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COVID-19: Overview of pregnancy issues

COVID-19: Overview of pregnancy issues
Literature review current through: May 2024.
This topic last updated: May 17, 2024.

INTRODUCTION — Pregnant people infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be asymptomatic or symptomatic for the disease caused by this virus: coronavirus disease 2019 (COVID-19). Those who are symptomatic appear to be at increased risk for developing severe sequelae of COVID-19 compared with infected nonpregnant reproductive-aged females. They also may be at increased risk for developing some pregnancy complications (eg, preterm birth) compared with uninfected or asymptomatic pregnant people. In utero transmission is rare, rates of miscarriage and congenital anomalies do not appear to be increased in pregnancies affected by COVID-19, and neonatal outcome is generally good.

Vaccination reduces the risk of developing COVID-19 and reduces the severity of disease if a breakthrough infection occurs. All available evidence supports the safety of administering currently available SARS-CoV-2 vaccines, regardless of pregnancy or breastfeeding status.

Most issues related to COVID-19 are the same for pregnant and nonpregnant people, but there are a few exceptions. This topic will provide an overview of these issues, provide links to UpToDate content that is relevant to both pregnant and nonpregnant people, and discuss aspects of the disease that are specific to pregnancy. Antepartum management of pregnant patients with COVID-19 and management of labor and birth during the pandemic are reviewed separately. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection" and "COVID-19: Intrapartum and postpartum issues".)

Information about the virus and COVID-19 continues to accrue, and guidance by multiple organizations is constantly being updated and expanded. Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See 'Society guideline links' below.)

VIROLOGY AND VARIANTS OF CONCERN — Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus that causes COVID-19. The host receptor for cell entry is the angiotensin-converting enzyme 2 (ACE2) receptor, which is found mostly in alveolar epithelial and stromal cells. SARS-CoV-2 binds to ACE2 through the receptor-binding domain of its spike protein. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Coronavirus virology'.)

Variants of the SARS-CoV-2 have evolved over time. "Variants of concern" are those with clinical and/or public health implications. Currently circulating variants of concern are Omicron sublineages (table 1). (See "COVID-19: Epidemiology, virology, and prevention", section on 'Viral evolution and variants of concern'.)

DEMOGRAPHICS — Racial and ethnic minority groups comprise a disproportionately high number of infections and deaths due to COVID-19 in the United States and United Kingdom, likely related to underlying disparities in the social determinants of health.

TRANSMISSION — Risk of transmission by exposure type, routes of transmission (direct person-to-person transmission is the primary means of SARS-CoV-2 transmission), incubation period, period of infectiousness, immune responses, and risk for reinfection are the same for pregnant and nonpregnant individuals. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Person-to-person transmission'.)

Sexual transmission has not been reported.

Vertical transmission is a concern in pregnant and recently pregnant people and is discussed below. (See 'Risk of vertical transmission' below.)

PREVENTION OF INFECTION

Overview

Vaccination – Vaccine types, dosing, administration, and side effects are described in the table (table 2). These issues as well as safety, efficacy, patient counseling, contraindications and precautions, and terminology (eg, definition of being up to date on vaccination) in the general population are reviewed separately. (See "COVID-19: Vaccines".)

Safety and benefits in pregnancy are discussed below. (See 'Vaccination in people planning pregnancy and pregnant or recently pregnant people' below.)

Personal preventive measures – (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

Issues for pregnant people with children. (See "COVID-19: Management in children".)

Occupational health measures, including for pregnant health care workers. (See "COVID-19: General approach to infection prevention in the health care setting", section on 'Management of HCP'.)

Infection control measures in the healthcare setting. (See "COVID-19: General approach to infection prevention in the health care setting".)

Infection control measures on the labor and delivery unit are reviewed separately. (See "COVID-19: Intrapartum and postpartum issues".)

Vaccination in people planning pregnancy and pregnant or recently pregnant people

Candidates — We recommend COVID-19 vaccination regardless of pregnancy or breastfeeding status, in agreement with major medical organizations and public health authorities [1]. This recommendation is based on data showing vaccine safety and efficacy in pregnant people and data that pregnancy itself is associated with an increased risk of severe infection (Centers for Disease Control and Prevention [CDC] tier 1c vaccine allocation). (See 'Safety and efficacy' below.)

A history of SARS-CoV-2 infection is not a factor; previously infected individuals should still receive COVID-19 vaccination.

Safety and efficacy — Although pregnant and breastfeeding people were not included in the initial large vaccine trials, subsequent data from vaccinated pregnant people demonstrated safety and efficacy before pregnancy, during pregnancy, postpartum, and during lactation [2-4]. The majority of data are for the mRNA vaccines.

Safety – None of the vaccines in the following table (table 2) contain virus that replicates; thus, they do not cause disease. Meta-analyses of large epidemiological studies of COVID-19 vaccination during pregnancy have not identified increased risks of any adverse outcome. There is no evidence of direct or indirect harmful effects on fertility, assisted reproduction outcome, embryo/fetal development, pregnancy outcome, parturition, or short-term postnatal development of offspring [5-15].

Side effects – Nonspecific side effects from activation of the immune system may occur and are similar in pregnant and nonpregnant females [16], except for a small (one day) and transient increase in menstrual cycle length (which also occurs in patients with COVID-19) and minor changes in postmenopausal bleeding in some nonpregnant females [17-20]. Serious side effects, such as thrombosis with thrombocytopenia syndrome, myocarditis and pericarditis, and Guillain-Barré syndrome, are rare and not increased among individuals who are vaccinated during pregnancy [21]. (See "COVID-19: Vaccines".)

Efficacy [4,6,7,14,22-27]

Reduction in maternal SARS-CoV-2 infection.

