In December 2019, a cluster of pneumonia cases in Wuhan, China, led to the identification of the novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 On January 30, 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) epidemic a Public Health Emergency of International Concern.2 SARS-CoV-2 is a betacoronavirus that is genetically similar to the severe acute respiratory syndrome coronavirus and the Middle East respiratory syndrome (MERS) coronavirus, both known to cause severe respiratory illness in humans and associated with high case fatality rates among affected pregnant women.3–5 Although the clinical presentation of COVID-19 appears to be less severe in children than adults, the pediatric spectrum of disease ranges from asymptomatic infection to acute respiratory failure.6,7
Neonates represent a unique at-risk population, with potential for exposure to infection in utero, intrapartum and after delivery. Neonatal susceptibility to infection is amplified by an immature immune system and frequent contact with family caregivers and healthcare workers, especially among preterm or critically ill neonates. Understanding the epidemiology of COVID-19 is essential for infection prevention and management of neonatal patients, as well as for anticipatory guidance for pregnant women and families. This literature review summarizes the emerging data on outcomes among pregnant women with COVID-19 and neonates with perinatal coronavirus disease (COVID) exposure.
MATERIALS AND METHODS
We conducted a literature review to identify studies published from February 1, 2020, until August 15, 2020, on outcomes among pregnant women with laboratory-confirmed SARS-CoV-2 [by polymerase chain reaction (PCR) or IgM] and neonates with perinatal COVID exposure. We searched Medline, Embase and Google Scholar and only included peer-reviewed articles for which full text articles could be retrieved. After the initial search, snowball searches were conducted to identify additional articles of interest. Studies including previously published cases were excluded except in provision of additional detail in maternal and neonatal outcomes, where appropriate. Personal communication (J.J. and S.M.) with corresponding authors was used to confirm exclusion of cases previously reported or clarify reported data when possible. Individual patient data from case series and case reports were used to assess overlap. In larger studies without individual patient data, but with confirmed overlap of enrollment dates or location, studies published earlier were preferentially included.
Data were abstracted independently by 2 reviewers (either E.G.M. and J.J. or J.J. and S.M.); discrepancies were resolved by discussion and consensus of a third reviewer (M.M.G). Descriptive analysis was performed to summarize demographic and clinical characteristics among neonates born to mothers with confirmed COVID-19. Maternal outcomes of interest included clinical presentation, adverse pregnancy outcomes, intensive care unit (ICU) admission, respiratory support and death. Neonatal outcomes of interest included gestational age, sex, mode of delivery, birthweight, APGAR scores at 1 and 5 minutes, neonatal ICU (NICU) admission, clinical course, laboratory parameters and chest imaging, SARS-CoV-2 testing results and disposition. Neonates with positive SARS-CoV-2 PCR testing before hospital discharge and within the first 14 days of life were considered infected in the perinatal period. Statistical analyses were performed using Stata version 15.1 (Stata Corp., College Station, TX).
RESULTS
We identified 233 studies describing outcomes among pregnant women with COVID-19 published from February 1, 2020, until August 15, 2020 (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/E323). After excluding 37 studies for overlap with previously published studies, 196 studies remained. Cumulatively, these studies reported 1922 women with COVID-19 during pregnancy and 1361 neonates with perinatal exposure; 9 studies reported prevalence estimates without detailed pregnancy or neonatal outcomes. The greatest number of publications (n = 55) and reported cases of COVID-19 in pregnancy (n = 709) were from the United States. A significant number of publications (n = 44) and cases (n = 206) were from China.
