|Year : 2015 | Volume
| Issue : 3 | Page : 164-168
Evaluating twins at risk for sepsis: The dilemma of the well-appearing co-twin
Eyad Almidani1, Ann Louise Jefferies1, Emad Khadawardi1, Vibhuti S Shah2
1 Department of Paediatrics, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
2 Department of Paediatrics, Mount Sinai Hospital; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
|Date of Web Publication||2-Jul-2015|
Vibhuti S Shah
Department of Pediatrics and Institute of Health Policy, Management and Evaluation, Mount Sinai Hospital, University of Toronto, Toronto, Ontario
Source of Support: None, Conflict of Interest: None
Background: Early-onset sepsis is a significant cause of mortality and morbidity in neonates. Currently, there are no recommendations on how to manage a well-appearing co-twin if one twin meets the criteria for evaluation for sepsis. Objective: Review our experience on management of well-appearing co-twins when one twin (index case) is evaluated for sepsis. Methods: Retrospective review of twins born at ≥36 weeks gestation. Index cases were categorized into two groups: (1) Presence of clinical signs of sepsis and no risk factors (RFs), and (2) presence of clinical signs with RF. All co-twins were well-appearing. Clinical presentation, diagnosis, and management are presented for all twins. Results: The study included 33 twin pairs. Septic workup was performed in index cases due to the presence of clinical signs with no RF (66.7%) or clinical signs with RF (33.3%) and all received antibiotics. Septic workup was performed in 18.2% of co-twins when clinical signs but no RFs were present in the index cases and 36.4% of co-twins when clinical signs and RF were present. No cases of sepsis were identified in either twin. Conclusion: Variation in the management of a well-appearing co-twin exists when the other twin is evaluated due to clinical signs of sepsis with or without the presence of RF. Our small dataset suggests that it may be reasonable to defer a septic workup of the well-appearing co-twin; particularly in the absence of RF. A larger study is required to confirm this suggestion.
Keywords: Early-onset neonatal sepsis, infant-newborn, infection, twins
|How to cite this article:|
Almidani E, Jefferies AL, Khadawardi E, Shah VS. Evaluating twins at risk for sepsis: The dilemma of the well-appearing co-twin. J Clin Neonatol 2015;4:164-8
|How to cite this URL:|
Almidani E, Jefferies AL, Khadawardi E, Shah VS. Evaluating twins at risk for sepsis: The dilemma of the well-appearing co-twin. J Clin Neonatol [serial online] 2015 [cited 2020 Feb 22];4:164-8. Available from: http://www.jcnonweb.com/text.asp?2015/4/3/164/159867
| Introduction|| |
Early-onset neonatal sepsis (EONS), defined as an infection occurring in the 1 st week of life, is a significant cause of mortality and morbidity in neonates.  It is believed to be caused by vertical transmission of organisms from the mother.  The organisms most commonly implicated in EONS include group B Streptococcus (GBS), Escherichia coli, Haemophilus influenza, Listeria monocytogenes and Staphylococcus aureus. , Other risk factors (RFs) associated with EONS include chorioamnionitis, prolonged rupture of membranes (PROM) >18 h, preterm birth, maternal fever >38° C, maternal GBS bacteriuria, and previous infant with invasive GBS disease. ,,
The centers for disease control (CDC) and the Canadian Paediatric Society (CPS) have published recommendations for management of infants at risk of sepsis based on the presence of clinical signs of sepsis, maternal GBS colonization status (positive, negative or unknown), treatment status of the mother (completed, incomplete or no intrapartum antibiotic prophylaxis [IAP]), and the presence or absence of RFs. , Women with a positive GBS colonization status are >25 times likely to deliver an infant with early-onset sepsis compared to women who are not colonized.  The American Academy of Paediatrics also recommends that a sibling of a multiple birth index case with confirmed early- or late-onset sepsis should be observed carefully and evaluated and treated empirically if the infant is symptomatic.  However, no recommendations are provided on how to manage a well-appearing co-twin if one twin meets the criteria for evaluation for sepsis (i.e., presence of clinical signs of sepsis with or without RFs) but does not have proven sepsis. Given that both infants have had similar exposure to maternal microflora and clinical conditions during delivery, it would be expected that the well-appearing twin is at increased risk of sepsis if the index twin presents with symptoms and signs of EONS. Indeed, limited studies of GBS disease in preterm infants born to mothers with GBS bacteriuria suggest that this is the case. ,,
The presence of clinical signs of sepsis in one twin, therefore, poses a dilemma for clinicians as the signs of sepsis can be very subtle and difficult to differentiate from other conditions and clinical deterioration can occur very rapidly. Some clinicians may choose to investigate and/or treat the co-twin while others may elect to observe the infant if the other twin is evaluated for sepsis. Clinicians must balance the likelihood of not treating infection (increased risk of morbidity and mortality) in the co-twin, versus performing unnecessary tests and treatment with antibiotics with the associated discomfort (procedural pain related to blood collection and antibiotic administration), cost and risk of developing antibiotic resistance; particularly in near-term and term infants who would otherwise be discharged home.