Reduction in maternal COVID-19 of any severity (especially severe and critical disease).

Reduction in perinatal death.

Reduction in hospitalization among infants up to six months of age.

Reduction in preterm births <28, <34, and <37 weeks.

The following large studies are examples of safety and efficacy data. Limitations of efficacy data is that vaccination is associated with known social determinants of maternal health [28] and efficacy wanes over time and with variants of concern. (See "COVID-19: Vaccines", section on 'Benefits of vaccination'.)

Pregnancy course in vaccinated individuals – In a meta-analysis of 23 observational studies including nearly 120,000 COVID-19 vaccinated pregnant people, the effectiveness of mRNA vaccination against reverse transcription–polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection seven days after the second dose was 89.5 percent (95% CI 69.0-96.4%), the risk of stillbirth was 15 percent lower in the vaccinated cohort (pooled OR 0.85, 95% CI 0.73-0.99), and there was no evidence of a higher risk of miscarriage, preterm birth, lower birthweight, placental abruption, pulmonary embolism, postpartum hemorrhage, maternal death, or maternal or neonatal intensive care unit admission in the vaccinated cohort [29].

Almost all data were for Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273, but early data from developmental and reproductive toxicity (DART) studies of the Janssen Ad26.COV2.S or JNJ-78436735 have also not demonstrated adverse outcomes [22]. Similar safety data have been reported for the ChAdOx1 nCoV-19 (AZD1222) vaccine, which has been administered outside of the United States [30].

Maternal course in vaccinated individuals – In a prospective cohort study of vaccine effectiveness and COVID-19 severity among pregnant people in 18 countries during the Omicron period, the primary vaccine series provided good protection against maternal development of severe symptoms and complications (effectiveness 48 percent, 95% CI 22-65) and even better protection after the booster dose (effectiveness 76 percent, 95% CI 47-89) [4]. Among pregnant people with COVID-19, the risk of progression to severe disease was reduced by 74 percent after the primary series and by 91 percent after the booster dose. Vaccination provided only modest protection against becoming infected (effectiveness 30 percent) and against developing moderate symptoms (effectiveness 48 percent).

Severe illness and death among the unvaccinated – In a study of pregnant patients with COVID-19 in Scotland, those who were unvaccinated at the time of COVID-19 diagnosis accounted for 77.4 percent of COVID-19, 90.9 percent of COVID-19 associated hospital admissions (ie, date of onset of infection occurred during a hospital admission or within 14 days before admission), 98 percent of COVID-19 associated critical care admissions (date of onset of infection occurred during a critical care admission or within 21 days before admission), and 100 percent of perinatal deaths (stillbirths and neonatal deaths) [31]. Among vaccinated patients with COVID-19, the perinatal death rate was similar to background rates and rates among pregnancies without confirmed infection. The authors did not have access to clinical records to determine whether COVID-19 directly or indirectly contributed these outcomes.

Infant effects – According to data from 30 pediatric hospitals in the United States during a period of Delta and Omicron variant circulation, maternal completion of both doses of a primary mRNA COVID-19 vaccination series during pregnancy was associated with reduced risk for COVID-19 hospitalization among infants <6 months of age (vaccine efficacy 52 percent) [25]. Vaccine efficacy was lower during circulation of the Omicron variant than during the Delta-predominant period (38 versus 80 percent) and higher when the second vaccine dose was given after 20 weeks of gestation compared with before 20 weeks (69 versus 38 percent). Vaccine efficacy against admission to an ICU for COVID-19 was 70 percent, 90 percent of the infants admitted to an ICU for COVID-19 were born to mothers who were unvaccinated, and the only two infants who died were born to unvaccinated mothers.

Choice of vaccine — We recommend vaccination with an updated mRNA COVID-19 vaccine (2023 to 2024 formula). In the United States, three COVID-19 vaccines are available (table 2). Two are monovalent formulations with an antigenic target based on the XBB.1.5 Omicron variant. The other is an adjuvanted recombinant protein vaccine (monovalent). Two adjuvants have been widely used in vaccines administered in pregnancy (eg, insoluble aluminum salts in Tdap, AS03-adjuvanted influenza vaccines) and have a documented good safety profile [32]. There is less safety data for other adjuvants, but harm is unlikely.

Timing — Vaccination is performed according to recommended schedules for the general population (table 2) regardless of gestational age or breastfeeding status.

The following issues relate specifically to people planning pregnancy and pregnant or recently pregnant people:

Early versus late pregnancy – Vaccine administration earlier rather than later in gestation provides the most maternal benefit as it reduces the maternal risk of hospitalization because of COVID-19, death from COVID-19, and COVID-19 related pregnancy complications during more weeks of the pregnancy. Although fetal and newborn antibody levels appear to be higher with vaccination later in pregnancy [33], this potential benefit does not outweigh the overall pregnancy (maternal, fetal, newborn) benefits of vaccination as soon as possible or account for the effects of additional doses when recommended by public health authorities [34].

Periconception – Currently available vaccines for prevention of COVID-19 do not affect fertility or success of infertility treatment [35-37], pregnancy testing is not a requirement prior to receiving any approved COVID-19 vaccine, and it is not necessary to delay pregnancy after vaccination. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'No proven effect'.)

Administration of non-COVID-19 vaccines and anti-D immunoglobulin – COVID-19 vaccines may be administered at the same time as other vaccines routinely administered in pregnancy (eg, influenza, Tdap); a separation period between vaccinations is unnecessary.

Anti-D immunoglobin does not interfere with the immune response to vaccines, so timing of administration for prevention of alloimmunization is based on standard clinical protocols. (See "COVID-19: Vaccines", section on 'Other administration issues'.)