Epidemiology of COVID-19 in Pregnancy, Maternal Clinical Course and Adverse Pregnancy Outcomes
Population prevalence of COVID-19 among pregnant women is difficult to estimate given geographic and temporal variability in the prevalence of COVID-19 and differing thresholds for testing pregnant women. However, some studies provide local estimates. Data from New York City in late March to early April 2020 report the highest prevalence of COVID-19 in pregnant women undergoing universal screening at the time of delivery, with results ranging from 15.4% to 19.9% of all women admitted.8–10 Outside of the endemic region of New York City, prevalence estimates in the United States were lower over the same month (April), ranging from 0.0% (in Los Angeles) to 3.9% (in Connecticut).8,11–14 Campbell et al11 highlight the temporal variability of COVID, with the prevalence among women admitted for delivery at the same 3 academic centers in Connecticut rising from 0.5% prevalence in the first 2 weeks of April 2020 to 5% in the second 2 weeks of April 2020. In Europe, prevalence estimates (based on universal screening data) differed based on region and time period, ranging from 0.6% in the Lombardy region of Italy in early March to 7.0% in March in London.15–17
Maternal severity of SARS-CoV-2 infection ranged from asymptomatic to critical illness. The concern for asymptomatic or presymptomatic disease among pregnant women admitted to Labor and Delivery was first reported by Breslin et al18 in a case series of 7 women with COVID-19, 2 of whom were asymptomatic and admitted for obstetrically indicated induction of labor, with intra- and postpartum onset of symptomatic COVID-19 ultimately necessitating ICU admission. Multiple studies on universal screening programs have confirmed high rates of asymptomatic or presymptomatic disease, ranging from 61.5% of women with a positive test in Belgium to 85–90% in areas of London and New York City.9,10,15,17
Critical maternal illness has been reported, with 181 (11%) women admitted to the ICU and 123 (8%) requiring mechanical ventilation (Table 1). Twenty-two maternal deaths caused by COVID-19 have been reported. Two women were successfully resuscitated after cardiac arrest, 1 in the setting of COVID-19–associated cardiomyopathy.19,20
TABLE 1. -
Outcomes Among Pregnant Women With Laboratory-confirmed SARS-CoV-2 Infection
| Maternal Characteristic |
Total, n = 1922 |
| Trimester (n = 1539), n (%) |
|
| First trimester |
36 (2) |
| Second trimester |
140 (9) |
| Third trimester |
1363 (89) |
| Hospital course, n (%) |
|
| ICU admission |
181 (11) |
| Mechanical ventilation |
123 (8) |
| Death |
22 (1) |
| Pregnancy outcome (n = 1825), n (%) |
|
| Delivered, live birth |
1359 (74) |
| Delivered, stillbirth |
19 (1) |
| Delivered, neonatal outcome not reported |
74 (4) |
| Induced abortion |
8 (0) |
| Spontaneous abortion |
12 (1) |
| Ectopic pregnancy |
1 (0) |
| Remained pregnant |
352 (19) |
Maternal and pregnancy outcomes among women with laboratory-confirmed SARS-CoV-2 infection. Pregnant women described as mild or asymptomatic were presumed to not have been admitted to an ICU or have required mechanical ventilation, even if not explicitly stated. Cases reported as critical were presumed to require ICU admission, even if not explicitly stated. ICU admission was not presumed for cases described as severe. N reported for individual pregnancy outcomes reflects number of pregnant women with each outcome, not number of fetuses or neonates; multiple gestation is not reflected. Live birth does not preclude later neonatal death; refer to Table (Supplemental Digital Content 2,
https://links.lww.com/INF/E324) and Table (Supplemental Digital Content 3,
https://links.lww.com/INF/E325) for neonatal outcomes. Percentages reported for each trimester reflect proportion of women for whom trimester could be assigned. Percentages reported for maternal ICU admission, mechanical ventilation, and death were calculating using denominator of women for whom outcomes were known (n = 1613, n = 1547, and n = 1718, respectively).
There was significant heterogeneity on reporting of maternal comorbidities. Multiple individual studies provided data on maternal comorbidities during pregnancy and their correlation with maternal SARS-CoV-2 infection and neonatal outcomes. In a retrospective cohort comparing 101 SARS-CoV-2 positive pregnant women with 1317 SARS-CoV-2 negative pregnant women at a U.S. academic center, Sakowicz et al21 found no significant difference in rates of hypertension or gestational diabetes but did note an increased association between obesity and COVID-19 infection. Pierce-Williams et al20 reported that, of 64 pregnant women with severe or critical disease, 17% had pre-existing cardiac comorbidities (including chronic hypertension), and 2 women (3%) developed gestational hypertension or preeclampsia. Vivanti et al22 reported on 100 SARS-CoV-2 positive women in France, of whom 52% required hospitalization. While 9% of women in this study had asthma, 6% had chronic hypertension and 7% had diabetes, the authors found no difference between pre-existing conditions and ICU admission. In a small cohort of women in the United Kingdom, Antoun et al23 found a prevalence of 10.5% (2/19) of severe preeclampsia, 1 of whom developed hemolysis, elevated liver enzymes, low platelet count syndrome and disseminated intravascular coagulation.
