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Clinical manifestations and diagnosis of early pregnancy

Clinical manifestations and diagnosis of early pregnancy
Authors:
Lori A Bastian, MD, MPH
Haywood L Brown, MD
Section Editor:
Charles J Lockwood, MD, MHCM
Deputy Editor:
Vanessa A Barss, MD, FACOG
Literature review current through: Dec 2022. | This topic last updated: Aug 29, 2022.

INTRODUCTION — The diagnosis of pregnancy and familiarity with the normal versus abnormal findings associated with early pregnancy are common issues in the medical care of reproductive-age females. An additional issue is whether the pregnant state warrants a change in maternal management because of teratogenicity risk.

The diagnosis of early pregnancy is based primarily upon measurement of human chorionic gonadotropin in urine or blood, but ultrasonography is also an accurate method of diagnosis. History and physical examination are not highly sensitive methods for early diagnosis, but knowledge of the characteristic findings of a normal pregnancy can be helpful in alerting the clinician to the possibility of an abnormal pregnancy, such as ectopic pregnancy, or the presence of coexistent disorders.

An impending miscarriage or ectopic pregnancy should be considered and excluded in any pregnant patient in the first trimester who presents with lower abdominal pain, bleeding, history of an ectopic pregnancy, an intrauterine device in place, or a history of tubal surgery (eg, tubal occlusion for permanent contraception, salpingectomy).

This topic will review the clinical manifestations and diagnosis of early pregnancy as well as signs and symptoms of concern. Miscarriage and ectopic pregnancy are nonviable pregnancies and are reviewed separately (see "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology" and "Ectopic pregnancy: Clinical manifestations and diagnosis"). The safety of specific medications in pregnancy is discussed in topic reviews where the medications are used and in the Lexicomp drug interaction monographs for each drug.

PHYSIOLOGY OF NORMAL PREGNANCY — Most of the clinical findings associated with normal pregnancy can be attributed to end-organ effects of the hormonal and mechanical changes associated with pregnancy. These pathophysiologic changes are described in detail separately:

(See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".)

(See "Maternal adaptations to pregnancy: Dyspnea and other physiologic respiratory changes", section on 'Physiologic cardiopulmonary changes in pregnancy'.)

(See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)

(See "Maternal adaptations to pregnancy: Gastrointestinal tract".)

(See "Maternal adaptations to pregnancy: Hematologic changes".)

(See "Breast development and morphology", section on 'Pregnancy and lactation'.)

(See "Maternal adaptations to pregnancy: Musculoskeletal changes and pain".)

(See "Maternal adaptations to pregnancy: Skin and related structures".)

(See "Immunology of the maternal-fetal interface".)

CLINICAL MANIFESTATIONS OF EARLY PREGNANCY

Presentation — Amenorrhea is the cardinal presenting symptom of early pregnancy. Pregnancy should be suspected whenever a female in their childbearing years misses (is late for) a menstrual period (ie, they note that a week or more has passed without the onset of an expected menses). Clinical suspicion is increased if they also report any sexual activity while not using contraception or with inconsistent use of contraception. However, even patients who report consistent use of contraception may become pregnant because of user issues and because no method is 100 percent effective (table 1). In addition, sexual behavior is not always reported accurately [1].

Cessation of menses can be a difficult symptom to evaluate because some females have irregular menstrual cycles and many have occasional prolongation of a cycle. Furthermore, vaginal bleeding/spotting is relatively common in early normal pregnancy and often occurs at or near the time that a menstrual period would be expected [2,3]. In one prospective study, 14 out of 151 participants (9 percent) experienced at least one day of vaginal bleeding during the first eight weeks of pregnancy [3]. Bleeding tended to occur around the time they expected their period to occur and was typically light (requiring only one or two pads or tampons in 24 hours). (See "Overview of the etiology and evaluation of vaginal bleeding in pregnancy", section on 'First-trimester bleeding'.)

Signs and symptoms — The most common signs and symptoms of early pregnancy are:

Amenorrhea

Nausea with or without vomiting

Breast enlargement and tenderness

Increased frequency of urination without dysuria

Fatigue

Additional signs and symptoms may include:

Mild uterine cramping/discomfort without bleeding

Abdominal bloating

Constipation

Heartburn

Nasal congestion

Shortness of breath

Food cravings and aversions

Mood changes

Lightheadedness

Spider angiomas

Palmar erythema

Increased skin pigmentation (face, linea alba, areola)

Difficulty sleeping

Low back pain

Adnexal discomfort

In a study that prospectively collected data on the onset of pregnancy symptoms in 221 females attempting to conceive, 60 percent experienced some signs or symptoms of pregnancy as early as 5 to 6 weeks of gestation (ie, five to six weeks after the first day of their last menstrual period [LMP]), and 90 percent were symptomatic by 8 weeks [4]. Their symptoms tended to develop abruptly and occur daily. However, the symptoms were nonspecific: they also occurred in 9 percent of nonpregnant cycles.