Breastfeeding – Breastfeeding should not influence timing of vaccination [38,39]. Maternal antibodies cross the placenta and are transferred into breast milk, conferring passive immunity against SARS-CoV-2 in newborns. Protective antibodies have been documented in cord blood 15 days after maternal mRNA vaccination and appear to persist and protect the infant for at least six months [40,41]. Although breastfeeding people were not included in the initial large vaccine trials, available vaccines are unlikely to pose a risk to the breastfeeding child as they do not contain infectious virus and the minimal amount of vaccine that crosses into breast milk [42,43] and ingested by the infant is likely to be inactivated by the infant's digestive system.

CLINICAL MANIFESTATIONS AND COURSE OF INFECTION

Overview — General issues regarding the incubation period, clinical presentation and course, spectrum of clinical findings (table 3), risk factors for severe illness (table 4), and laboratory and imaging findings (table 5 and image 1 and image 2) are primarily discussed in the following topic (see "COVID-19: Clinical features"), and briefly below. (See 'Maternal clinical findings of COVID-19' below.)

The course of infection appears to be more severe in pregnant people. Infection, particularly when symptomatic, is associated with an increased risk for some pregnancy complications. (See 'Maternal susceptibility to and acute course of infection' below and 'Pregnancy and newborn outcomes' below.)

Maternal clinical findings of COVID-19

Signs and symptoms – Signs and symptoms of COVID-19 during pregnancy are generally similar to those in nonpregnant individuals (table 3) [44,45], although one systematic review found that pregnant and recently pregnant people were less likely to manifest fever, cough, dyspnea, and myalgia than nonpregnant females of reproductive age [46]. Some of the clinical manifestations of COVID-19 overlap with symptoms of normal pregnancy (eg, fatigue, shortness of breath, nasal congestion, nausea/vomiting), which should be considered during evaluation of afebrile symptomatic pregnant people. (See "COVID-19: Clinical features" and 'Differential diagnosis' below.)

Frequency of asymptomatic infection – Asymptomatic cases are common, but the proportion of these cases is not well defined. In one systematic review, 54 to 77 percent of pregnant people with COVID-19 in a universal screening population were asymptomatic [46]. In another systematic review, 95 percent of COVID-19 infections in pregnant people were asymptomatic, and 59 percent (95% CI 49-68 percent) remained asymptomatic through follow-up [47].

Laboratory and imaging – Laboratory and imaging findings are generally similar to those in nonpregnant people. However, some laboratory findings of COVID-19 also overlap with those caused by pregnancy-related disorders (eg, thrombocytopenia and elevated liver chemistries in preeclampsia with severe features). (See "COVID-19: Clinical features", section on 'Laboratory findings' and "COVID-19: Clinical features", section on 'Imaging findings'.)

Maternal susceptibility to and acute course of infection

Overview — The body of evidence suggests that pregnancy does not increase susceptibility to SARS-CoV-2 infection. Limitations of available data include difficulties in distinguishing behavioral from biological determinants of infection susceptibility and differences in infection assessment.

Most (>90 percent) infected pregnant people recover without undergoing hospitalization; however, pregnancy does appear to worsen the clinical course of COVID-19 (increased risks for intensive care unit [ICU] admission, need for mechanical ventilation and ventilatory support, death) compared with nonpregnant females of the same age [44,46,48-55]. It is known that some patients with severe COVID-19 have laboratory evidence of an exaggerated inflammatory response (similar to cytokine release syndrome), which has been associated with critical and fatal illnesses. Whether the normal immunologic changes of pregnancy affect the occurrence and course of this response is unknown. (See "COVID-19: Clinical features", section on 'Acute course and complications'.)

Rapid clinical deterioration can occur and symptomatic pregnant people appear to be at increased risk of severe disease and death compared with symptomatic nonpregnant females of reproductive age [44,46,49,56-60]. Risk factors for severe disease and death in pregnancy include older age (especially ≥35 years), obesity, preexisting medical comorbidities (particularly hypertension, diabetes, or more than one comorbidity), and being unvaccinated [4,61,62]. For example, among the 15 maternal deaths from COVID-19 in Mississippi (nine deaths per 1000 SARS-CoV-2 infections in pregnant patients versus 2.5 deaths per 1000 SARS-CoV-2 infections in nonpregnant females of reproductive age), 14 of the 15 patients had comorbidities and zero of the 15 patients was fully vaccinated [60]. One meta-analysis also found that pregnant people who were underweight before pregnancy were at high risk for severe COVID-19 [62]. This finding may have been related, at least in part, to undernutrition as the analysis included many studies from low- and middle-income countries.

The following examples show the spectrum of the clinical course of COVID-19 in pregnant people in four large datasets:

In a systematic review of 435 studies including nearly 300,000 pregnant and recently pregnant people with suspected or confirmed COVID-19 [46]:

9 percent had severe disease.

4 percent were admitted to an ICU, and the risk was higher in pregnant people compared with nonpregnant females of reproductive age with COVID-19 (odds ratio [OR] 2.6).

2 percent received invasive ventilation.

0.2 percent received extracorporeal membrane oxygenation (ECMO).

0.2 percent died.

However, these findings have many limitations. For example, the primary studies included people with both suspected and confirmed infection; largely consisted of pregnant people who required visits to the hospital, such as for childbirth, thus affecting the generalizability of the estimates; often did not indicate timing of assessment of the clinical manifestations of disease; used different definitions of symptoms, tests, and outcomes; generally did not provide adequate information to distinguish iatrogenic effects from the true impact of the disease; and the findings for some outcomes were based on one or two studies.

