Easter SR, Gupta S, Brenner SK, Leaf DE. Outcomes of critically ill pregnant women with COVID-19 in the United States. Am J Respir Crit Care Med. 2021;203:122-125.
Stowe J, Smith H, Thurland K, et al. Stillbirths during the COVID-19 pandemic in England, April-June 2020. JAMA. 2021; 325:86-87.
Kadiwar S, Smith JJ, Ledot S, et al. Were pregnant women more affected by COVID-19 in the second wave of the pandemic? Lancet. 2021;397:1539-1540.
Bianchi DW, Kaeser L, Cernich AN. Involving pregnant individuals in clinical research on COVID-19 vaccines. JAMA. 2021;325:1041-1042.
Rasmussen SA, Jamieson DJ. Pregnancy, postpartum care, and COVID-19 vaccination in 2021. JAMA. 2021;325:1099-1100.
Information from viral illnesses such as influenza, severe acute respiratory syndrome, and Middle East respiratory syndrome suggests that viral respiratory infection during pregnancy may adversely affect both maternal and fetal outcome. The initial data in critically ill pregnant women with coronavirus disease 2019 (COVID-19) have been limited to case series or systematic reviews lacking nonpregnant control subjects. A larger series of over 30 pregnant patients with over 60 controls admitted to critical care units across the United States with COVID-19 represents 1 of the early series with data collected between March and May 2020. The median age was 32 years. The frequency and severity of acute respiratory failure were similar between pregnant and nonpregnant patients. The rate of invasive mechanical ventilation, prone positioning, and neuromuscular blockade during the 14 days after intensive care unit (ICU) admission was similar between groups. The incidence of venous thromboembolism and other acute organ injuries together with ICU and hospital length of stay were similar between groups. There were no maternal or fetal deaths, whereas 6 of the 64 nonpregnant women died during hospitalization.
Nineteen women delivered during hospitalization, with 11 of the 19 deliveries occurring on the day of ICU admission. Among the 19 deliveries, 18 were preterm, which was defined as occurring at less than 37 weeks’ gestation. Only 3 of the preterm births were spontaneous, with the remainder performed for medical or obstetric indications. The most common indications for delivery were maternal respiratory failure, spontaneous labor or rupture of membranes, and nonreassuring fetal status. Seventeen of the 19 women who delivered underwent cesarean section, with maternal critical illness reported as the most common indication for this procedure. Among the 17 women with pregnancies at more than 30 weeks’ gestation at the time of admission to the ICU, 15 delivered compared with 4 of 15 women who delivered at less than 30 weeks’ gestation. This initial report was encouraging because maternal and fetal outcomes among critically ill pregnant women with COVID-19 in this study were excellent, with no reported deaths. High rates of cesarean delivery and preterm birth were noted. The majority of preterm delivery occurred in the setting of maternal respiratory failure with a high rate of cesarean section for this indication. Recorded treatments and outcomes including the use of mechanical ventilation, acute organ injury, and ICU and hospital length of stay were similar between pregnant and nonpregnant women.
Similar encouraging early data come from England where stillbirths were recorded during the COVID-19 pandemic during April, May, and June 2020. National and regional hospitalization data in England were used to assess the risk of stillbirths during the COVID epidemic. The National Health Service hospital admissions in England were assessed from April 1, 2019, to June 30, 2020, using standard statistics gathered by the National Health Service. Stillbirth rates were compared for similar intervals before and after the onset of COVID-19. Nationally, the proportion of deliveries with a recorded stillbirth was similar throughout the surveillance. Regionally, the numbers fluctuated but with no evidence of any increase above baseline during the onset of the pandemic. There was no evidence of any increase in stillbirths regionally or nationally during the COVID-19 pandemic compared with comparable months in the previous year.
A relatively limited effect of COVID-19 occurring during pregnancy continued in the United States during the first wave of the pandemic reported from January to June 2020. The death rate from COVID-19 during pregnancy was low (0.19%) and consistent with that of nonpregnant women of childbearing age (0.25%). This pattern changed by September 2020; findings from a systematic review and a meta-analysis of global data revealed that pregnancy was a significant risk factor for hospitalization and more severe illness with critical care admission odds ratio for pregnant women with COVID-19 compared with infected women of childbearing age of 2.13 and invasive ventilation odds ratio of 2.59. Increased risk with COVID-19 during pregnancy has also been reported during second wave data from the United Kingdom.