Findings on physical examination

The pregnant uterus is more globular than in the nonpregnant state and enlarged, increasing in size by approximately 1 cm per week after 4 weeks of gestation. The correlation between uterine size and gestational age is often described in terms of fruit (eg, 6 to 8 week size = small pear; 8 to 10 week size = orange; 10 to 12 week size = grapefruit). The uterus remains a pelvic organ until approximately 12 weeks of gestation when it becomes sufficiently large to palpate abdominally just above the symphysis pubis, unless the patient has obesity. At 16 weeks, the uterine fundus is palpable midway between the symphysis pubis and umbilicus. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight", section on 'Uterine size'.)

The uterus and vaginal portion of the cervix soften beginning at approximately 6 weeks of gestation. Softening of the isthmus (lower portion of uterus adjacent to the cervix) allows the body of the uterus to flex against the cervix.

The mucous membranes of the vulva, vagina, and cervix become congested and may appear bluish (Chadwick sign) beginning at approximately 8 to 12 weeks of gestation.

The breasts become fuller and may become tender. The areola darkens, and the veins under the breast skin become more visible.

Fetal cardiac activity can usually be detected by a handheld Doppler device at 10 to 12 weeks of gestation and sometimes earlier if the patient is thin and the clinician is persistent (fetal heart size is <7 mm at 10 to 12 weeks [5]).

Laboratory findings

Human chorionic gonadotropin — Detection of human chorionic gonadotropin (hCG) in blood or urine is the basis of all pregnancy tests (table 2) (see 'Detection of human chorionic gonadotropin' below). hCG is secreted into the maternal circulation after implantation, which may occur as early as 6 days after ovulation but typically occurs 8 to 10 days after ovulation [6-9]. This is the earliest that hCG can be detected with a standard serum hCG test. However, the ovulation-to-implantation interval has been observed to vary by up to six days in naturally conceived pregnancies [6]. Late implantation has been associated with an increased risk of pregnancy loss [6,10].

The hCG concentration doubles every 29 to 53 hours during the first 30 days after implantation of a viable, intrauterine pregnancy; a slower rise is suggestive of an abnormal pregnancy (eg, ectopic, early embryonic death). (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Human chorionic gonadotropin'.)

In a study of females with normal menstrual cycles who were attempting to conceive, the median hCG concentration on the first day of expected but missed menses (ie, approximately 4 weeks of gestation) was 239 milli-international units/mL in serum and 49 milli-international units/mL in a spot urine, but there was a wide range among individuals [11,12]. The range of hCG values was narrower in a study of over 4400 females who conceived by in vitro fertilization, underwent embryo transfer two to three days after egg retrieval, and had at least one viable embryo at 8 weeks of gestation: the median hCG concentration on day 12 after embryo transfer/day 16 after ovulation (ie, approximately 4 weeks of gestation) was 118 milli-international units/mL (interquartile range 98 milli-international units/mL) [13].

The concentration of hCG peaks at 8 to 10 weeks of gestation, averaging 60,000 to 90,000 milli-international units/mL at that time, but again, the range of normal is quite wide (5000 to 150,000 milli-international units/mL or more); thus, hCG levels are not useful for estimating gestational age [7,14-21], except in the first one to three weeks postconception [22,23] (see 'Detection of human chorionic gonadotropin' below). After 8 to 10 weeks of gestation, hCG levels decline, reaching a median concentration of approximately 12,000 milli-international units/mL at 20 weeks, again with a wide range of normal: 2000 to 50,000 milli-international units/mL or more [24]. hCG concentration stays relatively constant from approximately the 20th week until term.

The factors accounting for the wide variation in interindividual hCG levels have not been studied extensively in accurately dated pregnancies; maternal weight accounts for some of the variation throughout pregnancy [25,26]. In some cases, an unrecognized vanishing twin affects the hCG level [27]. (See "Twin pregnancy: Overview", section on 'Vanishing twins'.)

Other laboratory findings — Numerous physiologic changes occur during pregnancy, sometimes accompanied by changes in laboratory test values (table 3). One diagnostically important change is an increase in the neutrophil count, which begins in the second month of pregnancy and should not be mistaken for the leukocytosis associated with inflammation/infection. (See "Normal reference ranges for laboratory values in pregnancy".)

Ultrasound examination — On transvaginal ultrasound examination, the timing of the first appearance of gestational landmarks based on LMP are as follows:

4.5 to 5 weeks – Gestational sac or intrauterine fluid collection compatible with pregnancy

5 to 6 weeks – Yolk sac (image 1), which remains until approximately 10 weeks

5.5 to 6 weeks – Fetal pole (image 2) with cardiac activity

These structures are observed slightly later with transabdominal ultrasound examination.

Biometric measurements (eg, crown-rump length, biparietal diameter) are used to estimate the gestational age (ie, duration of pregnancy) and delivery date. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)

In one retrospective study, the lowest human chorionic gonadotropin level at which a gestational sac was visualized in a viable pregnancy was 390 milli-international units/mL [28]. The threshold values for yolk sac and fetal pole visualization were 1094 milli-international units/mL and 1394 milli-international units/mL, respectively.