Most reported cases of COVID-19 in pregnancy to date have been third trimester infections; among women for whom trimester was reported, 89% had third trimester infections (Table 1). Among 1825 women with known pregnancy outcome, there were 1359 (74%) live births, 19 (1%) stillbirths, 20 (1%) abortions and 1 ectopic pregnancy; 352 (19%) remained pregnant. There were 35 (2%) multiple pregnancies, resulting in 1428 liveborn neonates and 21 stillborn neonates.
Among 1274 women with reported mode of delivery, 725 (57%) were delivered via Caesarean delivery. Maternal COVID-19 was reported as the indication for Caesarean delivery in 176 (12%) women, although not all studies explicitly reported indication for Caesarean delivery. Ninety-one (6%) pregnancies were complicated by decreased fetal movement or abnormal fetal heart rate tracing. Among 1341 women with reported gestational age, 377 (28%) delivered preterm (< 37 weeks gestation). Most studies did not report final delivery outcome among women who were infected in the first or second trimester and remained pregnant at the time of infection, although there have been a few case reports of uncomplicated deliveries at term in convalesced mothers.
Outcomes among neonates born to mothers with COVID-19
Among 1222 neonates with perinatal exposure for whom SARS-CoV-2 PCR results were reported, 61 (4%) tested positive within 14 days or before discharge, whichever came first (Table 2; Table, Supplemental Digital Content 2, https://links.lww.com/INF/E324). Details regarding hospital course and testing results for neonates who had positive SARS-CoV-2 PCR testing are provided (see Table, Supplemental Digital Content 3, https://links.lww.com/INF/E325).
Among neonates with positive SARS-CoV-2 PCR testing, 17 (28%) did not have testing site specifically reported. Of the remaining 44, 42 (95%) had a positive upper respiratory sample [nasopharyngeal (NP) versus oropharyngeal]. SARS-CoV-2 PCR testing was positive from tracheal/bronchial aspirates (n = 4; 17%), anal/rectal swabs (n = 7; 10%), stool (n = 3; 14%) and blood (n = 4; 21%). There were no positive tests from sputum, gastric aspirates, urine or cerebrospinal fluid. One of 34 (3%) cord blood samples was positive. Positive neonatal serologic testing for SARS-CoV-2 was reported by Zeng et al24 and Dong et al.25 These 2 studies cumulatively reported 3 neonates in whom IgM was elevated; all 3 neonates had negative SARS-CoV-2 PCR testing.
SARS-CoV-2 testing of maternal samples was reported by 40 studies, although number and type of samples obtained were highly variable (see Table, Supplemental Digital Content 2, https://links.lww.com/INF/E324). Among these studies, SARS-CoV-2 PCR testing was positive in samples from amniotic fluid (n = 2; 5%), placental tissue or swab (n = 4; 11%), vaginal swab (n = 2; 18%), maternal anal/rectal swab (n = 1; 25%) and stool (n = 1; 25%). Three of 45 breast milk samples (7%) were positive. Bastug et al26 report an asymptomatic infant with negative NP PCR testing at 8 hours of life, who was isolated from his mother and other caregivers, and tested positive for SARS-CoV-2 from multiple sites (NP, stool and blood) on day of life 4 after being fed breast milk with detectable virus.
Sixty-eight percent of neonates with known disposition were separated from mother immediately after delivery and cared for in an isolation room in the nursery or NICU. Regarding infants who were not separated, while some studies report use of parental hand hygiene and masking to reduce transmission risk, others describe close contact (such as breast-feeding without a mask) in the early postpartum phase, before a maternal or neonatal diagnosis of COVID-19.27–30 Suspected postnatal infection from close contact with caregivers was not only reported in full term, breast-feeding infants; Piersigilli et al31 reported likely postnatal transmission from an infected parent in a 26-week preterm neonate admitted to the NICU.
