosum is an acute nodular erythematous eruption on the extensor aspect of the lower legs; pathologic study shows a septal panniculitis without evidence of vasculitis. Erythema nodosum likely represents a hypersensitivity response to an unknown antigen (or antigens); its presence prompts workup for underlying rheumatic disease or infection. Common causes include streptococcal infection, tuberculosis, drugs (including oral contraceptives), sarcoidosis, Behçet syndrome, and enteropathies. Pregnancy is an uncommon but well-recognized cause of erythema nodosum, accounting for 2% of patients in a recent series of 100 patients. Recurrence of erythema nodosum in subsequent pregnancies and with the use of oral contraceptives has been reported.
Cutaneous manifestations of pregnancy
Physiologic skin changes induced by pregnancy are primarily of cosmetic concern. However, these changes may mimic those suggesting flare of existing rheumatic disease or prompt concern about a new rheumatic disease diagnosis. Changes are seen in pigmentation, hair growth, nails, glandular function, connective tissues of the skin, and vascular structures.
Pigment Changes
Hyperpigmentation occurs in up to 90% of pregnant women. Melasma (chloasma or mask of pregnancy) is a diffuse macular facial hyperpigmentation found in up to 70% of pregnant women. A malar distribution, mimicking a lupus rash, is most common, followed by a more generalized facial distribution (centrofacial pattern). Like rash associated with lupus, symptoms are often exacerbated by exposure to visible and ultraviolet light. Melasma is more common in those with darker baseline skin tone. Although the change usually resolves postpartum, it may persist in darker-skinned individuals and often recurs in subsequent pregnancies or with the use of oral contraceptives. Despite the malar distribution and sun sensitivity, true inflammatory changes, such as those associated with lupus rash, are not seen.
Vascular Changes
Blood flow to the skin increases significantly by the end of the second month of pregnancy because of elevated estrogen levels and increased blood volume. Spider angiomas and telangiectasias develop in up to two-thirds of White women, usually resolving in the postpartum period. Nonpitting edema is frequent and may occur early owing to hormonal factors. These changes may suggest skin abnormalities associated with the systemic sclerosis spectrum of disease. Palmar erythema is seen in 30% to 70% of women, and when prominent, it may mimic cutaneous vasculitis seen in SLE or other connective tissue diseases.
Other Changes
A common pregnancy-induced dermatologic change suggestive of connective tissue disease is postpartum hair loss (telogen effluvium), which can be noticeable and distressing even when expected. Although usually limited to a period of several months, the hair loss may take up to 15 months to resolve, prompting concern about an underlying process. Before delivery, some women note a less-typical frontoparietal hair recession and diffuse hair thinning in the later months of pregnancy. Nail changes may occur, including onycholysis, grooving, and subungual hyperkeratosis. These changes may suggest psoriatic arthritis, especially in the setting of the common pregnancy complaint of low-back pain. Pruritis and urticaria also occur in pregnancy, which are nonspecific symptoms that may also present in connective tissue and other systemic diseases.
Pregnancy-Associated Rashes
Uncommon dermatoses specific to pregnancy may be confused with new-onset autoimmune rashes. Uncommon dermatoses include autoimmune progesterone dermatitis, pruritic urticarial papules and plaques of pregnancy, impetigo herpetiformis (a form of pustular psoriasis), and herpes gestationis (which shares many features with bullous pemphigoid but is limited to pregnant women). It is especially important to appropriately identify impetigo herpetiformis and herpes gestationis because they may be associated with the risk of maternal or fetal adverse effects.
Erythema Nodosum
Erythema nodosum is an acute nodular erythematous eruption on the extensor aspect of the lower legs; pathologic study shows a septal panniculitis without evidence of vasculitis. Erythema nodosum likely represents a hypersensitivity response to an unknown antigen (or antigens); its presence prompts workup for underlying rheumatic disease or infection. Common causes include streptococcal infection, tuberculosis, drugs (including oral contraceptives), sarcoidosis, Behçet syndrome, and enteropathies. Pregnancy is an uncommon but well-recognized cause of erythema nodosum, accounting for 2% of patients in a recent series of 100 patients. Recurrence of erythema nodosum in subsequent pregnancies and with the use of oral contraceptives has been reported.
Hematologic manifestations of pregnancy
Blood volume increases by 40% to 50% during pregnancy, resulting from an increase in both plasma volume and red blood cell mass. However, the increase in plasma volume is proportionally greater than that of the red blood cell mass, and so maternal hematocrit falls during normal pregnancy, causing physiologic anemia that may exacerbate or mimic anemia of chronic disease.