DIAGNOSIS — The diagnosis of pregnancy is based on the presence of any of the following:

Detection of human chorionic gonadotropin (hCG) in blood or urine

Identification of pregnancy by ultrasound examination

Identification of fetal cardiac activity by Doppler ultrasound

Several studies have examined the value of patient history for diagnosing early pregnancy (table 4) [29-36]. Although patient report of delayed menses, sexual activity with imperfect use of contraception, and patient suspicion of pregnancy are predictive that a pregnancy test will be positive, these factors are not sufficiently reliable to diagnose or exclude pregnancy. Nausea with or without vomiting, if present, increases the likelihood of pregnancy, but some individuals do not experience these symptoms or merely have not experienced them before being tested.

Only a few studies have examined the value of physical examination for diagnosing early pregnancy (table 4) [30,35,36]. The likelihood of pregnancy increases if signs of pregnancy are present, but absence of these signs does not rule out pregnancy. Obviously, the ability to detect physical signs of early pregnancy is highly dependent upon the experience of the examiner. (See "The gynecologic history and pelvic examination".)

Detection of human chorionic gonadotropin — The number of days after the last menstrual period (LMP) before a pregnancy test becomes positive depends on several factors, including [37,38]:

Cycle length, which varies because the length of the follicular phase, and thus the timing of ovulation, varies by three to five days (or more) from cycle to cycle.

The hCG assay's detection limit (ability to measure hCG at levels below 2 milli-international units/mL) and reference range cutoff (ie, threshold for a positive test), which differ for serum versus urine tests.

The hCG assay's combination of antibodies to hCG isoforms.

Ovulation can occur as early as 8 days after the first day of the LMP; in such patients, hCG may be detected in serum on day 14 and in urine on day 16 of the cycle [7-9,39,40]. However, pregnancy tests are most likely to be positive at the time of the expected period [41].

As discussed above (see 'Human chorionic gonadotropin' above), the normal range for hCG concentration across most of the first trimester is quite wide; thus, hCG levels are generally not useful for estimating gestational age [7,14-21] except in the first one to three weeks postconception. Very early in gestation (ie, the first one to three weeks postconception), the rise in hCG levels is similar among patients with viable pregnancies at the same gestational age and allows estimation of pregnancy duration [22,23]. A study using a home-based urine testing device (Clearblue Advanced Pregnancy Test with Weeks Estimator) was able to estimate time since ovulation (one to two weeks, two to three weeks, three or more weeks) in singleton viable pregnancies with an accuracy of 93 percent when compared with standard reference methods using ultrasound and assessment of ovulation day [22].

Types of pregnancy tests — Pregnancy tests can be performed on urine or serum. Factors that influence the choice of a urine or serum pregnancy test include duration of missed menses, need for accuracy, convenience, and cost. Tests on urine are adequate for diagnosis of a suspected pregnancy in patients who have missed a menstrual period, especially when there is time to follow-up an initial negative test with a second test a week later. Because urine tests do not detect very low levels of hCG that would be detected by a serum test, a urine test may be negative and the serum test positive around the time of missed menses; therefore, serum tests are preferable when the patient's menstrual period is less than a week late, especially when exclusion of pregnancy is an important factor in patient care, such as before administering a potentially teratogenic agent.

Serum pregnancy test — In clinical practice, the most sensitive method for detecting hCG in early pregnancy is a serum pregnancy test. Serum pregnancy tests typically detect hCG levels as low as 1 to 2 milli-international units/mL, whereas a "negative" pregnancy test is reported as hCG <5 milli-international unit/mL. Despite a well-established reference limit of <5.0 international units/L for nonpregnant females, there is a wide variation in reporting quantitative hCG results [42]. By contrast, urine pregnancy tests are less sensitive, typically detecting hCG beginning at a level of 20 to 50 milli-international units/mL. In addition, the median hCG concentration is higher in serum than in urine [20,43]. Therefore, very early in pregnancy, a serum pregnancy test may be positive while the urine pregnancy test is still negative, as previously stated.

The only potential advantage of a qualitative serum pregnancy test over a quantitative test is that the qualitative test can usually be performed more rapidly [44]. The quantitative test procedure requires use of dedicated automated measurement equipment and may be processed only in a commercial or hospital-based laboratory. It takes approximately 15 minutes to complete a test, but because samples are typically processed in batches, it may take much longer to obtain a result.

When a quantitative serum test is performed, most patients with singleton pregnancies will have a peak value <100,000 milli-international units/mL. Therefore, if a higher hCG level is noted, an ultrasound examination is indicated to exclude a multiple gestation or gestational trophoblastic disease, which could account for the finding.

Urine pregnancy test — Urine pregnancy testing is the most common method for diagnosing pregnancy. A variety of affordable and reliable qualitative urine tests are available and take only one to five minutes to perform.