In a report from the Centers for Disease Control and Prevention (CDC) COVID-19 Response Pregnancy and Infant Linked Outcomes Team that included over 23,000 pregnant people and over 386,000 nonpregnant females of reproductive age with symptomatic laboratory-confirmed SARS-CoV-2 infection, pregnant people had a higher risk of [44]:

ICU admission (10.5 versus 3.9 per 1000 cases, adjusted risk ratio [aRR] 3.0, 95% CI 2.6-3.4)

Receiving invasive ventilation (2.9 versus 1.1 per 1000 cases, aRR 2.9, 95% CI 2.2-3.8)

Receiving ECMO (0.7 versus 0.3 per 1000 cases, aRR 2.4, 95% CI 1.5-4.0)

Death (1.5 versus 1.2 per 1000 cases, aRR 1.7, 95% CI 1.2-2.4)

Pregnant people with comorbidities and older pregnant persons appeared to be at particularly elevated risk of adverse maternal outcome. Some limitations of the study included ascertainment biases; lack of information on pregnancy status in over one-half of reported cases; and lack of information for the reason for hospital admission in many cases, limiting the ability to distinguish between admissions solely for labor and delivery and those for COVID-19-related illness.

Data from 463 US hospitals revealed that maternal death during birth hospitalization increased from 5.2 deaths per 100,000 pregnant patients before the pandemic to 8.7 deaths per 100,000 pregnant patients during the pandemic (March 1, 2020, to April 31, 2021; OR 1.75, 95% CI 1.19-2.58) [63]

A case-control study that compared 5183 pregnant with 5183 matched nonpregnant females of reproductive age with COVID-19 reported the following propensity score-matched risks [64]:

Death (1.5 versus 0.8 percent; OR 1.84, 95% CI 1.26-2.69)

Pneumonia (9.9 versus 5.6 percent; OR 1.86, 95% CI 1.60-2.16)

Intubation (8.1 versus 8.6 percent; OR 0.93, 95% CI 0.70-1.25)

ICU admission (13 versus 7.4 percent; OR 1.86, 95% CI 1.41-2.45)

Propensity score matching was conducted for chronic obstructive pulmonary disease, asthma, smoking, hypertension, cardiovascular disease, obesity, diabetes, chronic renal disease, immunosuppression, age, language, nationality, and level of health insurance.

Duration of symptoms — The PRIORITY (Pregnancy CoRonavIrus Outcomes RegIsTrY) registry of pregnant or recently pregnant people either under investigation for COVID-19 or confirmed to have COVID-19 found that [65]:

The median time until symptoms resolved was five weeks and two days

60 percent of participants had no symptoms by four weeks

25 percent of participants had persistent symptoms at eight weeks (5 percent cough and 8 percent loss of smell/taste)  

Potential complications — Complications of COVID-19 in adults include, but are not limited to:

Serious respiratory disorders – Such as pneumonia, respiratory failure, ARDS (see "COVID-19: Management in hospitalized adults", section on 'Management of hypoxemia, ARDS, and other complications')

Serious cardiac disorders – Such as arrhythmias, acute cardiac injury (see "COVID-19: Cardiac manifestations in adults")

Thromboembolic complications (see "COVID-19: Hypercoagulability")

Secondary infections (see "COVID-19: Clinical features", section on 'Acute course and complications')

Acute kidney failure (see "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Acute kidney injury')

Neurologic disorders – Such as headache, dizziness, myalgia, alteration of consciousness, disorders of smell and taste, weakness, strokes, seizures (see "COVID-19: Neurologic complications and management of neurologic conditions")

Cutaneous disorders – Morbilliform rash; urticaria; pernio-like, acral lesions; livedo-like, vascular lesions; and vesicular, varicella-like eruption (see "COVID-19: Cutaneous manifestations and issues related to dermatologic care")

Gastrointestinal and liver disorders (see "COVID-19: Issues related to gastrointestinal disease in adults" and "COVID-19: Issues related to liver disease in adults")

Psychiatric illness (eg, anxiety disorders, depressive disorders, insomnia disorder, posttraumatic stress disorder) (see "COVID-19: Psychiatric illness")

DIAGNOSIS — Diagnostic tests for COVID-19 (table 6) and making a diagnosis are the same, regardless of pregnancy status (algorithm 1). The diagnostic approach, including whom to test, choice of test and specimen collection, factors affecting test performance, test interpretation, follow-up/repeat testing, and use of serology to identify prior/late infection are discussed separately. (See "COVID-19: Diagnosis".)

Classification of disease severity — In the United States, the National Institutes of Health (NIH) have categorized degrees of disease severity in nonpregnant persons as follows [66]:

Asymptomatic or presymptomatic infection – Positive test for SARS-CoV-2 but no symptoms.

Mild illness – Any signs and symptoms (eg, fever, cough, sore throat, malaise, headache, muscle pain) without shortness of breath, dyspnea, or abnormal chest imaging.

Moderate illness – Evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SaO2) ≥94 percent on room air at sea level.

Severe illness – Respiratory frequency >30 breaths per minute, SaO2 <94 percent on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50 percent.

Critical illness – Respiratory failure, septic shock, and/or multiple organ dysfunction.

Disease severity has also been categorized (Wu classification) as [67]:

Mild – No or mild symptoms (fever, fatigue, cough, and/or less common features of COVID-19).

Severe – Tachypnea (respiratory rate >30 breaths per minute), hypoxia (oxygen saturation ≤93 percent on room air or PaO2/FiO2 <300 mmHg), or >50 percent lung involvement on imaging).

Critical (eg, with respiratory failure, shock, or multiorgan dysfunction).

Other definitions of severity exist (eg, severe = maternal peripheral oxygen saturation [SpO2] ≤94 percent on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation [ECMO]) and are discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Defining disease severity'.)