The observed increase in pregnant women with severe outcomes with COVID-19 could be related to the emergence of a more pathogenic strain of the virus. However, reported analysis suggests no evidence that more recent variants that originated in the United Kingdom at the onset of the second wave were particularly more infective or produced more severe disease in pregnant women than other variants did. This trend could also be explained by an increase in the total number of COVID-19 cases in the second wave, resulting in more pregnant women being infected. There are some data from the United Kingdom supporting this suggestion. However, case reporting may also reflect differences in the availability of testing and overall reporting between the first and second waves. Corresponding data come from Spain where the number of hospitalized pregnant women during the second wave of COVID-19 was 10 times higher than in the first wave, whereas the total number of patients hospitalized with the virus only increased by 30% during the same time frame. Neonatal infection appeared to occur primarily through postnatal exposure, but the true incidence of infections of congenital origin remains unclear, in part due to the lack of consensus for laboratory diagnosis of congenital infection and a specific mechanism for transmission. Thus, pregnant and peripartum women experienced more severe illness during the second wave of COVID-19 than was observed in the first wave. The true cause for this change is unclear.
Continued global expansion of coronavirus disease is becoming a greater concern for pregnant and lactating individuals. As is the case with other populations, many cases of COVID-19 are asymptomatic or relatively mild. However, more recent evidence suggests that pregnant people are at increased risk for hospitalization and have a 3-fold adjusted relative risk of needing critical care and mechanical ventilation compared with age-matched nonpregnant individuals. Pregnant people with laboratory-confirmed severe or critical COVID-19 have higher adjusted relative risks of cesarean delivery, postpartum hemorrhage, hypertensive disorders of pregnancy, and preterm birth. These complications are magnified in women who are older, have higher body mass index, and have medical comorbidities. Other data suggest that racial and ethnic disparities are also related to morbidity and mortality among pregnant people. With the development of COVID-19 vaccines, there is potential for the prevention of this illness; however, strength of evidence for the utility, safety, and effectiveness of the available vaccines in pregnancy remains unclear. Unfortunately, there are long-standing obstacles to the inclusion of pregnant and lactating people in clinical research. Thus, the implications and applications of vaccine therapy for these patients have not been conclusively demonstrated.
Task Force on Research Specific to Pregnant Women and Lactating Women statements have been included in recent legislation passed in the United States. Gaps in knowledge regarding the development of safe and effective therapies for pregnant and lactating people were identified. Initially, pregnant people were excluded from participating in clinical trials of COVID-19 vaccines, but they are now being encouraged to receive the vaccine on a clinical basis. Other government recommendations such as protocol planning for the inclusion of pregnant people could be implemented to reduce the gaps in knowledge for the care of pregnant individuals. The foremost recommendation is the development of a systematic plan to collect data from pregnant and lactating people in response to the current pandemic. These data will include preclinical, safety, pharmacokinetics, and pharmacodynamic data so that pregnant and lactating people need not wait to be included in ongoing clinical trials. In addition, the increased use of existing registries with usable data sources and federal E–funded research networks with specific expertise in the care of pregnant and lactating people could accelerate research and allow for common data elements to be shared and the use of central institutional review boards for multisite studies. Creating partnerships should encourage sharing of data, biospecimens, or both and promote clinical trial recruitment and funding.
Although revisions to federal regulations for the protection of people who participate in research removed pregnant individuals as an example of a vulnerable population, ethical concerns and the potential for liability remain barriers to research on therapeutics during pregnancy and lactation. Additional protection could be provided through rulemaking, and the development of regulations would help overcome these barriers, particularly for preventive or therapeutic interventions that are accelerated to address a public health emergency. Other government initiatives could provide benefits to pregnant and nonpregnant people who are injured by products designed to prevent or treat public health threats such as COVID-19 and may reduce the risk of liability for manufacturers. Pregnant people may provide informed consent to participate in a clinical trial if equivalent safety data from preclinical studies are available. The pregnant person needs the same evidence that all individuals who receive a medication, therapy, or vaccine receive to make an informed decision on whether to accept the treatment. The information that pregnant and lactating people need to make this decision should be tailored to their individual risks based on potential exposure in the home and work environment, medical comorbidities, demographics, evidence on safety, and effectiveness of a vaccine and its potential effects on the fetus. Pregnant and lactating persons should not be protected from participating in research but rather be protected through research.