Standard urine pregnancy tests used in clinical practice have a urine hCG threshold of 20 to 50 milli-international units/mL. Because the urine hCG concentration can be much lower than in serum and urine tests require a higher hCG level to detect the hormone, urine pregnancy tests may not be positive when the serum pregnancy test is positive, as previously stated [45]. At eight days postconception, the serum hCG concentration may be 10 milli-international units/mL, whereas urine hCG concentration may still be less than 1 milli-international unit/mL [23,46,47].

A random urine sample can be used for testing because hCG production is not circadian [48-50] and a low urine-specific gravity does not appear to alter the sensitivity of detecting hCG unless the test used has a high threshold for hCG positivity [51,52] or the urine specimen is extremely dilute.

A semiquantitative multilevel urine pregnancy test has been developed that measures hCG levels in concentrations of <25, 25 to 99, 100 to 499, 500 to 1999, 2000 to 9999, and >10,000 milli-international units/mL. It is not more useful than a standard urine qualitative test for routine diagnosis of pregnancy. It was developed primarily for follow-up of patients after first-trimester medication abortion and monitoring after treatment for ectopic pregnancy.

Home pregnancy test — Home pregnancy tests (HPTs) are generally highly accurate, but positive results should be confirmed, such as with Doppler confirmation of fetal cardiac activity, sonographic visualization of the pregnancy, an enlarged uterus on physical examination, or a serum or urine hCG test performed by a clinician.

Individuals choose to use HPT kits because of the speed of obtaining results and the convenience of testing at home. Use of HPT kits is associated with earlier pregnancy confirmation, but barriers to HPT use remain (eg, wanting to wait to see if menses begin, fear of the result, wanting time to think about what to do if pregnant), particularly among adolescents [53].

Many brands of HPT kits are available. They detect hCG in the urine using immunometric assay methods [12]. The performance of HPTs is affected by the users' technique and interpretation [47,54]. These tests are interpreted by noting the number of color bands/lines in the window of the device a few minutes after dipping it in urine for several seconds. A positive test will show two band/lines (eg, "ll" or "+"), while a negative test only shows one band/line (eg, "l" or "-"). Some devices have a digital display that shows "yes" or "no" or "pregnant" or "not pregnant" on an LCD screen.

Although manufacturers claim these kits are 99 percent accurate, this claim is based upon the ability of the test to detect an arbitrary amount of intact hCG added in vitro to urine samples from nonpregnant females. In many cases, it will not be sensitive enough to diagnose pregnancy in females who have recently missed a menstrual period.

The most common problem with HPT kits is a "false" negative result because the test was performed too soon after the expected onset of menses. The intervals between the first day of the LMP, ovulation, fertilization, implantation, and production of sufficient hCG for detection by an HPT are variable. If pregnancy is suspected despite a negative test, the test should be repeated in one week. Many HPT kits make this recommendation and provide an extra kit for this purpose.

HPT kits vary in sensitivity for detection of hCG; some do not detect levels below 100 milli-international units/mL [47,55]. This variability was demonstrated by a blinded in vitro sensitivity analysis of six commonly used HPT kits that found the following [56]:

First Response manual and First Response Gold digital devices were the most sensitive HPT kits with analytical sensitivity 5.5 milli-international units/mL. Over 97 percent of pregnancies could be detected on the first day of a missed period.

The next tier of tests had analytical sensitivity 11 to 22 milli-international units/mL.

EPT manual and digital devices detected 54 and 67 percent of pregnancies, respectively, on the first day of a missed period.

Clearblue Easy manual and digital devices detected 64 and 54 percent of pregnancies, respectively, on the first day of a missed period.

Practitioners can use these data to advise their patients on selection of HPT kits and their limitations.

Causes of a false negative test — The most common cause of a false negative result is performing the test too soon after conception (table 2). The test is negative because ovulation (and thus fertilization, implantation, and first day of the missed menstrual period) occurred later than expected [57,58].

If pregnancy is suspected despite a negative test, the test should be repeated in one week. Waiting a week or two after a missed period before performing a urine pregnancy test not only minimizes false negatives, but also decreases the tendency to perform a serum hCG test to exclude or confirm very early pregnancy after a negative urine test. Individuals with irregular cycles or an uncertain LMP should generally wait at least 14 days from the most recent sexual act before obtaining a pregnancy test.

Rarely, false negative results are due to a "hook effect." When a very high hCG concentration is present and the sample is tested without prior dilution, both the capture and tracer antibodies used in immunoradiometric assays become saturated, preventing the binding of the two to create a sandwich. Since the non-sandwiched tracer antibodies are washed away with the excess material, the test result will be negative. This is most commonly seen with the very high hCG levels associated with gestational trophoblastic disease; hCG levels are generally lower in normal pregnancies. (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease", section on 'High-dose hook or prozone effect'.)