Differential diagnosis

Other infections – Early symptoms of COVID-19 can be similar to those of multiple other viral and bacterial respiratory infections (eg, influenza, respiratory syncytial virus, adenovirus, Haemophilus influenzae pneumonia, Mycoplasma pneumoniae pneumonia). In a systematic review including nearly 300,000 pregnant and recently pregnant people with suspected or confirmed COVID-19, 12 to 33 percent of symptomatic people tested positive for SARS-CoV-2; thus, most had other etiologies for their symptoms [46].

If influenza is prevalent in the community, it is reasonable to also test for influenza when testing for SARS-CoV-2 as this could have management implications. Detection of another pathogen does not necessarily rule out SARS-CoV-2 in locations where there is widespread transmission because coinfection with SARS-CoV-2 and other respiratory viruses, including influenza, has been described. Coinfection with tuberculosis has also been reported and should be considered in patients with impaired immunity or at increased risk for exposure to Mycobacterium tuberculosis.

Preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) – The possibility of preeclampsia with severe features or HELLP syndrome should be considered in the differential diagnosis of persons under investigation for or with confirmed COVID-19 as these pregnancy-related disorders may mimic or coexist with the infection [68-70].

In pregnant people, some COVID-19-related laboratory abnormalities (elevated liver enzyme levels, thrombocytopenia) are identical to those that occur in preeclampsia with severe features and HELLP syndrome. Autoimmune hemolysis; prolonged prothrombin time; elevated D-dimer, procalcitonin, and C-reactive protein (CRP) levels; positive lupus anticoagulant screen; and low fibrinogen levels may also be observed in complicated COVID-19 cases (note the normal reference ranges for D-dimer, CRP, and fibrinogen levels are higher in pregnant people) [46,71]. Acute kidney injury can occur as a severe complication of COVID-19 or preeclampsia with severe features. Symptoms also overlap: Headache, acute cerebrovascular disease, and seizures can be neurologic manifestations of COVID-19 or preeclampsia with severe features/eclampsia.

The presence of acute hypertension can be helpful in differential diagnosis as it is a common finding in patients with preeclampsia or HELLP syndrome and not a feature of COVID-19 (although chronic hypertension is a risk factor for severe illness). (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis".)

Maternal-fetal medicine consultation can be helpful for further evaluation and management of patients with clinical findings that have been associated with both severe COVID-19 and preeclampsia with severe features. (See "COVID-19: Neurologic complications and management of neurologic conditions" and "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension".)

PREGNANCY AND NEWBORN OUTCOMES — Data suggest that infection with the Delta variant during pregnancy was associated with a higher risk of severe maternal illness, placental dysfunction, and fetal compromise than previous variants and the subsequent Omicron variants, including after adjustment for prior vaccination when possible [72-77].

Patients with COVID-19 at highest risk for adverse pregnancy outcome are those with comorbidities since these patients are also at high risk for severe disease [62].

Risk of vertical transmission — The overall rate of congenital infection has been reported to be 2.7 percent of maternal infections (95% CI 2.1-3.5 percent; 210 studies, 24,040 neonates) [78], but only a few well-documented cases of probable in utero transmission have been published [79-81]. In a 2024 systematic review, maternal risk factors for mother-to-child transmission included severe COVID-19 (OR 3.5, 95% CI 1.5-8.1), death (OR 14.1, 95% CI 4.1-48.0), and maternal postnatal infection (OR 5.0, 95% CI 1.2-20.1) [78]. Seven of the 14 confirmed mother-to-child infections in this review were attributed to transmission intrapartum or shortly after birth.

In utero transmission of infection typically occurs via a hematogenous route but sometimes via the ascending route. Viremia rates in patients with COVID-19 appear to be low (1 percent in one study [82] but higher in severe disease [83] and possibly with the Delta variant [84]) and transient, suggesting placental seeding and in utero transmission would not be common [85]. Most placentas studied to date had no evidence of infection, but the virus has been identified in a few cases [79,80,86-88]. At least four patients with a positive vaginal swab and one patient with a positive vaginal swab and amniotic fluid have been reported, suggesting the ascending route of infection and intrapartum transmission from contact with vaginal secretions are rare [79,80,89]. On the other hand, viral shedding in maternal feces is common, so fecal contamination of the perineum could theoretically be a source of intrapartum transmission, although there is no evidence of protective effect of cesarean. Postnatal transmission could occur from ingestion of breast milk or, more likely, from an infected mother (or other caregiver) to the infant through respiratory or other infectious secretions. (See "COVID-19: Intrapartum and postpartum issues", section on 'Breastfeeding and formula feeding'.)

SARS-CoV-2 cell entry is thought to depend on the angiotensin-converting enzyme 2 receptor and serine protease TMPRSS2, which are minimally coexpressed in the placenta [90,91]. This may account for the infrequent occurrence of placental SARS-CoV-2 infection and fetal transmission. However, SARS-CoV-2 (or maternal IgM) could reach the fetus as a result of ischemic injury to the placenta that compromises the syncytiotrophoblast barrier, without requiring placental cell infection [83].

Criteria for diagnosis of congenital infection — In a mother with SARS-CoV-2 infection, we would make a definitive diagnosis of congenital infection (ie, intrauterine transmission) in a live born neonate if SARS-CoV-2 is detected by polymerase chain reaction in umbilical cord blood or neonatal blood collected within the first 12 hours of birth or amniotic fluid collected prior to rupture of membranes, in agreement with criteria proposed by Shah et al for confirmed, probable, and possible congenital infection [92]. Using this system, a systematic review of 47 studies (1188 SARS-CoV-2 positive pregnant people, 985 neonates) found vertical transmission was confirmed in 0.3 percent, probable in 0.5 percent, and possible in 1.8 percent [93]. Others (eg, World Health Organization [WHO], Blumberg et al) have also published reasonable criteria [83,94].