Most studies confirm a mild decrease in platelet count within the normal range during gestation, which is attributed to increased destruction and hemodilution. About 8% of pregnant women develop a more significant decrease in platelet count, termed gestational thrombocytopenia, in the third trimester with platelet counts between 70,000 and 150,000/mm 3 , which is attributed to an acceleration of the usual increased platelet consumption associated with pregnancy. Counts return to normal within several weeks postpartum. Infants are rarely born with below-normal counts. Although gestational thrombocytopenia is not associated with maternal or perinatal complications, it may be confused with autoimmune thrombocytopenia or preeclampsia.
White blood cell (WBC) count increases slightly during pregnancy because of an increase in circulating neutrophils, and counts markedly increase from 20 to 30,000/mm 3 during labor, making WBC count less useful as an indicator of inflammation. The immune system changes overall during pregnancy to allow maternal tolerance of the fetus, resulting in a decrease in cell-mediated cytotoxic immune responses and an increase in humeral and innate responses. The decrease in cellular immunity leads to an increased susceptibility to intracellular pathogens. Serum complement levels are normal or slightly increased; as a result, these levels are less reliable in diagnosing or ruling out autoimmune disease activity.
Profound changes occur in the coagulation system during pregnancy and in combination with increased venous stasis, compression by the gravid uterus, and bed rest, which significantly increase the risk of thromboembolism during pregnancy and the postpartum period. Overall risk of thromboembolism in pregnancy is 1 per 1500, increased by a factor of 5. Most procoagulant factors increase, including fibrinogen and factors VII, IX, and X, whereas protein S levels decrease. The increase in fibrinogen is associated with an increase in the erythrocyte sedimentation rate (ESR), so that it is no longer useful as an indicator of inflammation.
Hematologic Complications
Although gestational thrombocytopenia is the most common cause of a low platelet count in pregnancy, less common conditions may also cause thrombocytopenia and, unlike gestational thrombocytopenia, can be associated with maternal and perinatal morbidity. These common conditions include immune thrombocytopenic purpura (ITP), severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count occurring in association with preeclampsia) syndrome, and disseminated intravascular coagulation (DIC); rarer causes include antiphospholipid syndrome (APS), SLE, thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS). Platelet antibody testing cannot distinguish among gestational thrombocytopenia, ITP, and preeclampsia, although the antibodies associated with gestational thrombocytopenia may not be specific antiplatelet antibodies.
Idiopathic thrombocytopenic purpura, although affecting only 3 in 1000 pregnancies, is of concern because profound neonatal thrombocytopenia may occur in infants; incidence of platelet count less than 50,000/mm 3 ranges from 5% to 38%. Despite the high incidence of low counts, neonatal complications are unusual and the mode of delivery does not seem to affect the outcome. Reported neonatal complications include intraventricular hemorrhage, hemopericardium, gastrointestinal bleeding, and cutaneous bleeding.
TTP and HUS are characterized by microangiopathic hemolytic anemia and severe thrombocytopenia. TTP is characterized by the presence of the hematologic abnormalities in combination with neurologic abnormalities, fever, and renal insufficiency and may be easily confused with, or occur in combination with, SLE or catastrophic APS. Seven percent of TTP cases are reported to occur during pregnancy or the postpartum period. In a series of 45 reported cases of TTP in pregnancy, 40 patients developed the disease antepartum, with 50% occurring before 24 weeks’ gestation. In contrast, HUS, which is characterized by more severe renal disease, usually has its onset in the postpartum period but may also be confused with postpartum preeclampsia, lupus nephritis, or vasculitis.
HELLP Syndrome
HELLP syndrome is identified by the triad of hemolysis (microangiopathic hemolytic anemia), elevated liver function tests, and low platelet count. HELLP syndrome is considered to be a variant of severe preeclampsia, but hypertension and proteinuria need not be present. Commonly associated symptoms include right upper quadrant or epigastric pain, nausea and vomiting, and headache. Severe associated complications include multiorgan dysfunction, DIC, liver infarction or hemorrhage, adult respiratory distress syndrome, and acute renal failure. Clinical findings may mimic severe gastrointestinal illness, ITP, SLE, TTP, and HUS. Therapy is determined by the gestational stage and clinical severity of presentation and may include immediate delivery or expectant management with plasma volume expansion, antithrombotic agents, corticosteroid, fresh frozen plasma, and plasmapheresis. Maternal mortality is estimated at 1% and the rates of morbidity are high. It was reported that 30% of cases develop in the postpartum period, most of these within 48 hours of delivery. The onset of HELLP in the second trimester has been associated with underlying APS. Early or severe presentation of HELLP, especially with liver infarction, should prompt evaluation for underlying APS or other connective tissue disease.
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