An assay's inability to recognize specific isoforms of hCG can also play a role in false negative results [38,59-61]. In early pregnancy serum, hCG consists predominantly of intact hCG (>95 percent) together with minor amounts of the free beta-subunit of hCG, the proportion of which may be up to 10 percent during the first weeks of pregnancy, decreasing to approximately 0.5 to 2.0 percent after the eighth week [62]. In urine, however, a large proportion of hCG is a metabolic fragment of the hormone known as the beta-core fragment of hCG. The beta-core fragment of hCG can interfere with urine tests that measure regular intact hCG because the beta-core fragment of hCG may saturate the binding capacity of either tracer or capture antibody, leading to falsely negative test strip results, most commonly at 7 to 12 weeks of pregnancy [61]. This has been called a "variant hook effect" or "hook-like effect."

In a series of 40 emergency department patients in which the urine hCG test was negative and the serum quantitative hCG was positive, the overall false negative rate was 0.34 percent (40/11,760) [59]. In 18 of the 40 cases, the serum hCG level was below the detection limit in urine; the other 22 cases were considered false negatives due to a hook effect. In a review of the US Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 1996 to 2014, of 707 cases of false negative urine hCG test results, 142 (20 percent) were attributed to the variant hook effect from beta-core fragment of hCG, and 132 (19 percent) were attributed to performing the urine test before the limit of detection (which was defined as LMP four to six weeks before the false negative test, gestational age 4 to 6 weeks by ultrasound, and/or concurrent serum hCG concentration <200 milli-international units/mL) [63].

Causes of a false positive test — Modern immunoassays for hCG, whether in urine or serum, specifically bind to the beta-subunit of hCG, thus preventing cross-reaction with subunits of other hormones, such as luteinizing hormone, follicle-stimulating hormone, and thyrotropin. False positive pregnancy tests are rare and due to:

Operator error in performing or interpreting the test, particularly with HPTs.

Biochemical pregnancy (ie, pregnancy loss very soon after implantation and before signs of pregnancy are apparent on ultrasound).

Exogenous hCG administered as part of infertility treatment or for athletic performance. Exogenous hCG should be cleared by two weeks postinjection.

hCG secretion from a tumor.

Pituitary hCG secretion, typically in perimenopausal and postmenopausal females.

Interference with the assay by anti-animal antibodies, anti-hCG antibodies, or other substances (eg, high doses of biotin may cause a positive serum test, but a urine test is usually negative).

Familial hCG syndrome (a very rare genetic condition).

Medications do not cause false positive pregnancy tests, unless the medication contains hCG or, rarely, certain antibodies.

The characteristics, causes, and evaluation of false positive pregnancy tests are discussed in detail separately. (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease", section on 'Analytical causes of erroneous results; antibody-related interference'.)

POSTPREGNANCY TEST CONSIDERATIONS — When human chorionic gonadotropin (hCG) is initially detected, the provider needs to think about the following:

Is the pregnancy intrauterine or extrauterine?

If intrauterine, is the pregnancy viable?

What are the patient's feelings about the pregnancy?

Determining pregnancy location — All females with a positive hCG test can be offered an appropriately timed ultrasound to assess for a viable intrauterine pregnancy and to confirm or revise the expected date of delivery based on the last menstrual period. Because 98 percent of pregnancies are intrauterine, the pregnancy is generally assumed to be intrauterine unless the patient has:

Adnexal pain, and/or

Vaginal spotting/bleeding, and/or

Risk factors for an extrauterine pregnancy (table 5)

In patients at increased risk of ectopic pregnancy, the possibility of an extrauterine pregnancy could be excluded by demonstrating an intrauterine pregnancy by transvaginal ultrasound examination [64]. However, ultrasound may not detect an intrauterine pregnancy before 5 weeks of gestation or at a serum hCG concentration below the discriminatory cutoff. The discriminatory zone varies by laboratory and institution, and some data suggest that a small percentage of patients do not have an intrauterine pregnancy visible on ultrasound until an hCG level of 3510 international units/L is reached. In a study of 651 patients with first-trimester bleeding or pain, among viable intrauterine pregnancies, a gestational sac was seen at differing hCG levels in the following proportion of pregnancies: 1500 milli-international units/mL (80 percent had a gestational sac visualized), 2000 milli-international units/mL (91 percent), and 3510 milli-international units/mL (99 percent) [28].

In the absence of sonographic evidence of an intrauterine pregnancy, serum is tested serially to determine the rate of rise of the hCG level. An abnormally slow rate of rise suggests either an ectopic pregnancy or a pregnancy that will eventually miscarry. The correlation between ultrasound findings, absolute hCG level, and change in hCG level over time for diagnosis of viable versus nonviable intrauterine pregnancy versus an ectopic pregnancy is complicated (algorithm 1) and reviewed in detail separately. (See "Ectopic pregnancy: Clinical manifestations and diagnosis".)

Determining viability — An intrauterine pregnancy can be assumed to be viable except in patients who report vaginal bleeding with or without suprapubic pain/cramping and/or cessation of symptoms associated with early pregnancy. For these patients, transvaginal ultrasonography is indicated to look for fetal cardiac activity, which confirms viability.