Respiratory distress was the most common symptom among neonates with perinatal COVID-19 exposure (n = 126; 21%) (Table 3). The most common laboratory abnormalities included lymphopenia (n = 12), thrombocytopenia (n = 21) and elevated aminotransferases (n = 92), although there was significant heterogeneity in reporting of neonatal laboratory studies. Among 65 neonates with reported chest imaging [radiogram or computed tomography (CT) scan], 43 (66%) had abnormal findings. Forty-four (5%) of 918 neonates required mechanical ventilation. Four neonates were reported as having disseminated intravascular coagulation; 1 had positive testing. There were seventeen neonates with asphyxia. One neonate with confirmed SARS-CoV-2 infection presented with encephalitic symptoms.32 Fourteen neonatal deaths have been described; 13 of these neonates had negative SARS-CoV-2 PCR testing. One neonate who died shortly after birth had no reported testing.33 Eight of these deaths occurred in the setting of maternal critical illness.33–39
TABLE 2. -
SARS-CoV-2 PCR Test Results Among Neonates With Perinatal COVID-19 Exposure
| Sample Type |
Total, n = 1361, n Positive/Total Samples (%) |
| Neonatal samples |
|
| NP/OP swab |
42/820 (5) |
| Sputum |
0/2 |
| Gastric aspirate |
0/15 |
| Anal/rectal swab |
7/68 (10) |
| Stool |
3/22 (14) |
| Urine |
0/20 |
| Blood |
4/19 (21) |
| CSF |
0/3 |
| Unspecified |
17/400 (4) |
| No reported testing |
139 (10) |
| Neonates with at least 1 positive SARS-CoV-2 sample |
61/1361 (4); 61/1222 with reported testing (5) |
| Maternal/delivery samples |
|
| Cord blood |
1/34 (3) |
| Amniotic fluid |
2/40 (2) |
| Placenta |
4/35 (11) |
| Vaginal |
2/11 (18) |
| Cervical |
0/1 |
| Anal/rectal swab |
1/4 (25) |
| Stool |
1/4 (25) |
| Urine |
0/4 |
| Blood |
2/8 (25) |
| Breast milk |
3/45 (7) |
CSF indicates cerebrospinal fluid; OP, oropharyngeal.
SARS-CoV-2 PCR test results by sample type. Multiple samples of the same sample type/location collected from a neonate at multiple time intervals are only counted once. For detailed test results by study, please see Table (Supplemental Digital Content 2,
https://links.lww.com/INF/E324).
TABLE 3. -
Clinical and Demographic Characteristics of Neonates Born to Mothers With SARS-CoV-2 Infection
| Clinical and Demographic Characteristic |
Neonates With Positive SARS-CoV-2 PCR Testing, n = 61 |
Neonates Without Positive SARS-CoV-2 Testing, n = 1269 |
All Neonates, n = 1330 |
| Maternal critical illness, n/total (%) |
10/31 (32) |
101/802 (13) |
121/973 (12) |
| Gestational age in completed weeks, median (IQR) |
35 (31–38); n = 38 |
38 (36–39); n = 554 |
38 (36–39); n = 592 |
| Preterm, n/total (%) |
22/40 (55) |
281/1056 (27) |
339/1273 (27) |
| Birth weight, g, median (IQR) |
2520 (1808–3184); n = 34 |
3110 (2675–3400); n = 431 |
3110 (2600–3380); n = 465 |
| Male sex, n/total (%) |
21/35 (60) |
226/398 (57) |
250/439 (57) |
| Caesarean delivery, n/total (%) |
31/45 (69) |
671/1164 (58) |
714/1230 (58) |
| APGAR score at 1 min, median (IQR) |
8 (5–9); n = 25 |
8 (8–9); n = 365 |
8 (8–9); n = 435 |
| APGAR score at 5 min, median (IQR) |
9 (8–9); n = 26 |
9 (9–10); n = 408 |
9 (9–10); n = 479 |
| Neonatal asphyxia, n (%) |
2/46 (4) |
15/1023 (1) |
17/1070 (2) |
| Separation from mother after delivery, n/total (%) |
34/40 (85) |
375/559 (67) |
415/611 (68) |
| Breast-fed, n/total (%) |
4/31 (13) |
184/575 (32) |
199/627 (32) |
| NICU admission, n/total (%) |
39/43 (91) |
296/932 (32) |
343/997 (34) |
| Fever, n/total (%) |
9/32 (28) |
8/511 (2) |
18/554 (32) |