One barrier to diagnosis of maternal-fetal transmission is that there are no accepted criteria for definitive evidence of congenital infection, thus the reported prevalence of in utero transmission depends on the criteria used for vertical transmission. For example, using Blumberg's criteria, a positive RT-PCR nasopharyngeal swab in the first 24 hours of life that persists on retesting meets diagnostic criteria for intrauterine transmission, but would be diagnosed as possible intrauterine transmission using WHO criteria.

Criteria for infection in neonates should distinguish between intrauterine (congenital) versus intrapartum and/or early postnatal transmission of SARS-CoV-2.

Risk of miscarriage — The body of evidence suggests that the frequency of miscarriage is not increased above baseline [95-102].

Risk of congenital anomalies — The body of evidence suggests that the frequency of congenital anomalies is not increased above baseline [95,103].

Risk of preterm birth — In a 2023 individual participant data meta-analysis, neonates born to mothers with symptomatic COVID-19 were more likely to be born preterm (<37 weeks: RR 1.41, 95% CI 1.15-1.73) and by cesarean birth (RR 1.16, 95% CI 1.04-1.29) than neonates of COVID-19 negative mothers [104]. Preterm birth rates are increased in many studies but not all, likely because initial data were not derived from nationally representative samples, lacked appropriate comparison groups, and were subject to bias [105]. In cohort studies, the increased risk appears to be limited to patients with severe or critical disease in late pregnancy [49,52,106,107], and underlying comorbidities also likely play a role. Despite an increase in preterm birth among pregnant COVID-19 patients, the overall frequency of preterm birth in 16 US hospitals of the Maternal-Fetal Medicine Units Network did not increase after the onset of the COVID-19 pandemic (rate during: 11.7 percent versus rate before: 12.5 percent, adjusted RR 0.94, 95% CI 0.86-1.03) [108].

Fever and hypoxemia may increase the risks for preterm labor, prelabor rupture of membranes, and abnormal fetal heart rate patterns, but preterm births also occur in patients without severe respiratory disease. Increases in preterm births could also be related to higher maternal stress during the pandemic and changes in maternity services [109]. A limitation of many studies is that they do not distinguish between spontaneous and iatrogenic preterm birth. It appears that many third-trimester cases were delivered by planned cesarean because of a bias to intervene catalyzed by the belief that management of severe maternal respiratory disease would be improved by delivery; however, this hypothesis is unproven.

Risk of cesarean birth — In a 2023 individual participant data meta-analysis, the risk for cesarean birth was slightly higher among those with COVID-19 (RR 1.10, 95% CI 1.01-1.20; 10 studies; >10,000 patients) [105]. 

Risk of preeclampsia — The risk of preeclampsia is probably increased. A meta-analysis of observational studies of SARS-CoV-2 infection during pregnancy found a 62 percent higher odds of developing preeclampsia among patients with COVID-19 (7 versus 4.8 percent; pooled unadjusted odds ratio [OR] 1.62, 95% CI 1.45-1.82, 26 studies, >786,000 patients), which remained elevated after limiting the analysis to the 11 studies with adjustment for confounders and the six studies with a low risk of bias [110]. Preeclampsia; preeclampsia with severe features; eclampsia; and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) were all increased. In contrast to preterm birth, both asymptomatic and symptomatic patients experienced an increased risk, with a higher risk among symptomatic patients (OR 2.11 versus OR 1.59).

In addition to the usual limitations of observational studies, another limitation of these data is that some COVID-19-related laboratory abnormalities (elevated liver enzyme levels, thrombocytopenia) are identical to those that occur in preeclampsia with severe features and HELLP syndrome. (See 'Differential diagnosis' above.)

Risk of stillbirth — Some data suggest an association between COVID-19 in pregnancy and stillbirth; however, initial studies were unable to adjust for potential confounders [46,111]. In a systematic review, fetal demise generally occurred 6 to 13 days after the diagnosis of infection or the onset of symptoms [112].

In an analysis of over 1.2 million delivery hospitalizations with over 8000 stillbirths in the United States (March 2020 through September 2021), pregnant patients with COVID-19 were at increased risk for stillbirth compared with pregnant patients without COVID-19 (1.26 versus 0.64 percent of deliveries; adjusted relative risk [aRR] 1.90, 95% CI 1.69–2.15) [113]. The highest risk for stillbirth was during the Delta variant period, July through September 2021 (2.7 versus 0.63 percent; aRR 4.04, 95% CI 3.28–4.97) and in patients with COVID-19 plus comorbidities (eg, chronic hypertension, multiple gestation, adverse cardiac event, abruption, sepsis, shock, acute respiratory distress syndrome (ARDS), mechanical ventilation). Of note, the stillbirth rate among patients without COVID-19 was similar to that in the prepandemic period (0.59 percent). Despite the study's limitations (eg, gestational age at SARS-CoV-2 infection, vaccination status, and maternal symptom status were not available; criteria for SARS-CoV-2 testing varied across hospitals), these findings provide further support for vaccination. Indeed, all reported cases of SARS-CoV-2 placentitis causing stillbirth and neonatal death have been in unvaccinated mothers [114].

In some other countries, such as India, a rise in stillbirths has been attributed to disruptions to maternal care and maternal supportive services (eg, food and micronutrient supplements) during the pandemic [115].