The objective of this study was to review our experience with the management of the well-appearing co-twin in near-term or term infants when the other twin is evaluated for EONS because of the presence of clinical signs with or without RFs. We sought to determine the frequency with which clinicians chose to investigate and treat a well-appearing co-twin.
| Methods|| |
We conducted a retrospective single-center cohort study of twins were born at ≥36 weeks gestational age at Mount Sinai Hospital from January 1, 2004 to June 30, 2009. We targeted this study period as during this period neonatal management of suspected sepsis was based on the CDC guidelines published in 2002.  In July 2009, we adopted the CPS recommendations published in 2007,  which although do not contain information regarding the management of twins differ from the CDC recommendations. We targeted this gestational age group because infants born at ≥36 weeks gestational age represent a population with few problems likely to necessitate a continued stay in hospital. If not necessary, prolonged admission and workup for sepsis represents a significant strain on healthcare resources and the infant's family.
Mount Sinai Hospital is a tertiary level perinatal center with approximately 6500 deliveries annually. For all births in which maternal or infant RFs for EONS are identified or the infant appears to be unwell, a member of the pediatric health care team (staff neonatologist, neonatal fellow, pediatric resident or nurse practitioner) assesses the infant at the time of birth and makes a decision regarding the need for workup for sepsis and antibiotic therapy. In most cases, a partial workup for sepsis is performed that includes a complete blood count (CBC) and blood culture. A full workup includes lumbar puncture and a chest X-ray if respiratory difficulties are present. , The decision to perform a lumbar puncture is made by a member of the team based on maternal history and the infant's clinical status. IAP is considered adequate if the mother receives antibiotics for more than 4 h prior to delivery.
Information on twin births at ≥36 weeks gestational age during the study period was identified from a list generated by our hospital health records database. Two investigators (EA, EK) then reviewed all maternal and neonatal charts and twin pairs were identified for inclusion in this study. The twin pairs were categorized into three groups: (1) Both twins had clinical signs of sepsis at or within 24 h of birth, (2) neither twin had clinical signs of sepsis, and (3) one twin had clinical signs of sepsis at or within 24 h of birth with or without the presence of RFs and had a full or partial septic workup performed while the other twin was well-appearing. Infants from group three were eligible for this study. Index cases in group three were further categorized into two groups: (1) Presence of clinical signs with no RFs and (2) presence of clinical signs with RFs. The index case was defined as the twin undergoing septic workup while the well-appearing twin was labeled as the "co-twin" for the purpose of data analysis and presentation of our results.
Clinical signs of sepsis included temperature instability, tachycardia, poor peripheral perfusion, and respiratory distress. RFs included positive maternal GBS status with inadequate IAP, maternal fever >38°C, chorioamnionitis, PROM >18 h, maternal GBS bacteriuria, and previous infant with GBS sepsis. Chorioamnionitis was considered as proven if the records indicated a maternal temperature >38°C, uterine tenderness and left shift on maternal white blood count, and suspected if maternal temperature was >38°C and broad spectrum antibiotics were administered by the attending obstetrician.