| Respiratory distress, n/total (%) |
35/51 (69) |
91/535 (17) |
126/590 (21) |
| Abnormal chest imaging, n (%) |
21/26 (81) |
22/39 (56) |
43/65 (66) |
| Need for PPV, n/total (%) |
11/38 (29) |
34/837 (4) |
45/885 (5) |
| Need for mechanical ventilation, n/total (%) |
14/50 (28) |
30/864 (3) |
44/918 (5) |
| GI symptoms, n/total (%) |
8/29 (28) |
16/481 (3) |
25/527 (5) |
| DIC, n/total (%) |
1/44 (2) |
3/836 (0) |
4/888 (0) |
| Lymphopenia, n/total (%) |
4/17 (24) |
8/190 (4) |
12/207 (6) |
| Thrombocytopenia, n/total (%) |
5/17 (29) |
16/170 (9) |
21/187 (11) |
| Elevated aminotransferases, n/total (%) |
8/16 (50) |
84/160 (53) |
92/176 (52) |
| Neonatal death, n (%) |
1/55 (2) |
13/1131 (1) |
14/1167 (1) |
APGAR indicates Appearance, Pulse, Grimace, Activity, and Respiration score; DIC, disseminated intravascular coagulation; GI, gastrointestinal; IQR, interquartile range; PPV, positive pressure ventilation.
Clinical and demographic characteristics of neonatal with perinatal COVID exposure. Studies not reporting neonatal outcomes were excluded. Neonates without positive SARS-CoV-2 PCR testing include neonates with negative testing and neonates in whom testing was not performed or reported. Not all variables of interest were reported for all neonates; denominators reported for individual variables as appropriate. Breast-feeding was defined as direct breast-feeding; use of expressed breast milk only was not considered breast-feeding. Neonates described as asymptomatic were presumed to not have clinical symptoms (fever, respiratory distress, GI symptoms, asphyxia) or have required PPV or mechanical ventilation. PPV includes noninvasive modalities including continuous positive airway pressure, synchronized intermittent positive airway pressure, and noninvasive PPV. GI symptoms include abdominal distention, feeding intolerance, vomiting, and diarrhea. Lymphopenia was defined as a lymphocyte count < 1500/mm3. Thrombocytopenia was defined as a platelet count < 150,000/mm3. Aminotransferases were considered elevated if either aspartate aminotransferase or alanine aminotransferase was > 40 U/L.
Neonatal length of stay was highly variable, with some case reports describing prolonged admission for isolation and observation despite lack of symptoms or positive testing. Ten studies reported follow-up via telephone or clinic visit, with good short-term neonatal outcomes.27,40–45 Salvatore et al45 prospectively followed 120 neonates born to SARS-CoV-2 positive mothers for up to 1 month of life. In their study, no neonates were positive in the perinatal period, and of the 82 who completed follow-up, 72 were asymptomatic and tested negative at both 5–7 days and 14 days of life. No cases of readmission after hospital discharge were reported, although most studies did not include this as an outcome of interest.
DISCUSSION
This literature review summarizes available data on outcomes among pregnant women with COVID-19 and neonates with perinatal exposure. Pregnancy complications in the setting of maternal COVID-19 include preterm delivery and fetal distress necessitating emergent delivery. The rates of Caesarean section (57%) and preterm delivery (28%) in pregnancies affected by COVID-19 in this study were higher than the general prevalence of Caesarean section and preterm birth as reported by the World Health Organization (21% and 11%, respectively).46,47 Limited data exist on the effects of maternal infection during early pregnancy, as most reported cases to date have occurred during the third trimester.