In patients who have an initial transvaginal ultrasound that demonstrates an intrauterine pregnancy without fetal cardiac activity, the diagnosis of early pregnancy loss is based on specific adjunctive criteria (eg, gestational sac ≥25 mm in mean diameter without a yolk sac or embryo, embryo with crown-rump length ≥7 mm), which are reviewed separately. (See "Pregnancy loss (miscarriage): Clinical presentations, diagnosis, and initial evaluation" and "Pregnancy loss (miscarriage): Ultrasound diagnosis".)

Counseling after diagnosis of intrauterine pregnancy — The individual's feelings and thoughts about the pregnancy should be addressed. A proportion of patients with positive pregnancy tests have unplanned pregnancies. If the pregnancy was not planned, parenthood may still be desired, but other options, such as adoption and pregnancy termination, should be explored in a nondirective way, as appropriate depending on the patient's reaction to receiving their test results. It is also appropriate to discuss the patient's personal circumstances, including their living situation, partner reaction to the pregnancy, intimate partner violence, and reproductive coercion [65].

Patients who elect to continue the pregnancy should receive a referral for early initiation of prenatal care and information about good health practices during early pregnancy (eg, take a multivitamin that has at least 400 mcg of folate; avoid smoking, alcohol, recreational drugs, nonprescription use of prescription drugs, and exposure to ionizing radiation; avoid consuming uncooked or undercooked meats or unpasteurized cheese; and use good practices to reduce the risk of maternal infection).

If the patient has a medical problem or is taking a medication(s) that may be harmful in pregnancy, they should discuss this issue with an appropriate health care provider in a timely way. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs".)

Special populations

Patients with an intrauterine device — Although rare, a female may become pregnant with an intrauterine device (IUD) in place. An ultrasound should be performed to determine whether the pregnancy is intrauterine or extrauterine; most pregnancies in this setting are intrauterine, but the risk of ectopic is higher than if no IUD were present.

If the pregnancy and IUD are intrauterine, the IUD should be removed because the risk of pregnancy complications is higher if it is left in place than if it is removed, as long as the IUD string is visible. The evaluation and management of pregnancies complicated by an in situ IUD are reviewed separately. (See "Intrauterine contraception: Management of side effects and complications", section on 'Pregnancy'.)

Females with positive "pregnancy tests" who are not pregnant — Rarely, a positive "pregnancy test" in a female is not due to pregnancy. In these cases, hCG may be secreted by gestational trophoblastic disease, a nontrophoblastic malignancy, the pituitary gland, or may be a false positive. Ultrasound can be useful to distinguish among these entities, as it will not identify a pregnancy and may identify the intrauterine or adnexal tumor that is the source of the hCG. A complete list of sources of hCG in these patients and their evaluation are discussed separately. (See "Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease", section on 'Interpreting laboratory findings'.)

WHEN TO BE CONCERNED ABOUT EARLY PREGNANCY SYMPTOMS — Knowledge of the clinical spectrum of normal early pregnancy is helpful when evaluating pregnant patients who present with one or more similar clinical symptoms but have an abnormal pregnancy or a coexistent medical or surgical disorder. In surveys of healthy pregnant people in all three trimesters, the top four often reported symptoms are urinary frequency (52 percent), feeling tired (46 percent), poor sleep (28 percent), and back pain (20 percent) [66].

Vaginal bleeding — Bleeding in early pregnancy that is heavier than spotting or accompanied by any pain may represent an ectopic pregnancy (table 5) or impending miscarriage; however, any amount of bleeding is worrisome. The approach to evaluation and management of patients with bleeding in early pregnancy is discussed in detail separately. (See "Overview of the etiology and evaluation of vaginal bleeding in pregnancy", section on 'First-trimester bleeding'.)

Nausea and vomiting — Most pregnant people experience nausea with or without vomiting, typically starting at 5 to 6 weeks of gestation, peaking at approximately 9 weeks, and usually subsiding by 16 to 20 weeks. The onset of nausea and vomiting after approximately 10 weeks of gestation should prompt an evaluation because this is after the typical period expected for onset of pregnancy-related nausea and vomiting. A cause other than pregnancy should be considered if nausea and vomiting are accompanied by pain, fever, vertigo, diarrhea, headache, or abdominal distension. (See "Approach to the adult with nausea and vomiting".)

Hyperemesis gravidarum is considered the severe end of the spectrum of nausea and vomiting of pregnancy and is commonly defined as persistent vomiting accompanied by weight loss exceeding 5 percent of prepregnancy body weight and ketonuria unrelated to other causes. Alternatively, the diagnosis can be made in patients with pregnancy-related vomiting that occurs more than three times per day with weight loss greater than 3 kg or 5 percent of body weight and ketonuria. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation".)

Acute fatty liver of pregnancy, preeclampsia with severe features, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) are potentially life-threatening pregnancy-related disorders that can present with nausea and vomiting, but the onset of these disorders is almost always after 20 weeks of gestation. (See "Acute fatty liver of pregnancy" and "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

Urinary frequency — Cystitis or an upper urinary tract infection should be suspected if pregnancy-related urinary frequency is accompanied by dysuria, hematuria, pyuria, fever, or flank pain. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology" and "Urinary tract infections and asymptomatic bacteriuria in pregnancy".)