Risk of psychiatric illness — COVID-19 may be associated with acute alterations in behavior, cognition, personality, or consciousness, including anxiety disorders and depressive disorders. It may exacerbate pre-existing psychiatric illness or result in posttraumatic stress disorder. The psychological impact of the pandemic and infection should be recognized and support offered [116-120]. (See "COVID-19: Psychiatric illness".)

Overall risk of serious maternal morbidity or mortality — Population-based cohort studies have reported increased risks for severe maternal morbidity or mortality in patients with COVID-19 [121,122]. As an example, in a study including over 14,000 pregnant or postpartum patients in the United States of whom 2352 had and 11,752 did not have a positive SARS-CoV-2 test result, compared with those without a positive SARS-CoV-2 test result, SARS-CoV-2 infection was associated with [121]:

Increase in the primary outcome of composite of maternal death or serious morbidity related to hypertensive disorders of pregnancy, postpartum hemorrhage, or infection other than SARS-CoV-2 (13.4 versus 9.2 percent; aRR 1.41, 95% CI 1.23-1.61). All five maternal deaths were in the SARS-CoV-2 group.

A trend towards an increase in cesarean birth (34.7 versus 32.4 percent; aRR 1.05, 95% CI 0.99-1.11).

In particular, moderate or higher COVID-19 severity (586 patients) was significantly associated with the primary outcome (26.1 versus 9.2 percent; aRR, 2.06, 95% CI 1.73-2.46) and cesarean birth (45.4 versus 32.4 percent; aRR 1.17, 95% CI 1.07-1.28), whereas mild or asymptomatic infection (1766 patients) was not.

In a prospective, multicenter observational study of 1500 pregnant people with COVID-19, post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID) occurred in 9 percent, which was less than the 23 percent in a nonpregnant cohort [123]. The most common symptoms were post-exertional malaise (82 percent), fatigue (75 percent) and dizziness (62 percent). Risk factors included obesity, preexisting depression or anxiety disorder, self-reported difficulty covering expenses, and treatment with oxygen during infection.

Newborn outcome — Over 95 percent of newborns of SARS-CoV-2-positive mothers are uninfected and in good condition at birth. Although some newborns of infected mothers have tested positive, they were usually asymptomatic or developed symptoms of mild infection (ie, not requiring respiratory support) and most of the cases were attributed to transmission from respiratory droplets postnatally when the neonates were exposed to mothers or other caregivers with COVID-19.

Neonatal morbidity (eg, need for mechanical ventilation) has largely been related to preterm birth and to adverse uterine environments resulting from critical maternal COVID-19 [46,124-128]. In a study that included maternal and infant data for 92 percent of births in Sweden during the pandemic, infants of SARS-CoV-2-positive mothers had a small increase in the rate of any respiratory disorder compared with infants of uninfected mothers (2.8 versus 2 percent, OR 1.42, 95% CI 1.07-1.90) and admission for neonatal care (11.7 versus 8.4 percent, OR 1.47, 95% CI 1.26-1.70) [129]. Neonatal mortality and length of hospital stay did not differ significantly between the groups. Preterm birth, which occurred in 8.8 percent of infected mothers and 5.5 percent of uninfected mothers, could explain approximately 89 percent of the association between maternal infection and neonatal respiratory morbidity. Interpretation of these data is limited by the lack of information on severity of maternal illness. Subsequent emerging research has suggested that in utero exposure to maternal COVID-19 may activate an inflammatory cascade in the fetus, particularly the fetal airway, that results in neonatal respiratory distress, even in neonates without SARS-CoV-2 infection (negative PCR of nasopharyngeal specimens), and that maternal vaccination reduces this risk [130,131].

An analysis of data from pregnant patients with confirmed or suspected SARS-CoV-2 infection in 12 countries reported all-cause early neonatal death rates of 0.2 to 0.3 percent, which is no higher than expected based on pre-COVID-19 national data [56]. A systematic review also found that the incidence of neonatal death was similar among individuals who tested positive compared with negative for SARS-CoV-2 when admitted to labor and delivery [57].

Long-term effects in offspring — Long-term outcome data are limited, given the relatively recent onset of the pandemic. It has been hypothesized that maternal immune activation and other inflammatory mechanisms may have adverse fetal effects, including neurodevelopmental effects. A narrative synthesis of 10 studies and a meta-analysis of three found no evidence of higher developmental delay rates in infants exposed to SARS-CoV-2 during pregnancy compared with nonexposed infants at up to 17 months of age, but exposed infants scored lower than nonexposed children or prepandemic cohorts in some domains (fine motor, problem-solving) [132]. The available studies had many limitations, underscoring the need for more long-term follow-up and analysis of the many factors that can affect these outcomes.

Factors potentially affecting pregnancy outcome

Severity of maternal disease — The risk of adverse pregnancy outcome is increased in symptomatic patients [45], especially those with severe/critical disease. Patients with asymptomatic infections appear to have similar outcomes as those without a COVID-19 diagnosis, except for an increased risk for preeclampsia [133].

In a study that specifically reported outcome by disease severity, 32 of the 64 pregnant people hospitalized for severe or critical COVID-19 delivered during the course of infection; 9 of 44 people with severe disease and 13 of the 20 people with critical disease were delivered because of the maternal status while only three deliveries were for fetal status [106]. Birth was preterm in 9 percent of people with severe disease and 75 percent of those with critical disease.

In a similar study, severe-critical COVID-19 was associated with an increased risk of cesarean birth (59.6 versus 34 percent, aRR 1.57, 95% CI 1.30-1.90) and preterm birth (41.8 versus 11.9 percent, aRR 3.53, 95% CI 2.42-5.14) compared with asymptomatic patients [49]. Mild and moderate COVID-19 were not associated with adverse perinatal outcomes compared with asymptomatic patients.