Data on pregnancy course, delivery room management, newborn clinical status, and maternal and neonatal laboratory results were collected from maternal and infant patient records on a predesigned data collection form by two investigators (EA, EK). Information on the eligible infants was cross-checked with a microbiology database to confirm that these infants did indeed undergo work-up for sepsis at birth. In addition to maternal characteristics, information was obtained on the type of twin pregnancy (monochorionic/dichorionic), maternal medical illness prior to and during the pregnancy, including infection during pregnancy, type of organism and antibiotics used in cases of infection, GBS status and use of IAP, history of previous infant with GBS sepsis, maternal fever >38°C, PROM for >18 h, and chorioamnionitis as documented by the obstetrical team, and treatment with broad-spectrum antibiotic therapy.
Neonatal data included gestational age, birth weight, mode of delivery, Apgar scores at 1 and 5 min, presence of symptoms and signs of sepsis (temperature instability, lethargy, respiratory distress, tachycardia, poor peripheral perfusion), investigations including CBC, blood culture, lumbar puncture and chest X-ray and treatment with antibiotics (type and duration). In addition, information regarding blood and/or cerebrospinal fluid (CSF) culture results and need for admission to the Neonatal Intensive Care Unit (NICU) was documented. Gestational age was defined as the best obstetric estimate based on early prenatal ultrasound, obstetric examination, and obstetric history. Sepsis was defined as isolation of organisms from a normally sterile site (blood or CSF).
The primary outcome was the proportion of co-twins who underwent partial/full workup for sepsis at birth. Secondary outcomes included the proportion of co-twins who were treated with antibiotics at birth, the rate of positive blood or CSF culture in the index case or the co-twin, and the number of infants who required admission to the NICU. The Research Ethics Board of our Institution approved the study.
Maternal characteristics are presented as means (standard deviations [SDs]), median (range), and number (percentages) as appropriate. Neonatal data for both the index case and co-twin are presented as means (SD), medians (range), and number (percentages) as appropriate. Neonatal demographic characteristics of the index case and co-twin were compared using χ2 or Fisher's exact test for categorical data and Student's paired t-test or the Wilcoxon signed-rank test for continuous data as appropriate. Statistical analysis was performed using SPSS version 20 (SPSS Inc., IL, USA). A P < 0.05 was considered significant.
| Results|| |
A total of 439 twin pairs were born at ≥36 weeks gestational age during the study period. In 11 pairs both twins were symptomatic, while for 395 twin pairs neither baby was symptomatic. The remaining 33 twin pairs (7.5%) were included in the study; in 22 pairs the index case had clinical signs of sepsis with no RFs, and in 11 pairs the index case had clinical signs plus RFs. Maternal baseline and clinical characteristics are presented in [Table 1]. Baseline neonatal characteristics of the twin pairs are presented in [Table 2]. There were no statistically significant differences between the twins except for Apgar scores at 1 and 5 min, which were lower in the symptomatic twin.
|Table 1: Maternal baseline and clinical characteristics of twin pairs born at ≥36 weeks gestational age|
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|Table 2: Baseline characteristics of twin pairs born at ≥36 weeks gestational age|
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Information on neonatal presentation, management, and diagnoses for the 22 twin pairs with clinical signs of sepsis without RFs is presented in [Table 3]. Four co-twins were evaluated for sepsis and the reasons for evaluation for sepsis were unclear except that two infants were growth restricted. Similarly, information on the neonatal presentation, management, and diagnoses for the 11 twin pairs with clinical signs plus RFs are presented in [Table 4]. Three co-twins born to mothers with suspected chorioamnionitis and one co-twin born to a GBS-positive mother who received inadequate IAP received a workup for sepsis and antibiotics. No cases of sepsis were identified in any of either the index or co-twins. All infants that received antibiotic therapy were administered ampicillin and gentamicin, which were discontinued after 48 h once the culture result was available.
|Table 3: Neonatal clinical presentation, management, and diagnosis of twins based on presence of clinical signs of sepsis with no RFs|
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|Table 4: Neonatal clinical presentation, management, and diagnosis of twins based on presence of clinical signs of sepsis with RFs|
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| Discussion|| |
In this study with a small sample size, we noted the variation in the management of the co-twin if asymptomatic twin with or without the presence of RFs were evaluated for sepsis. The presence of suspected chorioamnionitis was the most consistent RF for which both the symptomatic and asymptomatic twin were evaluated for sepsis; however, the sample was limited to three infants only. Therefore, no definitive recommendation can be made for clinical practice.