Dyspnea — Pregnancy-related dyspnea is usually mild, of gradual onset, and not associated with other pulmonary signs or symptoms (eg, cough, wheezing, pleurisy, hemoptysis, or rales) or systemic findings (eg, fever or increase in basal heart rate by more than 15 to 20 beats/minute). If dyspnea occurs acutely or is associated with any of these symptoms, then the patient should be evaluated for pulmonary embolism or other cardiopulmonary disease (eg, pneumonia, asthma, heart failure from cardiomyopathy). (See "Maternal adaptations to pregnancy: Dyspnea and other physiologic respiratory changes" and "Approach to the pregnant patient with a respiratory infection" and "Diagnosis of pulmonary embolism in pregnancy".)

Lightheadedness — Pregnancy-related lightheadedness typically occurs when the patient has been standing, especially in a warm environment. It should resolve when they lie on their left side. Lightheadedness is of concern when associated with an abnormal maternal heart rate/rhythm or signs suggestive of a seizure and when it does not resolve in the lateral or head-down position. (See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".)

Abdominal pain — The round ligaments begin near the uterine cornua, pass through the abdominal inguinal ring and along the inguinal canal, and end in the labia majora. Pain in the location of the round ligaments has been termed "round ligament pain"; it is common and a diagnosis of exclusion. The pain is typically on the right side of the abdomen/pelvis and often occurs upon waking, suddenly rolling over in bed, or other vigorous activity. The pain is believed to be caused by irritation of nearby nerve fibers or spasm of the ligament; rarely, it may be due to varicosities, myomas, or endometriosis associated with the ligament. A change in position may alleviate the pain, but no treatment is necessary, as the pain is usually mild and self-limited.

Adnexal disease (eg, ectopic pregnancy, ruptured ovarian cyst, ovarian torsion) should be excluded when the pain is moderate or severe, persistent or progressive, or accompanied by vaginal bleeding or peritoneal signs. (See "Ectopic pregnancy: Clinical manifestations and diagnosis" and "Adnexal mass in pregnancy".)

Midline pelvic pain and vaginal bleeding are the cardinal signs of impending or ongoing spontaneous abortion (see "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology"). After 20 weeks of gestation, preterm labor and placental abruption should be excluded in patients with these symptoms. (See "Preterm labor: Clinical findings, diagnostic evaluation, and initial treatment" and "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

Epigastric pain may be caused by gastroesophageal reflux (gastroesophageal reflux disease or heartburn), which is reported by 40 to 85 percent of pregnant people. Most studies report an increasing prevalence of symptoms from the first to the third trimester. Differential diagnosis and treatment are reviewed separately. However, epigastric and/or right upper quadrant pain in pregnant people can also be symptoms of preeclampsia with severe features, HELLP syndrome, or acute fatty liver of pregnancy, but the onset of these disorders is almost always after 20 weeks of gestation. (See "Acute fatty liver of pregnancy" and "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

Right lower-quadrant pain is a common symptom of appendicitis, which should be excluded. Although the location of the appendix migrates a few centimeters cephalad as the uterus enlarges, the most common symptom of appendicitis (ie, right lower-quadrant pain) occurs close to McBurney's point in the majority of pregnant people, regardless of the stage of pregnancy. (See "Acute appendicitis in pregnancy".)

Fatigue — Pregnancy-related fatigue has been attributed to the physiologic changes associated with pregnancy. It is most common in the first trimester, usually abates in the second trimester, and recurs to some degree in the third trimester. In nonpregnant adults, fatigue is a common nonspecific symptom with a broad range of etiologies including acute and chronic medical disorders (eg, sleep disorders), psychological conditions (eg, depression, anxiety), medication toxicity, and substance use. It is of potential medical concern when associated with other signs and symptoms (table 6). (See "Approach to the adult patient with fatigue".)

Poor sleep — Pregnant people experience poor sleep quality, insufficient nighttime sleep, and significant daytime sleepiness throughout pregnancy [67,68]. This is due, at least in part, to nocturia, difficulty finding a comfortable sleep position, and restless legs syndrome. (See "Restless legs syndrome during pregnancy and lactation".)

Poor sleep quality is of most concern when related to obstructive sleep apnea (OSA). Older age, higher body mass index, and frequent snoring (self-reported snoring ≥3 days per week) is predictive of prevalent and incident sleep-disordered breathing. In addition to the usual consequences of OSA, two potential effects in pregnancy include increased risks for developing preeclampsia and gestational diabetes. There are no clear adverse fetal effects, apart from sequelae from these pregnancy complications. (See "Obstructive sleep apnea in pregnancy".)

Back pain — Low back pain is a common problem among pregnant people. In most cases, it is due to mechanical factors resulting from altered posture, muscle weakness, joint laxity, and/or vertebral facet joint irritation. Risk factors include preexisting back pain, back pain in a previous pregnancy, multiparity, and high body mass index [69]. (See "Maternal adaptations to pregnancy: Musculoskeletal changes and pain".)