Gestational age at time of infection — In an international retrospective cohort study that compared obstetric and neonatal outcomes of 393 SARS-CoV-2-positive patients according to gestational age at the time of infection, maternal infection after 20 weeks of gestation increased the risk for a composite of adverse obstetric outcomes, and maternal infection after 26 weeks increased the risk for a composite of adverse neonatal outcomes, whereas earlier infection did not increase these risks [134]. These data support vaccination as soon as possible to reduce the risk of acquiring SARS-CoV-2 infection.

PRENATAL CARE

Uninfected pregnant patients — At the beginning of the COVID-19 pandemic in early 2020, the American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and others issued guidance for prenatal care to reduce disease transmission [135-138]. As the surge in the number of infected patients waned, the novel types of care models (eg, telehealth, reduced number of ambulatory visits) have been replaced by traditional models of prenatal care or a combination of traditional and novel models.

Infected pregnant patients

Care of asymptomatic infected patients — Care of asymptomatic patients with confirmed or probable SARS-CoV-2 infection involves self-monitoring for development of COVID-19 symptoms, infection control with self-isolation, and appropriate timing of discontinuation of precautions (table 7). (See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Duration and subsequent precautions'.)

Prenatal care is routine and may utilize telemedicine until discontinuation of precautions. Asymptomatic infected patients do not appear to be at increased risk for pregnancy complications, with the possible exception of preeclampsia, which is evaluated for during routine prenatal care. (See 'Risk of preeclampsia' above.)

Care of symptomatic infected patients — The outpatient evaluation of symptomatic patients with documented or suspected COVID-19 should focus on assessment of risk factors for severe illness (table 4), findings associated with severe illness (table 5), and identification of organ dysfunction or other comorbidities that could complicate potential therapy. Specific issues discussed separately include:

The initial outpatient evaluation, counseling, outpatient management (home care, COVID-19 specific drug therapy), and instructions on how to prevent transmission to others. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Initial evaluation of symptomatic patients' and "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Home care'.)

Indications for hospitalization and inpatient management. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Inpatient evaluation and care'.)

Medical and obstetric care of recovering patients. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Recovering patients'.)

Diagnostic or therapeutic fetal procedures — Diagnostic or therapeutic fetal procedures are generally thought to be safe in patients with COVID-19, based on data from invasive procedures in patients with other viral infections that have a low concentration of virus in maternal blood [139]. Therefore, postponement of procedures such as chorionic villus sampling is not required.

TIMING OF DELIVERY — Timing of delivery of asymptomatic and symptomatic patients should be individualized based on maternal status, concurrent disorders, gestational age, and shared decision-making with the patient or health care proxy. These issues are discussed separately. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Timing of delivery'.)

LABOR, BIRTH, AND POSTPARTUM CARE — (See "COVID-19: Intrapartum and postpartum issues".)

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: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – The prevention, clinical findings, and diagnosis of COVID-19 are the same for pregnant and nonpregnant people (see 'Transmission' above and 'Prevention of infection' above and 'Clinical manifestations and course of infection' above and 'Diagnosis' above), but some specific concerns exist in pregnancy:

Course of infection – Pregnancy does not increase susceptibility to SARS-CoV-2 infection; however, it appears to worsen the clinical course of COVID-19 compared with nonpregnant reproductive-aged females. Pregnant patients are at increased risk for severe illness. (See 'Maternal susceptibility to and acute course of infection' above.)

Vertical transmission – Although the overall rate of congenital infection has been reported to be approximately 2 percent of maternal infections, well-documented cases of probable in utero transmission are rare. (See 'Risk of vertical transmission' above.)

Vaccination – We recommend COVID-19 vaccination regardless of pregnancy or breastfeeding status (Grade 1B). Vaccination reduces the risk of developing COVID-19 and reduces the severity of disease if a breakthrough infection occurs. All available evidence supports the safety of administering currently available SARS-CoV-2 vaccines before, during, or after pregnancy. (See 'Vaccination in people planning pregnancy and pregnant or recently pregnant people' above.)

Pregnancy outcomes – Compared with uninfected pregnancies, pregnancies complicated by COVID-19:

Are not at increased risk for miscarriage or congenital anomalies. (See 'Risk of miscarriage' above and 'Risk of congenital anomalies' above.)

Appear to be at increased risk for preterm birth, cesarean birth, and stillbirth, but the increased risk appears to be limited to patients with severe or critical disease and third-trimester infections. (See 'Risk of preterm birth' above and 'Risk of stillbirth' above and 'Factors potentially affecting pregnancy outcome' above.)

Appear to be at increased risk for developing preeclampsia, even if the infection is asymptomatic. (See 'Risk of preeclampsia' above.)

Newborn outcome – Fewer than 5 percent offspring of infected mothers have developed symptoms of mild infection (ie, not requiring respiratory support) in the early neonatal period, and most such cases have been attributed to postnatal transmission from their mothers or other caregivers with COVID-19. (See 'Newborn outcome' above.)

Prenatal care – As the surge in the number of infected patients has waned, the novel types of care models (eg, telehealth, reduced number of ambulatory visits) used during the pandemic have been replaced by traditional models of prenatal care or a combination of traditional and novel models. (See 'Prenatal care' above.)

Diagnostic and therapeutic fetal procedures, such as chorionic villus biopsy, are generally thought to be safe in patients with COVID-19. (See 'Diagnostic or therapeutic fetal procedures' above.)

Timing of delivery of asymptomatic and symptomatic patients should be individualized based on maternal status, concurrent disorders, gestational age, and shared decision-making with the patient or health care proxy. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Timing of delivery'.)

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Topic 127535 Version 271.0

References

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