The most common presentation of the symptomatic twin was respiratory distress (90.9%) with approximately two-thirds of infants requiring respiratory support in terms of mechanical ventilation, continuous positive airway pressure, and/or low-flow oxygen. Term infants who present with respiratory distress soon after birth may have delayed reabsorption of fluid leading to transient tachypnea of the newborn (TTN), pneumonia, respiratory distress syndrome, persistent pulmonary hypertension or neonatal sepsis. Therefore, it is prudent to perform a septic workup and commence antibiotics for the symptomatic twin. However, in our series TTN, the most common respiratory disorder among newborns was the final diagnosis in more than 50% of the index cases. Almost 60% of these infants were delivered by elective or urgent cesarean section, which is the single most significant RF associated with TTN.  As noted from our results, no cases of EONS were detected. In a prospective cohort study, Salama et al. compared the outcome of 168 infants who presented with classic TTN who were treated with (n = 106) or without (n = 62) intravenous antibiotics at the discretion of the attending physician.  The authors concluded that with the application of strict criteria for classic TTN and close observation in the NICU, the empiric use of antibiotics could be avoided.
In addition to the possibility that symptoms suggestive of sepsis are in fact related to other conditions that can be managed without antibiotic treatment, there is increasing evidence of adverse consequences of exposure to antibiotics in early life. Using high-throughput sequencing and quantitative PCR, Fouhy et al. compared the gut microbiota of nine infants who were treated with intravenous ampicillin and gentamicin within 48 h of birth with that of nine matched healthy controls at 4 and 8 weeks after completion of antibiotics.  Infants who received antibiotics had significantly lower proportions of potentially beneficial organisms including Bifidobacterium and Lactobacillus at 4 weeks with recovery occurring around 8 weeks, while a significantly higher proportion of Proteobacteria persisted at 8 weeks post-antibiotic therapy. Even though the long-term implication of the changes in microbiota is unknown it is prudent to use antibiotics judiciously.
On reviewing the sepsis literature to date, Benitz et al.  and Edwards et al.  suggest that having a sibling or twin with culture-proven GBS sepsis can increase the risk of sepsis in the co-twin. Erez et al.  recently published a case-series on severe infection in twins. They report on 4 cases of twins with sepsis in the index case and subsequent management and course of the second twin. In two cases, the asymptomatic twin was investigated when the index case was identified to have a positive blood, CSF and/or urine culture. In both the cases, the asymptomatic twin was discharged after 48 h when the culture results were negative. However, both the asymptomatic infants became symptomatic 1-5 days later and had positive culture result. This highlights the fact that as soon as the infant becomes symptomatic, a prompt evaluation and antibiotic therapy should be commenced. In the remaining two cases, the second twin presented 2-4 days after admission of the index case. In both the cases viral infection was diagnosed (respiratory syncytial virus and Coxsackie B2 virus) in the index case and subsequently in the second twin. These cases emphasize that clinicians should include the possibility of viral infections in the differential diagnosis. We did not identify any study that specifically addressed the issue of how to manage the asymptomatic co-twin in twin pairs born at near-term or term if one twin is symptomatic at birth. As a result, the approach taken varies and remains non-evidence based. This is an important clinical problem as the incidence of multiple pregnancies is increasing , and clinicians will increasingly encounter this dilemma. Our study from a single perinatal center is the first to address this issue.
The major limitations of our study are its retrospective nature; notably, the inability to capture the clinical team's thought processes regarding the interpretation of the clinical presentations and management decisions, and the small sample size. Despite these limitations, it is reasonable to suggest deferring a septic workup for the asymptomatic co-twin in twins born at ≥36 weeks gestational age, given the low incidence of sepsis in the symptomatic infant with or without the presence of RFs. A larger study is required to confirm this recommendation.
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[Table 1], [Table 2], [Table 3], [Table 4]