Patients with the following symptoms warrant referral to a primary care physician, orthopedic surgeon, or neurologist:

Severe pain that interferes with function, particularly nonpositional persistent back pain at night

Increased pain with cough, sneezing, and Valsalva

Neurologic deficits on examination

At high risk of infection or compression fracture

Systemic symptoms such as fever, chills, or weight loss

The vast majority of patients do not require imaging. The general approach to imaging in nonpregnant individuals with acute back pain is shown in the algorithm (algorithm 2). When an imaging study is indicated, magnetic resonance imaging (MRI) is by far the most commonly used modality [70,71] as there are no reported adverse maternal or fetal effects from MRI during pregnancy. (See "Diagnostic imaging in pregnant and nursing patients".)

Serious causes of low back pain and risk assessment of patients with low back pain are presented in detail separately. (See "Evaluation of low back pain in adults", section on 'Serious etiologies' and "Evaluation of low back pain in adults", section on 'Risk assessment for acute back pain'.)

Chest pain — Chest pain not due to gastrointestinal reflux is not a normal finding in pregnancy. The evaluation of pregnant people with chest pain is the same as in nonpregnant females of similar age. (See "Outpatient evaluation of the adult with chest pain".)

Pseudocyesis — Pseudocyesis and delusion of pregnancy are rare psychiatric diagnoses applied to people with negative pregnancy tests who believe they are pregnant. These patients may have signs and symptoms that mimic those of actual pregnancy and can be quite convincing [72]. The signs of true pregnancy on physical examination are identification of a fetal heart rate that is distinguishable from the maternal heart rate and palpation of fetal parts. (See "Pseudocyesis".)

Neuropathy — Carpal tunnel syndrome is the most common neuropathy in pregnancy. Symptoms tend to occur during the last trimester but can occur at any time. Corticosteroid injection or surgery to release the flexor retinaculum is rarely indicated during pregnancy since the disease has a better prognosis than idiopathic carpal tunnel syndrome and often resolves postpartum. (See "Neurologic disorders complicating pregnancy", section on 'Neuropathy'.)

Headache — Headache is common in reproductive-age females. There is no change in the frequency or clinical manifestations of tension or cluster headaches during pregnancy whereas migraines may occur less frequently. The evaluation of headache in pregnancy is the same as that in nonpregnant females except preeclampsia with severe features must be excluded (or diagnosed) in all patients over 20 weeks of gestation. Management, including the choice and safety of drug therapy, depends on the type of headache and is reviewed separately. (See "Headache during pregnancy and postpartum".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General prenatal care".)

SUMMARY AND RECOMMENDATIONS

Signs and symptoms The most common signs and symptoms of early pregnancy are amenorrhea, nausea/vomiting, breast tenderness, urinary frequency, and fatigue (table 4). (See 'Clinical manifestations of early pregnancy' above.)

Diagnosis – The diagnosis of early pregnancy is based primarily on detection of human chorionic gonadotropin (hCG) in blood or urine. Identification of pregnancy by ultrasound examination or identification of fetal cardiac activity by Doppler ultrasound are other methods, but sensitivity depends on the gestational age. Transvaginal ultrasound examination can first visualize a gestational sac (without a fetal pole) at 4.5 to 5.0 weeks of gestation (table 7). Fetal cardiac activity can usually be detected by a handheld Doppler device by 10 to 12 weeks of gestation. (See 'Diagnosis' above and 'Ultrasound examination' above.)

Serum pregnancy tests – A serum pregnancy test is more sensitive than a urine pregnancy test in early pregnancy (just before or after a missed menstrual period). (See 'Serum pregnancy test' above.)

Urine pregnancy tests – Although the urine pregnancy test is less sensitive than the serum test, almost all pregnant people will have a positive urine pregnancy test one week after the first day of a missed menstrual period. (See 'Urine pregnancy test' above.)

Home pregnancy tests – The accuracy of home pregnancy tests is affected by the sensitivity of the specific test kit, as well as the user's technique and interpretation. On the first day after a missed period, as many as 46 percent of pregnant people will have a negative test. Positive results on a home-based test should be confirmed with a serum or urine hCG test performed by a clinician or another definitive test (eg, Doppler confirmation of fetal cardiac activity, sonographic visualization of the pregnancy). (See 'Home pregnancy test' above.)

Determining pregnancy location – Because 98 percent of pregnancies are intrauterine, the pregnancy is generally assumed to be intrauterine unless the patient has:

Adnexal pain, and/or

Vaginal spotting/bleeding, and/or

Risk factors for an extrauterine pregnancy (table 5)

The evaluation for intrauterine pregnancy versus ectopic pregnancy in a hemodynamically stable patient is shown in the algorithm (algorithm 1). (See 'Determining pregnancy location' above.)

Differential diagnosis of common pregnancy signs and symptoms – Knowledge of the clinical spectrum of normal pregnancy signs and symptoms is helpful when evaluating females who present with one or more similar clinical findings but have an abnormal pregnancy or coexistent medical or surgical disorder. (See 'When to be concerned about early pregnancy symptoms' above.)

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References