To be clear, whether pregnancy increases susceptibility to COVID-19 remains unclear. Many hospitals have instituted universal COVID-19 screening for individuals presenting for labor and delivery, providing information on the frequency of asymptomatic infection among pregnant individuals. Seroprevalence studies of pregnant individuals confirm that, as with nonpregnant individuals, asymptomatic infection is common. However, given the lack of data from universal screening of an appropriate comparison group such as nonpregnant women of reproductive age with similar levels of exposure, susceptibility to COVID-19 infection during pregnancy has not been assessed. Data on COVID-19 prevalence among pregnant individuals from universal screening have identified risk factors for infection including race, ethnicity, insurance status, and issues related to living status such as crowding in the neighborhood.
Although data cited earlier were initially unclear as to whether pregnant individuals are at increased risk for severe complications of COVID-19, a large more recent study from the Centers for Disease Control and Prevention (CDC) provides data suggesting an increased risk. Among more than 450,000 symptomatic women of reproductive age with COVID-19 for whom pregnancy status was known, admission to an ICU, invasive ventilation, extracorporeal membrane oxygenation, and death were all more likely among pregnant individuals than among nonpregnant women of reproductive age. Non-Hispanic black individuals accounted for a disproportionate number of deaths. Symptoms in pregnant individuals such as cough, headache, muscle aches, and fever were similar to those in nonpregnant women, although most symptoms were reported less often among pregnant individuals than nonpregnant women. Several studies of pregnancy outcomes suggest that preterm birth occurs more frequently among infants born to individuals with COVID-19, although findings have been inconsistent. A recent systematic review suggests that preterm delivery is approximately 3 times more common in individuals with COVID-19 than among those not infected with rates of 16% versus 6%, respectively. Whether this difference is due to direct effects of infection or maternal illness or is iatrogenic is unclear. Other recent data also suggest that the rate of stillbirths is 2 to 3 times higher among pregnant individuals during as opposed to before the pandemic.
Intrauterine transmission of COVID-19 has been documented but appears to be rare. Reasons for this are unclear but could be related to a lower expression of receptors and the protease needed for COVID-19 cell entry. Transmission through breast milk also appears unlikely. Data regarding mother-to-infant transmission in the postnatal period have been reassuring when appropriate precautions are taken. Common precautions taken include rooming the infant with the mother in a closed isolette and mothers using a surgical mask and careful hand and breast hygiene before breastfeeding and other interaction with the infant.
Outcomes in Children
Woodworth KR, Olsen EO, Neelam V, CDC COVID-19 Response Pregnancy and Infant Linked Outcomes Team; COVID-19 Pregnancy and Infant Linked Outcomes Team (PILOT), et al. Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy - SET-NET, 16 jurisdictions, March 29-October 14, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1635-1640.
Perl SH, Uzan-Yulzari A, Klainer H, et al. SARS-CoV-2-specific antibodies in breast milk after COVID-19 vaccination of breast-feeding women. JAMA. 2021;325:2013-2014.
Kidman R, Margolis R, Smith-Greenaway E, et al. Estimates and projections of COVID-19 and parental death in the US [e-pub ahead of print]. JAMA Pediatr. doi:10. 1001/jamapediatrics.2021.0161, accessed: 07-01-21.
Preston LE, Chevinsky JR, Kompaniyets L, et al. Characteristics and disease severity of US children and adolescents diagnosed with Covid-19. JAMA Netw Open. 2021;4:e215298.