Data from the effects of severe acute respiratory syndrome (SARS) and MERS in pregnancy stand in stark contrast to available data from the COVID-19 pandemic, with significantly higher reported case fatality rates and pregnancy complications (including spontaneous abortion and preterm birth) reported among women affected by SARS and MERS.48 There are no cases of confirmed vertical transmission of SARS; however, abnormal placental pathology with evidence of inflammation has been described.49,50 Among preterm neonates with perinatal SARS exposure, respiratory distress syndrome and gastrointestinal complications have been reported.51 Only 11 cases of MERS in pregnancy have been reported in the literature; 3 were complicated by maternal death and 3 resulted in neonatal death or stillbirth.52
The majority of neonates (68%) who tested positive for SARS-CoV-2 were separated from mother immediately after delivery and placed in isolation, which raises the concern for vertical transmission. Some studies describe only a single swab obtained immediately after birth, potentially limiting yield of testing. Demirjian et al53 report a full-term infant born via Caesarean section to an intubated, critically ill mother with documented viremia on day of delivery. The infant, who had negative testing for SARS-CoV-2 at birth from the respiratory tract, blood and stool samples, tested positive on day of life 3 despite strict isolation, airborne and droplet precautions. Oncel et al39 reported 4 positive neonates, 3 of whom became positive over 48 hours after birth despite negative swabs at birth and isolation practices in the NICU. Other studies reported neonates with early diagnosis (< 24 hours of life) with persistent positive testing, making false positive or transient colonization at birth less likely.39,54,55 Significant variability was noted in infection prevention practices, timing, number of tests and sample sites of neonatal SARS-CoV-2 PCR tests, which makes differentiation of vertical transmission and postnatal infections difficult. Standardized testing of neonates born to mothers with COVID, as recommended by the American Academy of Pediatrics, may increase test sensitivity and also differentiate between vertical and horizontal transmission of SARS-CoV-2.
Several reports describe concerning clinical features among neonates with negative testing that, in some cases, mirror COVID, including respiratory distress requiring positive pressure, imaging consistent with pneumonia and lymphopenia. It is unclear whether these neonates were infected and had false negative testing or whether maternal COVID-19 may be responsible for an inflammatory response in the neonate that accounts for these symptoms. These clinical features may also be because of other etiologies, such as respiratory distress syndrome associated with prematurity or early onset bacterial sepsis.
Two studies included in this review reported 3 neonates in whom SARS-CoV-2 IgM was elevated, raising concern for possible vertical transmission despite negative SARS-CoV-2 PCR testing.24,25 As noted by an accompanying editorial article, serologic diagnosis of congenital viral infection is limited by high rates of false-positive testing, and the rapid decline of IgM levels in these neonates suggests that true vertical transmission is unlikely.56 Tang et al57 reported positive IgG, but negative IgM and negative PCR testing in an asymptomatic premature infant born to a mother with positive IgM, but negative PCR testing. Given lack of wide implementation, further study is warranted to assess the utility of SARS-CoV-2 serologic testing to assess presence of perinatally acquired neonatal COVID-19.
Although multiple studies reported likely postnatal transmission, the risk of neonatal COVID-19 acquired in the postnatal period is not easy to quantify given variability in infection prevention precautions. Case-control and prospective cohort studies are needed to understand risk of horizontal transmission to neonates not isolated from infected caregivers. Available data are limited in assessing the transmissibility of SARS-CoV-2 via expressed breast milk, with only 3 of 45 reported breast milk samples in this study testing positive for SARS-CoV-2.36,58,59 The case reported by Bastug et al26 raises the suspicion for transmission via breast milk but highlights the difficulty of differentiating between various modes of likely postnatal transmission.
Recommended infection control measures in the home after hospital discharge of mother and baby include physical distancing when possible and use of a mask and hand hygiene during breast-feeding and other newborn care.60 Similarly, infection control measures must be implemented in healthcare facilities to reduce risk of postnatal acquisition from an infected caregiver, especially given high rates of asymptomatic infection.
Limitations of this literature review include availability of primarily case reports and case series, with variable reporting of detailed neonatal outcomes, including laboratory and imaging studies. Furthermore, we could not ascertain whether some of the studies included in this literature review reported overlapping cases of perinatal exposure. Several published studies appear to include cases from the same healthcare facilities and during similar time periods; we excluded studies with identified data overlap.
COVID-19 has presented significant novel challenges and medical risks to pregnant women. Vertical transmission from mother to infant does not seem common but remains possible based on available reporting. The significance of vertical transmission to the newborn is not clear. Most newborns who acquire COVID-19 have a self-limited illness with relatively good clinical outcomes. With the establishment of national and international COVID-19 registries, wide participation should be encouraged to standardize reporting. While the COVID-19 pandemic is rapidly evolving, we should strive to optimize maternal and neonatal outcomes, which can be best achieved by rigorous study and rapid dissemination of these data. For a full list of included studies, please see References (Supplemental Digital Content 4, https://links.lww.com/INF/E326).
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