Additional data regarding the outcomes of pregnant individuals with COVID-19 reveal an increased risk for severe illness and a relative increase in the likelihood of preterm birth (approximately 13%) relative to the general population in 2019 (approximately 10%). Because of inconsistent data collection and the difficulty in following COVID-19 in all pregnant individuals, this too must be considered preliminary data. Observations reported by the CDC include outcomes for patients hospitalized as well as those not hospitalized at the time of infection. Investigators again note that non-Hispanic black and Hispanic women were disproportionately represented in the surveillance cohort reported. The higher incidence and increased severity of COVID-19 among women of color may affect these disparities. Unfortunately, information regarding the frequency and severity of perinatal infection is lacking. The American Academy of Pediatrics and CDC recommend testing all infants born to mothers with suspected or confirmed COVID-19. Unfortunately, these testing results have been infrequently reported. Perinatal infection data suggest uncommon infection (2.6%) among infants tested for COVID-19 occurring primarily among infants born to women with infection reported within 1 week of delivery. Among infants with positive test results, one half were preterm, which may reflect more aggressive screening. Although severe COVID-19 may occur in neonates, the majority of term neonates experience asymptomatic infection or mild disease. The long-term outcome among exposed infants is unknown.
Initial data are available on the impact of national vaccination against COVID-19 among breastfeeding women. Data were collected in Israel because pregnant women were encouraged to receive the vaccine without being part of a formal trial. Israeli data investigated whether maternal immunization results in the secretion of antibodies to COVID-19 into breast milk and searched for any potential adverse effects among women and infants. A convenience sample of 84 breastfeeding women who received the COVID-19 vaccine was recruited between late December 2020 and early January 2021. Breast milk samples were collected weekly for 6 weeks after the administration of the vaccine starting at week 2 after the first dose. Immunoglobulin (Ig) G and IgA antibodies relevant to COVID-19 were measured. The mean levels of IgA antibody to COVID-19 increased rapidly in the breast milk and were significantly elevated at 2 weeks after the first vaccine dose when over 60% of the samples collected tested positive, increasing to 86% of positive milk samples at week 4 or 1 week after the second dose of the vaccine. The antibody levels in breast milk remained elevated for the duration of the follow-up, and at week 6, 66% of the samples tested positive. IgG antibodies remained low for the first 3 weeks with an increase at week 4 when approximately 92% of the samples tested positive, increasing to 97% by weeks 5 and 6. No mother or infant experienced any serious adverse event during the study. Women receiving the vaccine reported a vaccine-related adverse event after the first dose (56%) and 62% after the second dose, with local pain being the most common observation. Four infants developed fever at various times after maternal vaccination. Infants had symptoms of upper respiratory tract infection including cough and congestion, which resolved without treatment. Antibodies in the breast milk of these women showed strong neutralizing effects, suggesting potential protection against infection in the infant. Unfortunately, no functional assays were performed.
An important social outcome of COVID-19 is the impact of parental death on the children of these patients. Children who lose a parent are at increased risk of traumatic grief, depression, poor education outcome, unintentional death, or suicide. These consequences may persist into adulthood. Sudden parental death, as may occur with COVID-19, may be particularly traumatizing for children and leave families unprepared to navigate the consequences of this disease. In addition, because COVID-19 losses occur at a time of social isolation, bereaved children may be without the social support needed. A statistical model reported from New York suggests a 17.5% to 20.2% increase in parental bereavement relative to when COVID-19 is absent. By February 2021, 37,300 children 0 to 17 years of age had lost at least 1 parent due to COVID-19. Three quarters of these children were adolescents. Of these children with parental loss, 20,600 were non-Hispanic white children and 7,600 were non-Hispanic black children. The number of children experiencing a parent dying of COVID-19 is large relative to other situations. In comparison, the attacks on September 11, 2001, left 3,000 children without a parent. This burden will increase as the death toll from COVID-19 continues to mount. Black children are disproportionately affected, comprising only 14% of the children in the United States but 20% of those losing a parent to COVID-19. The identification of national resources is needed to address the health, educational, and economic fallout of COVID-19 affecting children.
A recent cohort study examined outcome associations for children and adolescents diagnosed with COVID-19 in the United States. Noting that more than 2 million pediatric COVID-19 cases were reported during 2020, investigators note that approximately one half of the pediatric patients with COVID-19 experienced mild disease, whereas a smaller number of children required admission to ICUs or the use of invasive mechanical ventilation. Demographic data were used to estimate associations between population segments and clinical characteristics including the presentation of severe COVID-19 among pediatric patients hospitalized with the virus. The study procedure was reviewed by the CDC.
Severe COVID-19 was defined as requiring treatment in an ICU or step-down unit, involving invasive mechanical ventilation, or resulting in death. Standard criteria for chronic health conditions were used to examine the impact of this outcome factor. In this most recent study, nearly one third of hospitalized pediatric patients with COVID-19 experienced severe disease. This analysis revealed an increased association of severe COVID-19 in younger children (ages 2-11 years) compared with older children (ages 12-18 years). Chronic conditions as defined by demographic data specifications and male sex were also independently associated with severe COVID-19. Non-Hispanic black and Hispanic or Latino children with COVID-19 were prominently represented in these data, but a significant association between severe COVID-19 disease and race or ethnicity was not identified among the hospitalized children reviewed.
A Special Problem
Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med. 2020;383:334-346.
Belay ED, Abrams J, Oster ME, et al. Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic [e-pub ahead of print]. JAMA Pediatr. doi:10.1001/jamapediatrics.2021.0630, accessed: 07-01-21.
Ouldali N, Toubiana J, Antona D, French Covid-19 Paediatric Inflammation Consortium, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA. 2021; 325:855-864.
Patients with symptoms consistent with multisystem inflammatory syndrome in children (MIS-C) were first identified in April 2020 during the height of the COVID-19 pandemic in the United Kingdom. These early patients had hyperinflammatory shock with features similar to Kawasaki disease and toxic shock syndrome. Public health authorities subsequently identified similar patients in Europe, the United States, and other countries. Most patients with MIS-C presented with fever, signs of general inflammation, hypotension, and shock with multiple organ dysfunction. In the large COVID-19 population in the United States, approximately 10% of the reported COVID-19 cases were in patients younger than 18 years, accounting for less than 2% of COVID-19 hospitalizations. Most children with COVID-19 have mild or no symptoms. However, some children, particularly those with other underlying conditions, may have severe illness. Clinical manifestations of hospitalized patients with COVID-19 may have a presentation that overlaps with that of MIS-C. However, patients with MIS-C chiefly have gastrointestinal or cardiovascular manifestations and less prominent respiratory symptoms and complications such as pneumonia and acute respiratory distress syndrome. Almost all patients with MIS-C had previously tested positive for COVID-19 by serology, indicating that the development of MIS-C was delayed by days to weeks after the initial COVID-19 infection.
The CDC has developed a case definition for MIS-C. Patients younger than 21 years were candidates if hospitalized with fever, involvement of at least 2 organ systems, laboratory evidence of inflammation, and laboratory confirmation of COVID-19 infection; patients were excluded if they had another clear explanation for illness. Patients presenting with respiratory manifestations in the absence of cardiovascular, neurologic, or dermatologic changes; patients having respiratory symptoms with a rash and no other symptoms and positive test results for COVID-19; and patients with a negative test for COVID-19 by serology were excluded as possible patients with MIS-C. The available data suggest a delay of 2 to 5 weeks between COVID-19 and MIS-C peaks.
A variety of epidemiologic data were collected from over 2,000 patients with suspected MIS-C younger than 21 years and reported to the CDC. The onset of illness for these individuals ranged from March 2020 through January 2021. Over 1,800 patients met the MIS-C case definition ultimately determined by the CDC. Of the affected patients with presumed MIS-C, nearly 58% were male, and of the patients with a known ethnicity, over 70% were either Hispanic or non-Hispanic black. The median age of patients was 9 years. The male to female ratio was roughly 1:1 for patients aged 0 to 4 years and progressively increased for subsequent age categories up until 2:1 for patients aged 18 to 20 years.
Overall, 90% of the patients with MIS-C had illness manifestations involving at least 4 organ systems. In addition to fever, the most common signs and symptoms included abdominal pain, vomiting, rash, diarrhea, and conjunctival hyperemia. Respiratory symptoms such as cough, shortness of breath, and chest pain were reported in less than 30% of patients. The median duration of fever was 5 days. Roughly 50% of patients had hypotension, and 37% of patients developed shock. Cardiac dysfunction was reported in 31% of patients, with pericardial effusion in 23%, myocarditis in 17%, and coronary artery dilatation or aneurysms in 17% of MIS-C patients. Patients 0 to 4 years of age had the lowest rate of involvement of more than 6 organ systems or with gastrointestinal symptoms, hypotension, shock, myocarditis, cardiac dysfunction, and admission for intensive care. These young patients were least likely to have lymphopenia and thrombocytopenia and to be treated with steroids, intubation, or mechanical ventilation. A significantly higher proportion of patients 18 to 20 years of age had myocarditis, pneumonia, and acute respiratory distress syndrome and were more likely to report preceding COVID-19 for 7 or more days before the onset of MIS-C.
Among the markers of inflammation in MIS-C, C-reactive protein, brain natriuretic peptide or probrain natriuretic peptide, and interleukin-6 median values were many times higher than the normal reference values. Thrombocytopenia and lymphopenia were reported in 40% and 30% of patients, respectively. Overall, in this large group of patients with MIS-C, 80% received intravenous immunoglobulin (IVIG), and 71% received intravenous steroids. The receipt of these treatments varied by age group. The proportion of patients treated with IVIG was lowest in patients 18 to 20 years of age, whereas the proportion of patients treated with steroids was lowest in patients aged 0 up to 4 years. Overall, 58% of patients were admitted for intensive care, and approximately 1.5% of the patients died. In this cohort, the median number of days from COVID-19 diagnosis before MIS-C onset was 27 days; 95% of the patients developed MIS-C within 60 days of preceding COVID-19.
In summary, patients with MIS-C chiefly presented with gastrointestinal symptoms including abdominal pain, vomiting, and diarrhea along with skin rash and conjunctival hyperemia. Many patients developed hypotension or shock, with about 60% being admitted to the ICU. Myocarditis, cardiac dysfunction, or coronary artery dilatation were reported in approximately 30% of MIS-C patients. The long-term effect of these complications is unclear.
Compared with patients in older age categories, the very young patients had fewer cardiovascular complications and fewer admissions to the ICU. Although MIS-C in this young age group seemed milder, patients still had a more severe course compared with Kawasaki disease with which MIS-C may be confused. The progressive increase in the male to female ratio by age among patients with MIS-C is poorly understood.
Most MIS-C illness is believed to result from asymptomatic or mild COVID-19 with hyperinflammation coinciding with peak antibody production several weeks after the initial COVID-19 infection. Patients with MIS-C had higher titers of COVID-19 receptor binding domain IgG antibodies compared with a comparison population of patients hospitalized with COVID-19. It is interesting to note that patients with a symptomatic preceding clinical picture of COVID-19 had a milder course of MIS-C with a lower incidence of shock and cardiac dysfunction.
The initial data on the impact of COVID-19 on pregnant individuals were benign during the first wave of infections with the virus. Unfortunately, for reasons that remain unclear, outcomes in pregnant patients with COVID-19 in multinational data have worsened with subsequent waves of infections with the virus.
The enrollment of pregnant patients in trials of COVID-19 vaccinations has been slow. Traditionally, pregnant individuals are a special risk group and not included in routine clinical research. COVID-19 requires a different view regarding the impact of vaccine research in the peripartum patient because of the high likelihood that these individuals will encounter the virus. Intrauterine transmission and transmission of COVID-19 through breast milk seem unlikely. Little data have been collected.
In peripartum women who are breastfeeding and have received the COVID-19 vaccine, a significant fraction of breast milk samples tested positive for antibodies to the virus. Functional data are not available.
An important social outcome is children who lose 1 or both parents to COVID-19. Additional resources are needed to address this growing national problem. Affected children may present with symptoms of acute grief, depression, poor education outcome, unintentional death, or suicide.
A small number of children present with MIS-C featuring multiple organ dysfunction and a toxic shock picture. Focused treatment includes IVIG and steroids. Patients with MIS-C are less likely to have pulmonary complaints in comparison with patients with “standard” infection from COVID-19. MIS-C typically presents several weeks after a mild case of COVID-19.
David J. Dries, MSE, MD, is a Senior Fellow with the HealthPartners Institute and a professor of surgery and an adjunct clinical professor of emergency medicine at the University of Minnesota in St Paul, MN, and can be reached at [email protected]
Published online: July 06, 2021
© 2021 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.